Safety Monitoring of Ophthalmic Biologics: A Systematic Review of Pre- and Postmarketing Safety Data

Abstract

Purpose:

The present study evaluates the safety of the biologics approved for the treatment of ocular diseases.

Methods:

The European medicines agency Website was searched to identify biologics with approved ophthalmologic therapeutic indications. A systematic search was performed using MEDLINE, the Cochrane Central Register of Controlled Trials (CENTRAL) and the International Clinical Trials Registry Platform up to December 2013. Pre-marketing, phase III randomized controlled trials (RCT), postmarketing clinical trials, observational longitudinal studies, and case reports involving adverse events (AE) were included. Methodological quality was assessed by Downs & Black checklist. All European spontaneous reports of AE included in the Eudravigilance up to December 2013 were also considered. AE were classified as ocular (related and non-related with the injection procedure) and non-ocular (related or non-related with vascular endothelial growth factor inhibition). Incidences of all reported AEs were estimated.

Results:

Pegaptanib, ranibizumab, and aflibercept were identified as ophthalmic biologics. Fourteen premarketing RCT, 7 postmarketing clinical trials, 31 observational studies, along with 31 case reports and 7,720 spontaneous reports were identified and included in this study. Both in pre- and postmarketing settings, ocular AEs were more frequent than non-ocular AEs. Premarketing safety data inform the most common AEs. Postmarketing studies suggest an increased number of events such as retinal pigmented epithelium tears (0.6%–24%), thromboembolic events (0.8%–5%), and mortality (2.8%–4%).

Conclusions:

This study highlights the need to properly evaluate the risk for rare, serious, and long-term AEs, such as thromboembolic events, since they can lead to imbalances in the benefit-risk ratio of biologics in ophthalmology.

Introduction

The vascular endothelial growth factor (VEGF) has an important physiologic role in promoting angiogenesis, vasodilatation, and increased vascular permeability, among other vital functions.^1,2 However, VEGF has also a pathophysiologic role when it is overexpressed.^1,2 In 1994, researchers noted elevated levels of VEGF in the ocular fluid of patients with neovascular diseases.³ Since then, several studies have shown the pathologic role of VEGF in ocular diseases such as age-related macular degeneration (AMD), diabetic macular edema (DME), branch retinal vein occlusion (BRVO), central retinal vein occlusion (CRVO), and pathologic myopia (PM),^1,2 which are characterized by neovascularization, angiogenesis, increased permeability, and/or formation of edema.¹

The pharmacotherapy used to treat ocular diseases mainly consists of small molecules for topical administration, with one important exception seen with photodynamic therapy with verteporfin and laser photocoagulation.^4–7

Recently, 3 biologics were approved, increasing therapeutic options available to treat ocular diseases.^8–10 These new medicines are specific inhibitors of VEGF, binding with high specificity and sensitivity the isoforms of VEGF, preventing its interaction with its receptors and inhibiting its activity.^11–13 They are also administered directly into the eye through intravitreal injections and their efficacy seem to be promising, reducing the progression of the ocular disease and achieving a therapeutic advantage in improving visual acuity.^11–13

The safety of ophthalmic biologics has been studied in randomized controlled trials (RCTs); however, the predictability of preclinical to clinical data is limited for biologics compared to small molecules.¹⁴ Biologics' specific characteristics including large size, different structural properties, complex manufacturing and purification processes, a high potential for immunogenicity, and the mechanism of action contribute to a unique safety profile.^14,15 Such characteristics may result in more uncertainties about the benefit-risk ratio of biologics at the point of approval.^14,15 Thus, there is a need for increasing knowledge regarding the safety profiles of the marketed ophthalmic biologics based on the available evidence to confirm and/or to identify safety concerns.

This study is aimed at characterizing the safety profile of ophthalmic biologics, in both pre- and postmarketing settings, by carrying out a systematic review based on experimental and observational data.

Methods

This systematic review followed the recommendations of the PRIMA (Preferred Reporting Items for Systematic Reviews and Meta-analyses) statement.¹⁶

The study included all the biologics approved for the treatment of ocular diseases according to their Summary of Product Characteristics (SPC). Biologic was defined as “a medicinal product whose active substance is made or derived from a living organism.”¹⁷ Pegaptanib, although manufactured of entirely synthetic chemical components, was included since it is a modified, pegylated nucleic acid and nucleic acids originate in living organisms.¹¹ European Medicines Agency (EMA) Website was searched to identify those biologics.

The study of the safety of the ophthalmic biologics was divided into 2 periods: before and after their marketing authorization.

A systematic search was conducted up to December 31, 2013 in MEDLINE and Cochrane Central Register of Controlled Trials (CENTRAL) to identify studies describing the safety of these drugs. The literature search was carried out for each ophthalmic biologic and comprised the drug name [including the international nonproprietary name (INN) and brand name] and its approved therapeutic indications. International Clinical Trials Registry Platform (ICTRP) was also searched to identify all studies with available results. The search strategy is listed in Appendices, Table A1.

Two researchers independently screened by hand the titles and abstracts and selected full articles for inclusion. Disagreement was resolved by discussion and consensus with a third investigator.

Studies were included according to the following criteria: (1) premarketing safety data: premarketing authorization phase III RCTs; (2) postmarketing safety data: postmarketing authorization phase III and phase IV clinical trials, case reports published describing spontaneous adverse events (AE), and all observational longitudinal studies assessing safety as primary endpoint and describing incidences. Only studies assessing ophthalmic biologics treatment of wet AMD, DME, BRVO, CRVO, and PM were included. Only citations published in English, French, Spanish, and Portuguese were considered for inclusion.

The quality of the retrieved studies was assessed using the checklist proposed by Downs and Black.¹⁸ Studies' methodological quality was assessed as good, fair, or poor when the total score was ≥20, from 15 to 19, and ≤14, respectively. When more than one reference was found for the same study, the methodological quality evaluation was based on the total set of information.

