ORIGINAL ARTICLE

JOURNAL OF OCULAR PHARMACOLOGY AND THERAPEUTICS Volume 00, Number 00, 2015 ª Mary Ann Liebert, Inc. DOI: 10.1089/jop.2014.0165

Drug-Induced Ocular Adverse Reactions: Review of the Safety Alerts Issued During the Last Decade Ana Penedones,1,2 Diogo Mendes,1,2 Carlos Alves,1,2 and Francisco Batel Marques1,2

Abstract

Purpose: The purpose of this study was to evaluate ocular-related adverse events associated with the use of drugs by analyzing the content of safety alerts issued by major regulatory authorities during the last decade. Methods: The websites of 4 health regulatory authorities were reviewed to identify safety alerts issued on ocular adverse events. Safety alerts were included if they have been issued between January 2005 and December 2014. Only safety alerts on drugs with market authorization were considered for inclusion. Results: Thirty-eight safety alerts were included in the study. Urologicals (n = 11; 29%), followed by drugs used in diabetes, antibacterials for systemic use, antineoplastic agents, and ophthalmologicals were the most frequently suspected drugs evaluated in the safety alerts (n = 4; 10%, each). The most frequently evaluated adverse events were visual disorders NEC (n = 12; 32%), including visual impairment, diplopia, and blurred vision. The majority (n = 25; 66%) of the safety alerts were supported by postmarketing spontaneous reports. The most commonly updated drug label section was the Warnings and Precautions section (n = 33; 87%), followed by the Adverse Reactions section (n = 26; 68%). Conclusions: Ocular adverse events, newly identified during this decade, come mostly from systemic drugs, some of them marketed for several years. Physicians should be aware of drug-induced adverse events in the eye to avoid, as soon as possible, their progression, which can lead to visual impairment.

development of open-angle glaucoma.5 Close-angle glaucoma has been reported in patients receiving adrenergic agonists, namely adrenaline and salbutamol, anticholinergics, including antidepressants, such as fluoxetine, paroxetine, fluvoxamine, or venlafaxine, and sulfa-based drugs, namely topiramate.6–12 It is also interesting to note that there are data suggesting that ocularly administered drugs may be associated with the development of systemic adverse events. For example, the vascular endothelial growth factor (VEGF) inhibitors, which are administered through intravitreal injection, have been associated with an increased incidence of thromboembolic events and mortality.13 In this context, the investigation of the regulatory actions resulting from the identification of serious ocular disorders associated with the use of drugs, irrespective of being locally or systemically administered, is of utmost importance given its implication for the clinical practice. Frequent and well-recognized adverse events are potentially observed in randomized controlled trials. However, rare and long-term latency events are detected with

Introduction

D

rugs used either in the treatment of ocular or systemic pathologic conditions have the potential to cause adverse events in the eye and to affect ocular functions. The blood–ocular barriers, namely the blood–aqueous barrier and the blood–retinal barrier, constitute a feature of the eye that plays an important role in limiting the ability of drugs to adversely affect this organ.1,2 However, such structures may be subject to changes in their permeability that adversely impact the regulation of flow of molecules, such as water, ions, nutrients, or drugs, between the retina, retinal pigment epithelium, and blood vessels.3 Thus, ocular disorders may be induced not only by drugs administered directly into the eye but also by systemically administered drugs, which reach the eye through the vascular supply. There are several examples of ocular adverse drug events. Intraoperative floppy iris syndrome has been reported in patients treated with tamsulosin and who were undergoing cataract surgery.4 Antineoplastic agents, namely docetaxel and paclitaxel, have been reported to be associated with the

1 CHAD–Centre for Health Technology Assessment and Drug Research, AIBILI–Association for Innovation and Biomedical Research on Light and Image, Coimbra, Portugal. 2 School of Pharmacy, University of Coimbra, Coimbra, Portugal.

1

2

difficulty in such studies due to their structural limitations.14 Therefore, most evidence on harm is obtained from postmarketing surveillance, which may comprise spontaneous reporting systems and/or observational studies.15 The additional knowledge on the safety profile of drugs arising from clinical practice is continuously evaluated to assure public health protection. To keep patients and healthcare professionals updated, authorities frequently issue drug safety alerts regarding benefit/risk ratio reevaluations being conducted and subsequent regulatory decisions.16,17 The aim of this study is to evaluate ocular-related adverse events associated with the use of drugs by analyzing the content of safety alerts issued by major regulatory authorities during the last decade (2005–2014).

Methods The websites of 4 health regulatory authorities were reviewed to identify safety alerts issued on ocular adverse events. Data were extracted from the following publicly accessible addresses: the United States Food and Drug Administration (US FDA) ‘‘Drug Safety Communications,’’ ‘‘Potential Signals of Serious Risks/New Safety Information Identified from the FDA Adverse Event Reporting System (FAERS),’’ ‘‘Postmarket Drug and Biologic Safety Evaluations’’ completed, ‘‘MedWatch Safety Alerts for Human Medical Products,’’ and ‘‘Biologics Safety and Availability Communications’’; ‘‘Advisories, warnings and recalls’’ and ‘‘Canadian Adverse Reaction Newsletter’’ of Health Canada, European Medicines Agency (EMA); ‘‘News and press release archive,’’ ‘‘Meeting Highlights,’’ and ‘‘Agendas’’ from the ‘‘Committee for Medicinal Products for Human Use (CHMP)’’ and ‘‘Pharmacovigilance Risk Assessment Committee (PRAC)’’ monthly plenary meetings; and the Australian Therapeutics Goods Administration (TGA) ‘‘All alerts,’’ ‘‘Medicines Safety Update,’’ and ‘‘All monitoring communications.’’16–29 Safety alerts were included if they have been issued between January 2005 and December 2014. Natural and healthcare products, medical devices, contrast agents, drug– drug interactions, drug–food interactions, medication errors, and evaluations of lack of efficacy and adverse events occurring during off-label use were not considered for inclusion. Only safety alerts on drugs with market authorization were considered for inclusion. The bibliographic lists of all relevant safety alerts were hand-searched to identify additional eligible safety alerts. The website search and the safety alerts selection were conducted by one researcher (A.P.). A second researcher scanned the included safety alerts (C.A.). Discrepancies were resolved by majority (2 out of 3) decision involving a third investigator (D.M.). The following information from each safety alert was extracted: (1) date of first publication; (2) regulatory authority issuing the safety alert; (3) adverse event(s) of interest; (4) suspected drug(s); (5) type of data source supporting the evaluation; and (6) drug label section(s) updated. Drug remains under revision was used when the drug(s) were still under evaluation. Benefit/risk ratio unchanged was considered when the regulatory authority(ies) considered no iatrogenic increased risk. The suspected drugs involved in each safety alert were coded according to the second-level therapeutic subgroup of

PENEDONES ET AL.

the Anatomical Therapeutic Chemical (ATC) classification system.30 The adverse events were coded in the primary system organ class (SOC) and in the high-level term (HLT), according to the Medical Dictionary for Regulatory Activities (MedDRA), version 17.0.31 Updates of the same safety alert were revised to retrieve further information on the regulatory authority decision and/ or other data sources evaluated. A safety alert may contain one or more drugs and one or more adverse events. As an example, a safety alert issued by EMA in 2013 assessed ivabradine for phosphenes/vision blurred/diplopia/visual impairment and pegylated interferon alpha-2b for serous retinal detachment. Two safety alerts were considered to be evaluating the same clinical question when they assessed the same adverse event for the same suspected drug(s). Each safety alert could have been supported by more than one type of data source. More than one section of the drug label could have been updated. Regulatory authorities could have decided to keep the suspected drug(s) under revision, despite labeling changes having been carried out.