The European database EudraVigilance was searched for spontaneous reports of AEs since approval date of each biologic to December 31, 2013. The search was carried out by brand name because one of the biologics has 2 commercial designations for the same INN with different therapeutic indications. The information was retrieved from the Web site of EudraVigilance (http://eudravigilance.ema.europa.eu/human/index.asp). A spontaneous report contains one or several AEs to a medicinal product that occur in a single patient. Only serious AEs were available online. A serious AE is a “reaction which results in death; is life-threatening; requires hospitalization or prolongation of existing hospitalization; results in persistent or significant disability/incapacity; is a congenital anomaly/birth defect; or results in some other medically important conditions.”¹⁹

The extracted data from each clinical trial were the following: ocular AEs, ocular AEs related with injection procedure such as “endophthalmitis,” “traumatic cataract” and “retinal detachment,” non-ocular AEs, non-ocular AEs related with systemic inhibition of VEGF, including “hypertension,” “non-ocular hemorrhage,” thromboembolic events, “death” and positive tests for antibodies.

Information extracted from case reports included all AEs. Incidences of AEs were collected from all identified observational studies. Data about patients' age, frequencies of ocular and non-ocular AEs, ocular AEs related with injection procedure, and non-ocular AEs related with systemic inhibition of VEGF were extracted from spontaneous reports.

The AEs were categorized in “Preferred Term (PT)” and “Primary System Organ Class (SOC),” according to the dictionary of medical terms for regulatory activities, MedDRA, version 16.1.

The thromboembolic events corresponded to the Antiplatelet Trialists' Collaboration classification system and included “nonfatal myocardial infarction,” “nonfatal stroke” and “death” from a “vascular” or “unknown cause” (includes all deaths attributed to cardiac, cerebral, hemorrhagic, embolic and other vascular or unknown causes).²⁰ Data were analyzed using descriptive statistics. To estimate the incidence of AEs per patient, in clinical trials and observational studies, the number of reported AEs was divided by the total number of exposed patients. For spontaneous reports, the frequency of the AEs was estimated as the percentage of AEs more frequently reported.

Results

Three biologics were identified for the treatment of ocular diseases: pegaptanib, ranibizumab, and aflibercept. In 2006, pegaptanib was the first biologic receiving a marketing authorization from EMA for the treatment of wet AMD.^8,11 In 2007, ranibizumab was the second biologic being approved by EMA for the treatment of wet AMD.^9,12 Currently, ranibizumab is also authorized for the treatment of visual impairment owing to DME, due to macular edema secondary to BRVO and CRVO and due to choroidal neovascularization secondary to PM.¹² Aflibercept was also approved for the treatment of wet AMD,¹³ in 2012 by EMA¹⁰ and recently, received marketing authorization for CRVO treatment.¹³

The search yielded a total of 2,811 potentially relevant references. After excluding for duplicates, 2,244 abstracts were reviewed and screened for eligibility. Based on above inclusion criteria, 256 references were selected for full-text further evaluation. A final sample of 95 references was eligible for inclusion. Twenty-five references of premarketing RCTs correspond to 14 studies; 8 references of postmarketing clinical trials correspond to 7 studies; along with these 31 observational longitudinal studies and 31 case reports were included. The selection of references is shown in Fig. 1. The references of the included studies and reports are listed in the Appendices under Appendix References.

FIG. 1.

Flow diagram of Literature Search. CR, case reports; CT, clinical trials; ICTRP, International Clinical Trials Registry Platform; OS, Observational Studies; RCT, randomized controlled trial.

Premarketing

Randomized controlled clinical trials

Two clinical trials designated VISION study evaluated pegaptanib for the treatment of wet AMD.^w1–w4 Ranibizumab was evaluated in 3 studies for the treatment of wet AMD (MARINA study; ANCHOR study; and PIER study),^w5–w9 in 4 studies for the treatment of DME (RESTORE study; RISE/RIDE studies and REVEAL study) ^w10–w14 in 2 studies for the treatment of BRVO and CRVO (BRAVO and CRUISE studies)^w15–w18, and in 1 study for the treatment of PM (RADIANCE study).^w19 Two studies named VIEW1 and VIEW2 assessed aflibercept for the treatment of wet AMD^w20,w21 and 2 studies for the treatment of CRVO (GALILEO and COPERNICUS studies).^w22–w25 All studies were assessed as having good methodological quality (Appendix, Table A2).

Ocular AEs

Ocular AEs occurring in more than 5% of the population subjects are summarized in Table 1. The most common ocular AEs were “conjunctival hemorrhage” (9.3%, 26.4%, and 22.3%, for pegaptanib, ranibizumab, and aflibercept, respectively); “eye pain” (29.4%, 12.7%, and 8.8%); “vitreous floaters” (28.2%, 7.3%, and 7.5%); and “increased intraocular pressure (IOP)” (20.5%, 7.9%, and 3.2%).^w1-w25

Table 1.