Results A total of 38 safety alerts evaluating ocular adverse events were identified, of those, 4 (11%) were issued for ophthalmic medicines. Eighteen safety alerts were published by EMA, 14 by US FDA, 5 by Health Canada, and 1 by Australian TGA. Table 1 describes the characteristics of the safety alerts.

Drugs issued in safety alerts The therapeutic subgroups of the suspected drugs reported in the safety alerts are presented in Figure 1. Urologicals (n = 11; 29%), followed by drugs used in diabetes, antibacterials for systemic use, antineoplastic agents, and ophthalmologicals were the most frequently suspected drugs evaluated in the safety alerts (n = 4; 10%, each).

Adverse events evaluated in safety alerts The adverse events evaluated in safety alerts, classified according to HLT MedDRA dictionary coding, are described in Table 2. The most frequently evaluated adverse events were visual disorders not elsewhere classified (NEC) (n = 12; 32%), including visual impairment, diplopia, and blurred vision. Retinal structural change, deposit, and degeneration, such as retinal detachment, were the second most frequently evaluated adverse events (n = 6; 15%). Optic nerve bleeding and vascular disorders, namely optic ischemic neuropathy, and retinal, choroid, and vitreous infections and inflammations, such as macular edema, were evaluated in 5 safety alerts each.

Data sources evaluated in safety alerts Twenty-five (66%) safety alerts issued by regulatory authorities were supported by postmarketing spontaneous reports. The periodic safety update report (PSUR) supported 4 (10%) safety alerts. In 2 safety alerts, the regulatory authority considered 2 different types of evidences to support its revision. The risk of blindness/visual acuity reduced associated with aflibercept (Eylea) was evaluated by EMA through spontaneous reports and PSUR. The risk of anophthalmia

3

EMA

EMA

2013

2013

EMAa

US FDA

Ivabradine (Procoralan, Corlentor)

Pioglitazone (Actos, Glustin)

G03 Sex hormones and modulators of the genital system 2008 US FDA Clomiphene citrate (Clomid)

C09 Agents acting on the renin–angiotensin system EMA Irbesartan/hydrochlorothiazide 2012{ (CoAprovel, Karvezide, Irbesartan HCT Zentiva) Amlodipine/valsartan/ hydrochlorothiazide (Exforge HCT, Copalia HCT, Dafiro HCT, Imprida HCT)

C01 Cardiac therapy 2013 EMAb

2005

2006

A10 Drugs used in diabetes 2005 EMAa, Health Rosiglitazone (Avandia, Avandamet) Canada

Cefuroxime for intracameral use (Aprokam)

Aflibercept (Eylea)

Pegaptanib sodium (Macugen)

EMA

2012

Drug name [international nonproprietary name (commercial designation)]

Dexamethasone (Ozurdex)

Regulatory authority

Visual disorders

Acute angle-closure glaucoma

Acute myopia, secondary acute angle-closure glaucoma

Luminous phenomena (phosphenes), vision blurred, diplopia, visual impairment

Macular edema

Macular edema

Eye inflammation and/or macular edema

Blindness, visual acuity reduced

Implant migration, Hypotony of the eye (associated with vitreous leakage due to injection) Increase of intraocular pressure

Adverse event

Spontaneous reports

Spontaneous reports

PSUR

Spontaneous reports

Spontaneous reports

Spontaneous reports

Spontaneous reports, PSUR Spontaneous reports

Postmarketing observational study

Not specified*

Evidence supporting safety alert

(continued)

Warnings and Precautions section updated

Warnings and Precautions and Adverse Reactions sections updated

Adverse Reactions section updated

Warnings and Precautions and Adverse Reactions sections updated Warnings and Precautions and Adverse Reactions sections updated Warnings and Precautions and Adverse Reactions sections updated

Benefit/risk ratio unchanged

Contraindications, Warnings and Precautions, and Adverse Reactions sections updated Posology and method of administration, Warnings and Precautions, Adverse Reactions, and Special Precautions for disposal sections updated Adverse Reactions section updated

Label sections update/regulatory decision

Safety Alerts Describing Adverse Event and Drug Name, Data Sources Evaluated, and Decisions Taken by the Regulatory Authorities

S01 Ophthalmologicals 2012 EMA

Date

Table 1.