Ocular and Non-Ocular Adverse Events from Premarketing RCTs

Study drug	Pegaptanib			Ranibizumab			Aflibercept			Total
AEs	AE^a (n)	Patients (n)	%	AE^a (n)	Patients (n)	%	AE^a (n)	Patients (n)	%	AE^a (n)	Patients (n)	%
Ocular AEs
Worsening of macular edema							36	104	34.6%	36	104	34.6%
Conjunctival hemorrhage	15	161	9.3%	565	2,143	26.4%	494	2,212	22.3%	1,074	4,516	23.8%
Punctate keratits	413	1,427	28.9%	33	928	3.6%	5	284	1.8%	451	2,639	17.1%
Vitreous opacities	224	1,427	15.7%							224	1,427	15.7%
Eye pain	419	1,427	29.4%	187	1,467	12.7%	195	2,212	8.8%	801	5,106	15.7%
Vitreous floaters	402	1,427	28.2%	90	1,232	7.3%	98	1,299	7.5%	590	3,958	14.9%
Anterior-chamber inflammation	142	1,053	13.5%							142	1,053	13.5%
Visual disturbance	117	892	13.1%							117	892	13.1%
Retinal exudates				85	500	17.0%	19	388	4.9%	104	888	11.7%
Corneal edema	98	1,053	9.3%							98	1,053	9.3%
Macular edema				89	779	11.4%	20	492	4.1%	109	1,271	8.6%
IOP increased	292	1,427	20.5%	204	2,593	7.9%	123	3,856	3.2%	619	7,876	7.9%
Abnormal sensation in eye	68	892	7.6%							68	892	7.6%
Vitreous detachment				91	1,095	8.3%	81	1,403	5.8%	172	2,498	6.9%
Eye redness	25	374	6.7%							25	374	6.7%
Visual acuity reduced	176	1,053	16.7%	68	1,925	3.5%	215	4,140	5.2%	459	7,118	6.4%
Cataracts	247	1,427	17.3%	310	4,335	7.2%	53	3,818	1.4%	610	9,580	6.4%
Cataract subcapsular				31	500	6.2%				31	500	6.2%
Ocular inflammation				159	2,684	5.9%				159	2,684	5.9%
Maculopathy				56	1,039	5.4%	58	1,195	4.9%	114	2,234	5.1%
Lacrimation increased	39	535	7.3%	39	901	4.3%	12	388	3.1%	90	1,824	4.9%
Retinal hemorrhage				132	2,114	6.2%	157	3,932	4.0%	289	6,046	4.8%
Vision blurred	11	374	2.9%	42	735	5.7%				53	1,109	4.8%
RPE detachment				15	291	5.2%	45	1,017	4.4%	60	1,308	4.6%
Foreign body sensation				62	1,205	5.1%	42	1,299	3.2%	104	2,504	4.2%
Eye pruritus	8	161	5.0%	20	901	2.2%				28	1,062	2.6%
Traumatic cataract	6	1,587	0.4%	20	401	5.0%				26	1,988	1.3%
Non-ocular AEs
Blood and lymphatic system disorders
Anemia	16	374	4.3%	12	595	2.0%	34	1,824	1.9%	62	2,793	2.2%
Cardiac disorders
Atroventricular block first degree				10	291	3.4%	43	913	4.7%	53	1,204	4.4%
Gastrointestinal disorders
Nausea	36	892	4.0%	21	967	2.2%	29	911	3.2%	86	2,770	3.1%
Diarrhea				19	595	3.2%	55	1,824	3.0%	74	2,419	3.1%
Constipation				18	705	2.6%	14	911	1.5%	32	1,616	2.0%
Gastroesophageal reflux disease				6	304	2.0%	16	911	1.8%	22	1,215	1.8%
General disorders and administration site conditions
Pyrexia				9	692	1.3%	28	913	3.1%	37	1,605	2.3%
Infections and infestations
Nasopharyngitis	72	1,266	5.7%	129	1,523	8.5%	169	2,032	8.3%	370	4,821	7.7%
Bronchitis	39	892	4.4%	32	996	3.2%	71	1,824	3.9%	142	3,712	3.8%
Upper respiratory tract infection	15	374	4.0%	19	595	3.2%	62	1,938	3.2%	96	2,907	3.3%
Influenza	12	374	3.2%	32	996	3.2%	56	1,824	3.1%	100	3,194	3.1%
Sinusitis				8	304	2.6%	29	911	3.2%	37	1,215	3.0%
Urinary tract infection	13	374	3.5%	32	1,261	2.5%	60	1,824	3.3%	105	3,459	3.0%
Pneumonia				44	1,664	2.6%	43	2,839	1.5%	87	4,503	1.9%
Immune system disorders
Hypersensitivity				21	401	5.2%				21	401	5.2%
Seasonal allergy				4	304	1.3%	24	911	2.6%	28	1,215	2.3%
Injury, poisoning and procedural complications
Fall				40	2,820	1.4%	91	3,752	2.4%	131	6,572	2.0%
Investigations
Protein urine present				7	304	2.3%	24	911	2.6%	31	1,215	2.6%
Urine protein/creatinine ratio increased				3	304	1.0%	21	911	2.3%	24	1,215	2.0%
Blood glucose increased				10	996	1.0%	45	1,824	2.5%	55	2,820	2.0%
Electrocardiogram T wave inversion				5	291	1.7%	18	913	2.0%	23	1,204	1.9%
Blood urine present				4	304	1.3%	18	911	2.0%	22	1,215	1.8%
Musculoskeletal and connective tissue disorders
Back pain	13	374	3.5%	37	1,273	2.9%	57	1,928	3.0%	107	3,575	3.0%
Arthralgia	36	892	4.0%	20	996	2.0%	48	1,928	2.5%	104	3,816	2.7%
Arthritis				9	304	3.0%	10	911	1.1%	19	1,215	1.6%
Neoplasms benign, malignant, and unspecified (incl cysts and polyps)
Basal cell carcinoma				4	304	1.3%	20	911	2.2%	24	1,215	2.0%
Nervous system disorders
Headache	81	1,266	6.4%	56	1,258	4.5%	41	1,015	4.0%	178	3,539	5.0%
Dizziness	9	374	2.4%	15	996	1.5%	30	1,824	1.6%	54	3,194	1.7%
Psychiatric disorders
Insomnia				6	304	2.0%	9	911	1.0%	15	1,215	1.2%
Respiratory, thoracic, and mediastinal disorders
Cough				18	595	3.0%	31	1,824	1.7%	49	2,419	2.0%
Vascular disorders
Hypertension	90	1,266	7.1%	217	3,544	6.1%	132	2,042	6.5%	439	6,852	6.4%
Key AEs of potential interest
AEs related with injection procedure
Retinal detachment	14	1,848	0.8%	8	4,652	0.2%	3	3,648	0.1%	25	10,148	0.2%
Endophthalmitis	18	1,848	1.0%	20	4,901	0.4%	6	3,876	0.2%	44	10,625	0.4%
Cataract	6	1,848	0.3%	43	3,856	1.1%	12	3,876	0.3%	61	9,580	0.6%
AEs related with systemic inhibition of VEGF
Hypertension	119	1,688	7.0%	233	4,306	5.4%	163	1,824	8.9%	515	7,818	6.6%
Thromboembolic events (APTC)
Non-fatal myocardial infarction				68	5,166	1.3%	25	3,648	0.7%	93	8,814	1.1%
Non-fatal stroke	0	422	0.0%	39	4,735	0.8%	13	3,648	0.4%	52	8,805	0.6%
Death
Vascular cause	3	422	0.7%	45	4,603	1.0%	22	3,648	0.6%	70	8,673	0.8%
Unknown cause				25	3,807	0.7%				25	3,807	0.7%
Non-ocular hemorrhage	9	1,688	0.5%	92	3,056	3.0%	10	1,824	0.5%	111	6,568	1.7%

Ocular AEs reported in ≥5% of subjects; non-ocular AEs reported in ≥2% of subjects.