4

Spontaneous reports

Spontaneous reports Spontaneous reports

Spontaneous reports Spontaneous reports Spontaneous reports

EMAc

Health Canadad

US FDA

EMAc

US FDA

Health Canadad

Health Canadad

US FDA

EMAc

EMAc

2006

2005

2005

2006

2005

2005

2005

2005

2006

2006

Vardenafil (Vivanza)

Vardenafil (Levitra)

Tamsulosin HCl (Flomax)

Tadalafil (Cialis)

Spontaneous reports

US FDA

Nonarteritic anterior ischemic optic neuropathy

Nonarteritic anterior ischemic optic neuropathy

Intraoperative floppy iris syndrome

Nonarteritic anterior ischemic optic neuropathy

Spontaneous reports

Spontaneous reports

Not specified*

Spontaneous reports

Spontaneous reports

2005

Nonarteritic anterior ischemic optic neuropathy

Sildenafil (Viagra)

Spontaneous reports

Evidence supporting safety alert

Health Canadad

Nonarteritic anterior ischemic optic neuropathy

Adverse event

2005

Drug name [international nonproprietary name (commercial designation)]

Sildenafil (Revatio)

Regulatory authority

G04 Urologicals 2006 EMAc

Date

Table 1. (Continued)

(continued)

Contraindications, Warnings and Precautions, and Adverse Reactions sections updated Contraindications, Warnings and Precautions, and Adverse Reactions sections updated Warnings and Precautions and Patient Counseling Information updated Contraindications, Warnings and Precautions, and Adverse Reactions sections updated Contraindications, Warnings and Precautions, and Adverse Reactions sections updated Warnings and Precautions and Patient Counseling Information updated Contraindications, Warnings and Precautions, and Adverse Reactions sections updated Warnings and Precautions and Adverse Reactions sections updated Warnings and Precautions and Adverse Reactions sections updated Contraindications, Warnings and Precautions, and Adverse Reactions sections updated Warnings and Precautions and Patient Counseling Information updated Contraindications, Warnings and Precautions, and Adverse Reactions sections updated Contraindications, Warnings and Precautions, and Adverse Reactions sections updated

Label sections update/regulatory decision

5

Regulatory authority

Drug name [international nonproprietary name (commercial designation)]

EMA

Health Canada

2013

2013

Fluoroquinolones: ciprofloxacin, enoxacin, flumequin, lomefloxacin, levofloxacin, moxifloxacin, ofloxacin, pefloxacin, prulifloxacin, rufloxacin, norfloxacin

EMA

EMA

2013

2014

Pegylated interferon alpha-2b (IntronA, Pegintron, ViraferonPeg)

Ponatinib (Iclusig)

Docetaxel (Taxotere, Docetaxel Winthrop)

Capecitabine (Xeloda)

Adalimumab (Humira), golimumab (Simponi) 2012 US FDA Fingolimod (Gilenya) M05 Drugs for treatment of bone diseases 2014 EMA Strontium ranelate (Osseor, Protelos)

L04 Immunosuppressants 2011 US FDA

L03 Immunostimulants 2013 EMAb

EMA

2013

L01 Antineoplastic agents 2006 US FDA Denileukin diftitox (Ontak)

J05 Antivirals for systemic use 2008 US FDA Efavirenz (Sustiva)

US FDA

2012

J01 Antibacterials for systemic use 2007 EMA Telithromycin (Ketek)

Date

Spontaneous reports Not specified* Spontaneous reports

Retinal vein occlusion Eye disorders

Spontaneous reports

PSUR

Spontaneous reports

Spontaneous reports

Not specified*

Spontaneous reports— Antiretroviral pregnancy registry

Postmarketing observational study

Optic neuritis

Serous retinal detachment

Eyelid edema

Loss of visual acuity, with loss of color vision, persistent visual impairment Ophthalmologic complications (corneal disorders, keratitis, punctate keratitis) Cystoid macular edema