Total serious and non-serious AEs as reported in clinical trials.

AE, adverse event; APTC, Antiplatelet Trialists' Collaboration; IOP, intraocular pressure; RCT, randomized controlled trial; RPE, retinal pigment epithelial; VEGF, vascular endothelial growth factor.

Source: Appendix References.^w1-w25

The ocular AEs more frequently reported for pegaptanib were “punctuated keratitis” (28.9%) and “vitreous floaters” (28.2%).^w1–w4 Ranibizumab was more frequently associated with “macular edema” (11.4%) and “retinal hemorrhage” (6.2%).^w5–w19 The most frequent ocular AE after intravitreal injections of aflibercept was “worsening of macular edema” (34.6%).^w23

Ocular AEs related with injection procedure

Injection-related serious AEs described in RCTs, such as “retinal detachment,” “traumatic cataract,” and “endophthalmitis,” were rare. The incidence of these events were higher at 1-year of pegaptanib treatment.^w1 The results on the following years were lower than 1%.^w2–w4 The same incidence was observed for all RCTs reviewed for ranibizumab and aflibercept treatment.^w5–w25

Non-ocular AEs

The incidence of non-ocular AEs was similar between ophthalmic biologics.^w1–w25 The non-ocular AEs most reported were “nasopharyngitis” (5.7%, 8.5%, and 8.3% for pegaptanib, ranibizumab, and aflibercept, respectively), “hypertension” (7.1%, 6.1%, and 6.5%), “headache” (6.4%, 4.5%, and 4.0%) and several “infections and infestations,” such as “bronchitis,” “upper respiratory tract infection,” “influenza,” “sinusitis,” and “urinary tract infection” (3.0%–3.8%).^w1–w25 “Hypersensitivity” (5.4%) occurred with increased frequency for intravitreal ranibizumab treatment (Table 1).^w5–w19

Non-ocular AEs related with the systemic inhibition of VEGF

“Hypertension” (6.6%) and “non-ocular hemorrhage” (1.7%) were the non-ocular AEs related with systemic inhibition of VEGF more frequently reported.^w1–w25 The other specific AEs such as thromboembolic events were low (0.6%–1.1%) (Table 1).^w1–w25

Immunogenicity

Subjects in all groups were tested for circulating antibodies.^w1–w25 There were no noted antibodies against pegaptanib or hypersensitivity reactions.^w1–w4 For the treatment of wet AMD, a small rate of subjects tested positive for antibodies against ranibizumab before study treatment.^w5–w9 The rates of immunoreactivity were similar among the treatment groups at the first year of treatment. However, at the second year, the rates of immunoreactivity with ranibizumab treatment increased compared with sham treatment.^w5–w9 There were no detected cases of antibodies against ranibizumab for the treatment of BRVO and CRVO.^w15–w18 One case of antibodies against aflibercept was observed.^w20

Postmarketing

Clinical trials

One phase IV clinical trial named LEVEL study evaluated intravitreal pegaptanib.^w26 Five clinical trials of phase III and one phase IV clinical trial have assessed ranibizumab treatment. Two of them were follow-up and extension trials (SAILOR^w27 and HORIZON,^w28,w29 respectively) of some RCTs previously described. The aim of these clinical trials was to investigate long-term efficacy and safety of ranibizumab.^w27–w29 The other postmarketing clinical trials assessed ranibizumab in different dosing regimens (EXCITE,^w30 SUSTAIN,^w31 HARBOR,^w32 and phase IV SECURE^w33 studies). Four studies were assessed as having good methodological quality, 2 studies were assessed as fair, and 1 study was assessed as poor (Appendices, Table A2).

The most frequent ocular AEs were “macular degeneration” (4.9% for pegaptanib and 16.0% for ranibizumab treatment); “conjunctival hemorrhage” (6.3% and 14.0%); “eye pain” (10.7% and 8.0%); and “vitreous floaters” (10.0% and 6.3%).^w26–w33 “Punctuated keratitis” (12.9%) was more frequently reported for pegaptanib treatment,^w26 whereas “vitreous detachment” (7.9%) and “retinal hemorrhage” (6.5%) were the ocular AEs mostly reported for intravitreal ranibizumab (Table 2).^w27–w33

Table 2.