Birth defects involving the eye— anophthalmia

Spontaneous reports

Retinal detachment

Spontaneous reports

Spontaneous reports

Evidence supporting safety alert

Temporary visual disturbances (blurred vision, difficulty focusing, and diplopia)

Adverse event

Table 1. (Continued)

(continued)

Benefit/risk ratio unchanged

Warnings and Precautions section updated Remains under revision

Warnings and Precautions and Adverse Reactions sections updated

Warnings and Precautions and Adverse Reactions sections updated Warnings and Precautions and Adverse Reactions sections updated Adverse Reactions section updated

Warnings and Precautions section updated

Use in specific populations section updated

Warnings and Precautions section updated Benefit/risk ratio unchanged

Warnings and Precautions, Effects on ability to drive and use machines, and Adverse Reactions sections updated Benefit/risk ratio unchanged

Label sections update/regulatory decision

6

Regulatory authority

EMA

EMA

Antidepressant products (except monoamine oxidase inhibitors (MAOIs)

Risperidone-containing (Risperdal, Risperdal M-Tab, Risperdal Consta) and paliperidone-containing products (Invega, Invega Sustenna) aripiprazole (Abilify, Abilify Maintena)

Retigabine (Trobalt)

{

Ezogabine{ (Potiga)

Drug name [international nonproprietary name (commercial designation)]

Fluticasone fluorate (Avamys)

Mefloquine hydrochloride (Lariam)

Cataracts

Ocular changes in children

Visual disturbances

Visual impairment

Angle-closure glaucoma

Diplopia

Intraoperative floppy iris syndrome

Pigment changes in the retina with potential vision loss Retinal pigmentation

Adverse event

PSUR

Not specified*

Postmarketing data*

Spontaneous reports

Spontaneous reports

Spontaneous reports

Spontaneous reports

Long-term studies

Clinical trials

Evidence supporting safety alert

Superscript lowercase alphabets (a, b, c, d) indicate the same safety alert issued. *Evidence source was not specified. { The safety alert was issued to the hydrochlorothiazide substance. { Ezogabine is the United States adopted name of retigabine. x The change was referred in the safety alert. Specific references of the occurrence of these adverse events in the pediatric population were not verified. # The change was referred in the safety alert, but not verified in the label of the product at the time of this revision. PSUR, periodic safety update report; TGA, therapeutics goods administration.

R07 Other respiratory system products 2014 EMA Ivacaftor (Kalydeco)

R01 Nasal preparations 2012 EMA

P01 Antiprotozoals 2013 TGA Australian

N07 Other nervous system drugs 2008 US FDA Varenicline (Chantix)

N06 Psychoanaleptics 2014 US FDA

2014

N05 Psycholeptics 2014 Health Canada

2013

N03 Antiepileptics 2013 US FDA

Date

Table 1. (Continued)

Warnings and Precautions section updated#

Warnings and Precautions, Adverse Reactions, and Pharmacodynamic properties sections updatedx

Warnings and Precautions and Adverse Reactions sections updated

Warnings and Precautions, Adverse Reactions, and Medication Guide sections updated

Remains under revision

Benefit/risk ratio unchanged

Warnings and Precautions section updated

Boxed warning, and Warnings and Precautions sections updated Therapeutic indications, Warnings and Precautions, and Adverse Reactions sections updated