Ocular and Non-Ocular Adverse Events from Postmarketing CTs

Study drug	Pegaptanib			Ranibizumab			Aflibercept			Total
AEs	AE^a (n)	Patients (n)	%	AE^a (n)	Patients (n)	%	AE^a (n)	Patients (n)	%	AE^a (n)	Patients (n)	%
Ocular AEs
Maculopathy				411	1,095	37.5%				411	1,095	37.5%
Macular degeneration	28	568	4.9%	340	2,119	16.0%				368	2,687	13.7%
Conjunctival hemorrhage	36	568	6.3%	392	2,797	14.0%				428	3,365	12.7%
Punctuated keratitis	73	568	12.9%	4	234	1.7%				77	802	9.6%
Eye pain	61	568	10.7%	176	2,195	8.0%				237	2,763	8.6%
CNV				20	234	8.5%				20	234	8.5%
Vitreous detachment				86	1,095	7.9%				86	1,095	7.9%
Vitreous floaters	57	568	10.0%	91	1,448	6.3%				148	2,016	7.3%
Ocular hyperemia				25	353	7.1%				25	353	7.1%
Retinal hemorrhage	1	568	0.2%	516	7,887	6.5%				517	8,455	6.1%
Visual acuity reduced	31	568	5.5%	168	2,797	6.0%				199	3,365	5.9%
IOP increased				184	3,570	5.2%				184	3,570	5.2%
Eye irritation	34	568	6.0%	43	1,682	2.6%				77	2,250	3.4%
Non-ocular AEs
Cardiac disorders
Cardiac failure congestive	18	568	3.2%							18	568	3.2%
Gastrointestinal disorders
Gastroesophageal reflux	21	568	3.7%							21	568	3.7%
Nausea	15	568	2.6%	9	234	3.8%				24	802	3.0%
Abdominal pain upper				7	234	3.0%				7	234	3.0%
Vomiting				6	234	2.6%				6	234	2.6%
Diarrhea				6	234	2.6%				6	234	2.6%
Dyspepsia				5	234	2.1%				5	234	2.1%
Constipation				5	234	2.1%				5	234	2.1%
Infections and infestations
Upper respiratory tract infection				12	234	5.1%				12	234	5.1%
Sinusitis	25	568	4.4%							25	568	4.4%
Urinary tract infection	26	568	4.6%	23	587	3.9%				49	1,155	4.2%
Pneumonia	20	568	3.5%							20	568	3.5%
Bronchitis	19	568	3.3%	18	587	3.1%				37	1,155	3.2%
Influenza				32	1,100	2.9%				32	1,100	2.9%
Injury, poisoning and procedural complications
Fall				31	1,100	2.8%				31	1,100	2.8%
Musculoskeletal and connective tissue disorders
Arthralgia				18	587	3.1%				18	587	3.1%
Osteoporosis				7	234	3.0%				7	234	3.0%
Back pain				20	747	2.7%				20	747	2.7%
Musculoskeletal pain				5	234	2.1%				5	234	2.1%
Nervous system disorders
Headache	16	568	2.8%	27	866	3.1%				43	1,434	3.0%
Psychiatric disorders
Depression				8	234	3.4%				8	234	3.4%
Anxiety				6	234	2.6%				6	234	2.6%
Insomnia				5	234	2.1%				5	234	2.1%
Respiratory, thoracic, and mediastinal disorders
Nasopharyngitis	16	568	2.8%	168	2,492	6.7%				184	3,060	6.0%
Cough				14	587	2.4%				14	587	2.4%
Asthma				5	234	2.1%				5	234	2.1%
Vascular disorders
Hypertension	43	568	7.6%	467	8,892	5.3%				510	9,460	5.4%
Key AEs of Potential Interest
AEs related with injection procedure
Retinal detachment	0	568	0.0%	4	5,324	0.1%				4	5,892	0.1%
Endophthalmitis	2	568	0.4%	16	7,021	0.2%				18	7,589	0.2%
Cataract	0	568	0.0%	10	5,649	0.2%				10	6,217	0.2%
AEs related with systemic inhibition of VEGF
Hypertension	43	568	7.6%	408	7,653	5.3%				451	8,221	5.5%
Thromboembolic events (APTC)
Non-fatal myocardial infarction	5	568	0.9%	72	7,887	0.9%				77	8,455	0.9%
Non-fatal stroke	3	568	0.5%	70	7,887	0.9%				73	8,455	0.9%
Death	6	568	1.1%	81	7,300	1.1%				87	7,868	1.1%
Vascular cause				78	7,300	1.1%				78	7,300	1.1%
Unknown cause				133	6,863	1.9%				133	6,863	1.9%
Non-ocular hemorrhage	5	568	0.9%	72	7,887	0.9%				77	8,455	0.9%

Ocular AEs reported in ≥5% of subjects; Non-ocular AEs reported in ≥2% of subjects.

Total serious and non-serious AEs as reported in clinical trials.

CNV, choroidal neovascularization; CT, clinical trial.

Source: Appendix References.^w26-w33

The non-ocular AEs most described were “nasopharyngitis” (2.8% for pegaptanib and 6.7% for ranibizumab); “hypertension” (7.6% and 5.3%); and several “infections and infestations” such as “urinary tract infection” and “bronchitis” (3.2%–4.2%) (Table 2).^w26–w33

The incidence of AEs related with injection procedure was low (0.1%–0.2%). “Hypertension” (5.5%) and “non-ocular hemorrhage” (1.9%) were the non-ocular AEs related with systemic inhibition of VEGF most reported.^w26–w33 The rates of thromboembolic events were similar to those reported previously.^w26–w33 However, in SAILOR study, “non-vascular death,” “stroke,” and “non-ocular hemorrhage” rates were numerically higher in the 0.5 mg ranibizumab group.^w27 Death rate (1.1%) was superior compared with previous clinical trials (Table 2).^w26–w33

Case reports

Fourteen cases of AEs associated with pegaptanib were found in the literature. Ranibizumab injections for the treatment of wet AMD resulted in 75 cases. For the treatment of DME and PM, no cases of AEs were reported. Three cases of suspected AEs associated with ranibizumab in BRVO and CRVO were reported. One case report was identified for aflibercept during the treatment of wet AMD. The total of case reports are presented in Table 3.

Table 3.

Case Reports Identified for Ophthalmic Biologics

	Pegaptanib	Ranibizumab				Aflibercept
Case reports–AEs	AMD	AMD	DME	BRVO/ CRVO	PM	AMD	CRVO	References
RPE tears	10	9	0	0	0	1	0	Dhalla et al.^w34; Singh et al.^w35; Chang et al.^w36; Apte et al.^w37; Kiss et al.^w38; Bakri and Kitzmann^w39; Carvounis et al.^w40; Lee et al.^w41; Cornish and Harvey^w42; Saito et al.^w43
Hypersensitivity reactions	2	0	0	0	0	0	0	Steffeinsmeier et al.^w44
Infectious endophthalmitis	1	2	0	0	0	0	0	Chen et al.^w45, Ness et al.^w46; Cornut et al.^w47
Lack of efficacy	1	0	0	0	0	0	0	Williams and Fekrat^w48
Increased IOP	0	34	0	1	0	0	0	Loukianou et al.^w49 Tseng et al.^w50; Martel et al.^w51; von Hanno et al.^w52; Skalicky et al.^w53
Vitritis	0	10	0	0	0	0	0	Ness et al.^w46
Persistent ocular hypertension	0	4	0	0	0	0	0	Bakri et al.^w54
Choroidal detachment	0	1	0	0	0	0	0	Martel et al.^w51
Hipotony	0	2	0	0	0	0	0	Martel et al.^w51; Georgalas et al.^w55
Macular hole	0	2	0	0	0	0	0	Clemens et al.^w56; Grigoropoulos et al.^w57
Anterior uveitis	0	1	0	0	0	0	0	Damasceno et al.^w58
Intraocular central nervous system lymphoma	0	1	0	0	0	0	0	Gambrelle et al.^w59
Bleb leakage	0	1	0	0	0	0	0	Georgalas et al.^w55
Acute generalized exanthematous pustulosis	0	1	0	0	0	0	0	Bosanquet et al.^w60
Submacular hemorrhage	0	1	0	0	0	0	0	Rouvas et al.^w61
Acute decrease in kidney function	0	1	0	0	0	0	0	Pellé et al.^w62
Nonimmune microangiopathic hemolytic anemia	0	1	0	0	0	0	0	Pellé et al.^w62
Thrombocytopenia	0	1	0	0	0	0	0	Pellé et al.^w62
RPE detachment	0	1	0	0	0	0	0	Clemens et al.^w56
Pyogenic granuloma	0	1	0	0	0	0	0	Jung et al.^w63
Subacute cutaneous lupus erythematosus	0	1	0	0	0	0	0	Andric et al.^w64
Retinal artery occlusion	0	0	0	1	0	0	0	von Hanno et al.^w52
Iris rubeosis	0	0	0	1	0	0	0	von Hanno et al.^w52

AMD, age-related macular degeneration; BRVO, branch retinal vein occlusion; CRVO, central retinal vein occlusion; DME, diabetic macular edema; PM, pathologic myopia.