Label sections update/regulatory decision

OCULAR ADVERSE DRUG REACTIONS

7

FIG. 1. Suspected drugs Anatomical Therapeutic Chemical (ATC) classification. A, alimentary tract and metabolism; A10, drugs used in diabetes; C, cardiovascular system; C01, cardiac therapy; C09, agents on the renin–angiotensin system; G, genitourinary system and sex hormones; G03, sex hormones and modulators of the genital system; G04, urologicals; J, anti-infectives for systemic use; J01, antibacterials for systemic use; J05, antivirals for systemic use; L, antineoplastic and immunomodulating agents; L01, antineoplastic agents; L03, immunostimulants; L04, immunosuppressants; M, musculoskeletal system; M05, drugs for treatment of bone diseases; N, nervous system; N03, antiepileptics; N05, psycholeptics; N06, psychoanaleptics; N07, other nervous system drugs; P, antiparasitic products, insecticides, and repellents; P01, antiprotozoals; R, respiratory system; R01, nasal preparations; R07, other respiratory system products; S, sensory organs; S01, ophthalmologicals.

Table 2.

Adverse Events Evaluated in Safety Alerts, Classified According to HLT MedDRA Dictionary Coding Total number of safety alerts analyzed = 38

Adverse events HLT coding

n

%

Visual disorders NEC Retinal structural change, deposit, and degeneration Optic nerve bleeding and vascular disorders Retinal, choroid, and vitreous infections and inflammations Floppy iris syndrome Glaucoma (excluding congenital) Ocular disorders NEC Blindness (excluding color blindness) Corneal infections, edemas, and inflammations Partial vision loss Cataract conditions Color blindness (including acquired) Corneal disorders NEC Device issues NEC Lid, lash, and lacrimal infections, irritations, and inflammations Ocular disorders congenital NEC Ocular infections, inflammations, and associated manifestations Ophthalmic function diagnostic procedures Optic nerve disorders NEC Refractive and accommodative disorders Retinal bleeding and vascular disorders (excl retinopathy)

12 6

32 15

5

13

5

13

3 3 3 2 2

8 8 8 4 4

2 1 1 1 1 1

4 2 2 2 2 2

1 1

2 2

1

2

1 1 1

2 2 2

HLT, high-level term; NEC, not elsewhere classified, a standard abbreviation used to denote groupings of miscellaneous terms that do not readily fit into other hierarchical classifications within a particular SOC; SOC, system organ class; MedDRA, Medical Dictionary for Regulatory Activities.

associated with efavirenz (Sustiva) was assessed by US FDA through spontaneous reports and antiretroviral pregnancy registry. The type of the evidence supporting the evaluation of 6 safety alerts (16%) was not specified. Table 3 describes the different data sources evaluated in safety alerts.

Label section change and regulatory decision Table 4 describes the different safety regulatory actions and their frequency. The most commonly updated drug label section was the Warnings and Precautions section (n = 33; 87%), followed by the Adverse Reactions section (n = 26; 68%). Updates of the Contraindications and Patient Counseling Information sections due to new recommendations were made in 7 (8%) and 3 (3%) evaluations, respectively. A boxed warning was issued on 1 occasion (1%). In 6 safety alerts (7%), the authority did not take a regulatory action. Two safety alerts (2%) remain under revision.

Adverse event–drug pairs evaluated by more than one authority Macular edema induced by rosiglitazone was evaluated by 3 regulatory authorities (EMA, Health Canada, and US FDA). The same 3 agencies assessed nonarteritic anterior ischemic optic neuropathy induced by sildenafil, tadalafil, and vardenafil, as well as fluoroquinolones for retinal detachment. US FDA and Health Canada also

Table 3.

Data Sources Supporting Safety Alerts Total number of safety alerts analyzed = 38

Type of data source

n

%

Spontaneous reports PSUR Postmarketing observational study Antiretroviral pregnancy registry Clinical trials Long-term studies Not specified

25 4 2 1 1 1 6

66 10 5 3 3 3 15

8

PENEDONES ET AL.

Table 4. Drug Label Sections Updated and Regulatory Decisions Total number of safety alerts analyzed = 38 Label sections update/regulatory decision

n

%

Warnings and Precautions Adverse Reactions Contraindications Patient Counseling Information Boxed warning Effects on ability to drive and use machines Pharmacodynamic properties Posology and method of administration Special precautions for disposal Therapeutic indications Use in specific populations Benefit/risk ratio unchanged Remains under revision

33 26 7 3 1 1

87 68 18 8 1 1

1 1 1 1 1 6 2

1 1 1 1 1 15 2

evaluated the association of tamsulosin HCl with intraoperative floppy iris syndrome.