Patients experienced some AEs that have already been identified during ophthalmic biologics' clinical development, such as “increased IOP.”^w49–w53 New suspected adverse drug reactions have been identified such as “retinal pigment epithelium (RPE) tears,”^w34–w43 “hypersensitivity reactions,”^w44 and intraocular inflammation (include “endophthalmitis,” “vitritis,” and “anterior uveitis”).^{w45–w47,w58}

Observational studies

Thirty-one observational studies were identified. Four studies had a prospective study design, whereas 27 were retrospective (of these, 17 were cohort studies, 7 were chart review studies, and 3 were case–control studies). The studies' results, their main characteristics, and their methodological quality assessment, are summarized in Appendices, Table A3.

Pegaptanib and ranibizumab were evaluated in 2 and 8 studies, respectively, and 6 studies evaluated both drugs. Fifteen studies assessed both ranibizumab and intravitreal bevacizumab. Ten studies were controlled with “no treatment” or with photodynamic therapy (Appendices, Table A3).

Some ocular AEs studied in these observational studies have been previously identified, such as “increased IOP,”^w65–w71 “retinal pigment epithelial AEs,”^w72–w75 “endophthalmitis,”^w76,w77 “retinal detachment,”^w83,w86 and “ocular hemorrhagic AEs.”^w80,w84 Non-ocular AEs assessed were, mainly, “thromboembolic AEs.”^w87,w89,w90 Two studies assessed intravitreal injections in anticoagulated patients.^w84,w95 Bilateral injections were also studied (Appendices, Table A3).^w94

Spontaneous reports

A total of 127 individual cases reported for Macugen^® (pegaptanib) were identified in the EudraVigilance database.^w96 The number of individual cases identified after Lucentis^® (ranibizumab) intreavitreal injections were numerically superior (6,793 cases).^w97 Eylea^® (aflibercept) treatment was reported as a suspected drug in 800 individual cases.^w98

AEs were more common in patients older than 65 years (64.6% for pegaptanib treatment, 66.6% for ranibizumab treatment, and 69.5% for aflibercept treatment).^w96–w98

According to the primary SOC classification, the most frequently reported AEs were “eye disorders” (27.2% for pegaptanib, 26.3% for ranibizumab, and 49.0% for aflibercept); “infections and infestations” (6.7% for pegaptanib, 10.4% for ranibizumab, and 16.9% for aflibercept); “nervous system disorders” (16.1% for pegaptanib, 9.4% for ranibizumab, and 7.8% for aflibercept); and “general disorders and administration site conditions” (7.1% for pegaptanib, 16.1% for ranibizumab, and 7.4% for aflibercept).^w96–w98

For pegaptanib and ranibizumab treatment, “reduced visual acuity” was the most reported ocular AE (12.0% and 21.0%, respectively).^w96,w97 Intraocular inflammation (include “non-infectious endophthalmitis,” “vitritis,” “uveitis,” “iritis,” and “ocular inflammation”) was mainly AE reported after aflibercept injections (31.5%).^w98 Similar to RCTs, “eye pain,” “retinal hemorrhage,” and “eye hemorrhage” were also the AE after anti-VEGF treatment mainly reported.^w96–w98

The frequency of potential AEs of interest during clinical practice is described in Table 4.

Table 4.

Adverse Events of Potential Interest from Spontaneous Reports

Spontaneous reports–AEs	Pegaptanib^w96 (n)	Ranibizumab^w97 (n)	Aflibercept^w98 (n)
AEs related with injection procedure
Retinal detachment	1	153	16
Endophthalmitis	10	660	266
Cataract	4	259	2
AEs related with systemic inhibition of VEGF
Hypertension	6	79	4
Thromboembolic events (APTC)
Non-fatal myocardial infarction	1	205	7
Non-fatal stroke	13	424	23
Death
Vascular cause	7	470	12
Unknown cause	1	908	40
Non-ocular hemorrhage	1	106	13

“Endophthalmitis” was the ocular AE related with injection procedure more commonly reported.^w96–w98

“Stroke” was one of the most reported non-ocular AEs after treatment with ophthalmic biologics (8.1% for pegaptanib, 4.5% for ranibizumab, and 4.1% for aflibercept). For ranibizumab and aflibercept treatment, “death” was the most reported non-ocular AEs (9.5% for ranibizumab and 6.6% for aflibercept).^w96–w98

There were no cases of antibodies against pegaptanib or aflibercept, whereas 7 cases of antibodies were detected against ranibizumab treatment.^w96–w98

Discussion

This study was conducted to systematically review the safety profile of ophthalmic biologics considering both pre and postmarketing data.

Pegaptanib was the first medicine approved, shortly followed by intravitreal ranibizumab.^11,12 Despite the lack of experimental studies directly comparing pegaptanib with ranibizumab, ranibizumab treatment has been associated with greater clinical benefit.^w1–w8 Ranibizumab not only stops vision loss, but also improves visual acuity.^w1-w8,21 Several regulatory agencies recommend intravitreal ranibizumab as the preferential treatment.^22,23 In addition, intravitreal ranibizumab has been approved for several therapeutic indications.¹² Aflibercept received its marketing authorization in 2012, 6 years after ranibizumab.^9,10 Because it has been marketed for nearly as many years as pegaptanib, has greater efficacy, and is used in more therapeutic indications, ranibizumab has been used in more patients compared with the other 2 biologics. Thus, there is a rational for ranibizumab being associated with a larger number of spontaneous reports, which does not necessarily mean a worse safety profile.

In both pre- and postmarketing settings, ocular AEs have occurred more frequently than non-ocular AEs. This is expected due to the specific characteristics of the eye, which is a small, contained organ, protected by blood-ocular barriers (blood-aqueous barrier and blood-retina barrier).^24,25 In addition, ophthalmic anti-VEGF are administered by intravitreal injections directly into the eye.^11–13 Thus, the possibility of drug systemic exposure is low.^w1–w25

“Conjunctival hemorrhage,” “eye pain,” and “vitreous floaters” were the most frequently reported ocular AEs in premarketing RCTs.^w1–w25 These results were consistent to those reported in postmarketing studies.^w26–w33 Similarly, both in pre- and postmarketing, “punctuated keratitis” was more reported with pegaptanib treatment^w1–w4,w26 and “retinal hemorrhage” with intravitreal ranibizumab.^{w5–w19,w27–w33} Some AEs identified during the clinical development were subject of assessment during postapproval period. This was the case of “increased IOP” whose incidence was evaluated in observational studies (1.1%–13.1% per eye).^w65–w71 Case reports have also associated this AE with ophthalmic biologics.^w49–w53 Postmarketing studies led to the identification of new ocular AEs such as “RPE tears,” “hypersensitivity reactions,” and intraocular inflammation.^{w34–w47,w58} The frequency and seriousness of “RPE tears” after anti-VEGF injections were studied in some observational studies whose incidence varied between 0.61% and 24% per eye.^w73–w75 Two published case reports described “hypersensitivity reactions” with pegaptanib treatment.^w43 Indeed, the SPC of Macugen^® was reviewed after cases of anaphylaxis/anaphylactoid reactions have been reported after pegaptanib administration.¹¹ Intraocular inflammation associated with aflibercept injections was spontaneously reported very often. ^w98

During clinical trials, the incidence of ocular AEs resulting from the injection procedure was low.^w1–w33 Similar results have also been reported in observational studies with incidences of 0.3%–0.7% per patient.^w82,w85,w93 In the VISION study, it was noted a reduction in the frequency of these events with the improvement of the injection technique from the first to second year of pegaptanib treatment.^w1,w2

“Nasopharyngitis,” “hypertension,” and several “infections and infestations” were the most frequently reported non-ocular AEs in both pre- and postmarketing settings.^w1–w3 The frequency of AEs related with the systemic inhibition of VEGF was evaluated as low in premarketing studies.^w1–w25 However, these results are conflicting with those collected after ophthalmic biologics reach the market.^{w27–w29,w96–w98} Postmarketing studies demonstrated that thromboembolic events such as “stroke” and “death” (for “vascular” or “unknown cause”) occurred more frequently than during the clinical development.^{w27–w29,w96–w98} Four observational studies evaluated the incidence of thromboembolic events (0.8%–5%) and all-cause mortality (2.8%–4%) and confirmed an increased incidence of these type of events.^w87–w90

The risk for some non-ocular AEs may be increased in the patients receiving this treatment due to their intrinsic characteristics. As noted, according to spontaneously reported cases, most of the patients were aged 65 or older.^w96–w98 The prevalence of diseases increases with age and their associated complications.²⁶ Similarly, polypharmacy is usual in the elderly.^27,28 These risk factors taken together with age-related physiologic changes, such as diminished liver and renal function, may increase the odds for adverse drug reactions.^27,28 This may be particularly relevant for thromboembolic, cardiovascular, and cerebrovascular diseases and others affecting the vascular endothelium since they commonly occur in people older than 65 years.^27–29 Additionally, the role of cardiovascular diseases in the development of ophthalmic conditions have been studied, such the association between hypertension and AMD or DME.^30,31

This study has several limitations. The methodological quality level of the evidence is varied. According to the Guideline of Safety by EUnetHTA (European network for Health Technology Assessment),³² different types of studies may be considered to assess safety and to identify both common and rare AEs. The methodological quality of most of the clinical trials was assessed as good. Clinical trials are designed to evaluate the efficacy of an intervention and hardly draw robust safety conclusions owing to their limited duration and their strict inclusion/exclusion criteria that can result in a homogeneous set of patients.^33–35 However, the most frequent AEs can be identified during these studies. Observational studies, case reports, and spontaneous reports are important tools in pharmacovigilance since they are useful to detect rare and/or long-term AEs, in different sets of patients.^14,35 Nonetheless, observational designs are more likely to be subject of bias.³² Differences in the studies' designs such in the demographic characteristics of the included populations, the follow-up time durations, or the effect size measures used, and the limited data reported in clinical trials, can make the safety profile assessment difficult. Such difficulties were encountered in this systematic review. Additionally, the spontaneous reports analyzed included only serious AEs. Moreover, important information is absent from these reports, like the therapeutic indication, patients' past medical history, or case's causality assessment. Further, it was not possible to calculate incidences of AEs because no data of the exposed patients to each biologic were measured.

This systematic review provides useful information for clinicians. A summary of the premarketing data and the complementary information of postmarketing safety monitoring are of major importance in the therapeutic decision process. Safety monitoring must be performed since the disease is diagnosed to identify patients who are susceptible for the occurrence of particular AEs. As an example, patients with RPE detachment are predisposed to have RPE tears after receiving ophthalmic biologic therapy.^36,37 During the treatment and follow-up, clinicians should take into account the benefit-risk relationship of each intravitreal antiangiogenic drug and other safety issues, namely those related with medical procedures. For instance, a correct injection technique must be performed to minimize the risk for serious increase of IOP.³⁸ The results of this study point out needs for further research. The occurrence and frequency of thromboembolic AEs, and other safety issues, namely long-term AE and immunogenicity should be addressed in future studies. In addition, the utilization of the biologics in pediatrics and in polymedicated patients and/or with co-morbilities deserves further research.

Although ophthalmic biologics have been recently introduced, their use is expected to rapidly increase. The documentation of iatrogenic effects associated with those biologics is a valuable contribution for daily clinical practice. This study provides a comparative review of evidence about the safety profile of ophthalmic biologics in both pre- and postmarketing settings.