Discussion The development of ocular adverse events could be, in a certain way, more expected for ophthalmic pharmacological therapies locally administered than for systemic drugs.32 However, drugs systemically administered to treat or prevent nonophthalmic conditions can also cause ocular adverse events.33 The suspected drugs more frequently associated with ocular adverse events subject to regulatory evaluation were the urologicals, namely sildenafil, vardenafil, and tadalafil. These 5-phosphodiesterase inhibitors have been associated with nonarteritic anterior ischemic optic neuropathy, a rare adverse event, which can lead to loss of visual acuity.34 The most common adverse effects of this drug class are changes in color perception, blurry vision, and increased light sensitivity.32 Regulatory authorities also reviewed the safety profile of drugs included in other classes, such as antidiabetic, antibacterial, or antineoplastic drugs. This diversity of suspected drugs has also been identified in other studies dedicated to review ocular toxicity.35 We identified a relatively low proportion of safety alerts (9%) issued for drugs indicated to treat ophthalmologic conditions. Moreover, these safety alerts were issued in the past 2 years for ophthalmic drugs introduced recently in the market when compared with medicines marketed more than a decade ago, such as pioglitazone, tamsulosine, or fluoroquinolones. Thus, this study suggests that, in the cases of the safety alerts evaluated herein, most of the newly identified ocular adverse events during the postmarketing surveillance are associated with nonophthalmic drugs. Although ocular barriers may impair drugs causing eye toxicity, such structures may suffer permeability changes that adversely affect visual capacity.2 Moreover, the rich blood supply and relatively small mass of the eye make it particularly susceptible to drug-induced adverse events.33

Drug molecules present in the system may become deposited in specific ocular tissues, causing varied symptoms of drug toxicity.33 The most frequently evaluated adverse events by regulatory authorities were the visual disorders NEC, a hierarchical classification, including events such as visual impairment, diplopia, and blurred vision. Other severe conditions, such as retinal detachment, ischemic neuropathy, or macular edema, have also been associated with pharmacological treatment side effects during the last years. This indicated that the drugs affected several ocular structures, causing multiple disorders, which is consistent with previous findings.35 Most of the ocular drug adverse events observed in the clinical practice appear to be nonserious, usually harmful, and resolving with drug suspension.35 The eyelids are the eye structures more frequently affected by drug toxicity, which commonly manifests as an inflammation resulting from hypersensitivity reactions.32 However, the ocular adverse events evaluated in this study are considered serious since they may progress and cause significant visual impairment, therefore leading regulatory authorities to reevaluate the benefit/risk ratio of the suspected drugs. As an example, the use of pegylated interferon alpha-2b in combination with ribavirin has been associated with the Vogt–Koyanagi–Harada disease, which is a multisystem syndrome characterized by ocular (uveitis and retinal detachment), neurological, and integumentary involvement.36 As another example, thiazolidinedione use was associated with an increased risk of macular edema among patients with type 2 diabetes.37 Spontaneous reports of adverse events supported the majority of the safety alerts addressed in this study. Rare and unpredicted events, as most of the ocular adverse reactions described herein, are prone to be spontaneously reported by healthcare professionals and patients to regulatory authorities when they occur within a relatively short period of time after the initiation of a drug therapy.38 Moreover, drug-induced ocular adverse events are the second most frequent reasons for claims against ophthalmologists.33 This could have influenced ophthalmologists to report adverse events to authorities. However, we do not know the extension to which such factors prompt regulatory decisions. Previous studies investigating data sources used to support regulatory decisions highlighted the value of spontaneous reporting systems in providing evidence to risk assessment.15 As an example, the development of acute myopia or acute angle-closure glaucoma in association with the use of hydrochlorothiazide was detected by means of spontaneous reporting in existing few case reports described in literature.39–41 A boxed warning and a change in the Therapeutic indications label section were the major regulatory actions taken. The use of retigabine (ezogabine in the United States) for the treatment of partial seizures in adults with epilepsy was associated with retinal pigmentation in long-term studies.42,43 Of the 36 patients (of the ongoing studies) who had eye examinations, 11 developed retinal pigmentations associated with visual acuity reduced.42 These data were sufficient to address a boxed warning alert for the importance of eye monitoring during the treatment and a change in therapeutic indications to patients for whom other antiepileptic medicines have proved inadequate or have not been tolerated.42,43

OCULAR ADVERSE DRUG REACTIONS

The Warnings and Precautions section was the most frequently updated label section. Although no drugs have been withdrawn, there was a need to apply risk minimization measures during the last 10 years to reduce the incidence of ocular adverse effects. Most of the drugs evaluated in this study have been introduced in the market for several years. Unknown and serious adverse events are more likely to be identified for recently approved drugs. A previous study found that half of drug withdrawals occur within 2 years after a market authorization has been granted and that half of the major label changes (defined as drug withdrawal or black box warning inclusion) occur within 7 years after drug approval.44 Despite some ocular adverse events having been well described in premarketing clinical trials, their inclusion in the Adverse Reactions label section was dependent on the clarification of the relationship between these events and the suspected drug. This is the case of luminous phenomena (phosphenes) with ivabradine treatment, which were clearly identified in clinical trials; however, only after the dose relationship and pharmacological effect had been clarified, its inclusion in the drug label was performed.45–47 None of the 38 safety alerts have been simultaneously raised and evaluated by the 4 regulatory authorities. It should be taken into consideration that the majority of the drugs evaluated in this study are approved in the countries regulated by the selected authorities. Thus, due to this difference on safety regulation, similar populations are exposed to different levels of risk. Moreover, during the last 10 years, it was also found that there is a significant difference in the number of drug-induced ocular disorder evaluations conducted in the selected countries since only 1 safety alert was raised by Australian TGA compared with 15 issued by US FDA during the same period. In a previous study conducted using a similar methodology, it was identified that different regulatory authorities took similar decisions within different time frames.15 Although discrepancies in label changes were rarely identified in this study, Hirst et al. have described some examples of different regulatory actions conducted for the same medicines in different countries.48 Guidelines and cooperative agreements have been developed to harmonize pharmacovigilance activities worldwide, but drug safety regulation might be affected by healthcare systems, regulatory procedures, and even cultural differences.49–52 This study has some limitations. Only information posted by 4 regulatory authorities was considered for inclusion. Publications from other countries or regions and in languages other than English were not analyzed. This could lead to the exclusion of drug safety alerts, which might have been released elsewhere during the same period of time. The information evaluated in the study was collected from press releases and communications posted in the regulatory authorities websites. Therefore, some data could have not been entirely published as well as we did not attempt to confirm the findings with the authorities. Over the last decade, innovative pharmacological treatments have been approved to treat serious ophthalmic conditions, such as biologic molecules for intravitreal injection.53–55 These therapeutic options, although able to delay the progression of vision loss and improve patients’ quality of life, have been associated with relatively frequent and severe iatrogenic profiles.56–59 However, ocular adverse events newly identified during this decade come mostly

9

from systemic drugs, some of them marketed for several years. Physicians should be aware of drug-induced adverse events in the eye to avoid, as soon as possible, their progression, which can lead to visual impairment.

Author Disclosure Statement No competing financial interests exist.

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Received: December 23, 2014 Accepted: March 12, 2015

Address correspondence to: Dr. Ana Penedones CHAD–Centre for Health Technology Assessment and Drug Research AIBILI–Association for Innovation and Biomedical Research on Light and Image Azinhaga de Santa Comba Celas 3000-548 Coimbra Portugal E-mail: [email protected]