Footnotes

Author Disclosure Statement

No competing financial interests exist. The authors have no proprietary interest in the materials presented herein.

Appendices

Table A3.

Results, Main Characteristics, and Methodological Quality of the Observational Studies

		Drugs
Study reference	Study design	Interventions	Control	Therapeutic indication	Population (n)	Main objective	Results ^a	MQ
Ocular adverse events
Intraocular pressure
Hoang et al., 2013^w65	Retrospective, cohort	IVR; IVB; IVR+IVB	207 contralateral non-injected eyes	AMD	449 eyes	“…(to) assess the frequency…related to sustained IOP elevation…”	Sustained IOP increased=32/449 eyes	21
Menke et al., 2013^w66	Retrospective	IVR	—	AMD	320 eyes	“…to investigate whether there is a long-term effect on IOP…”	21<IOP<25 mm Hg=7/320 eyes	19
Hoang et al., 2012^w67	Retrospective, cohort	IVR; IVB; IVR+IVB	207 contralateral non-injected eyes	AMD	414 eyes	“…(to) assess the frequency and possible predictive factors related to IOP elevation>5, >10, or>15 mm Hg over baseline IOP…”	>5 mm Hg—injected eyes: 24/207 eyes; non-injected eyes: 11/207 eyes. >10 mm Hg—injected eyes: 10/207 eyes; non-injected eyes: 1/207 eyes. >15 mm Hg—injected eyes: 4/207 eyes; non-injected eyes: 0/207 eyes	21
Wehrli et al., 2012^w68	Retrospective, cohort	IVR; IVB; IVR+IVB	Non-injected eyes	AMD	No glaucoma—injected=270 eyes; control=195 eyes; glaucoma—injected=32 eyes; control=31 eyes	“…to determine the incidence of delayed OHT…”	Eyes with delayed OHT—no glaucoma: injected=3/270 eyes; control=4/195 eyes. Glaucoma: injected=2/32 eyes; control=3/31 eyes	20
Choi et al., 2011^w69	Retrospective, cohort	IVP; IVR; IVB; IVR+IVB; IVR+IVP; IVP+IVB; IVP+IVR+IVB	Non-injected eyes	AMD	Total injected eyes: 155; non-injected eyes: 99	“…to evaluate the prevalence of sustained elevated IOP measurements…”	Non-injected eyes: IOP>25 mm Hg=2/99 eyes; sustained IOP=1/2 eyes. Injected eyes: IOP>25 mm Hg=14/155 eyes; sustained IOP=9/155 eyes	18
Good et al., 2011^w70	Retrospective, cohort	IVR; IVB; IVB+IVR	Pre-existing glaucoma	AMD	Control: 21 eyes; IVR: 96 eyes; IVB: 101 eyes; IVB+IVR: 18 eyes	“…(to) examine whether intravitreal bevacizumab or ranibizumab has an association with elevated IOP…”	Eyes with IOP: control=7/21 eyes; IVR=3/96 eyes; IVB=10/101 eyes; IVB+IVR=0/18 eyes	20
Hariprasad et al., 2005^w71	Retrospective	IVP	—	AMD	122 eyes	“To report the changes and trends in intraocular pressures…”	IOP>30 mm Hg=16/122 eyes	12
Retinal pigment epithelial adverse events
Lois et al., 2013^w72	Retrospective	IVR	—	AMD	72 eyes—atrophy at baseline=34 eyes; no atrophy at baseline=38 eyes	“…to investigate the possible occurrence and development of RPE atrophy…”	Progression of atrophy=45/72 eyes	19
Iotroini et al., 2012^w73	Retrospective, cohort	Period 1: PDT; period 2: triamcinolone+PDT; period 3: anti-VEGF (IVB, IVR)	—	AMD	1: 38 eyes; 2: 44 eyes; 3: 50 eyes (IVR: 27 eyes; IVB: 23 eyes)	“…to assess acute retinal pigment epithelium (RPE) tear incidence”	RPE tear—1: 14/38 eyes; 2: 6/44 eyes; 3: 12/50 eyes (IVR: 5/27 eyes; IVB: 7/23 eyes)	20
Konstantinidis et al., 2010^w74	Retrospective	IVR	Eyes with a PED	AMD	IVR: 74 eyes; control: 55 eyes	“…(to) evaluate the incidence…of RPE tears…”	IVR=4/74 eyes; control=7/55 eyes	18
Smith et al., 2009^w75	Retrospective	IVR	—	AMD	164 eyes	“…to determine the incidence of retinal pigment epithelial (RPE) tears…”	RPE tear=1/164 eyes	17
Endophthalmitis
Abell et al., 2012^w76	Retrospective, cohort	IVR; IVB	—	AMD; macular edema; BRVO; CRVO	12,249 injections—in office: 3,376; in theatre: 8,873	“…to compare endophthalmitis rates after intravitreal injection in two different settings (in office vs. in theatre)…”	In office=4/3,376 injections; in theatre: 0/8,873 injections	22
Moshteghi et al., 2011^w77	Retrospective, cohort	IVP; IVR; IVB	—	AMD; CRVO; BRVO	IVP: 2,015 injections; IVR: 18,607; IVB: 39,700	“…to determine the rate of clinically suspected endophthalmitis…”	Endophthalmitis=12/60,322 injections (IVP: 0/2,015 injections; IVR: 5/18,607 injections; IVB: 7/39,700 injections)	19
Shah et al., 2011^w78	Retrospective, case-control	IVB; IVR	—	Any therapeutic indication	27,736 injections—IVB: 10,958; IVR: 16,778	“This study evaluates a large series of endophthalmitis cases…”	Infectious endophthalmitis=23/27,736 injections (IVB: 12/10,958 injections; IVR: 11/16,778 injections)	20
Other ocular complications
Geck et al., 2013^w79	Prospective	IVB; IVR; triamcinolone; IVB+triamcinolone	—	AMD; RVO; DME; cystoid macular edema after cataract surgery; uveitis	61 eyes—IVB: 25 eyes; IVR: 27 eyes; triamcinolone: 6 eyes; IVB+triamcinolone: 3 eyes	“…to evaluate the incidence of posterior vitreous detachment…”	PVD=15/61 eyes (IVB: 7/25 eyes; IVR: 6/27 eyes; triamcinolone: 2/6 eyes; IVB+triamcinolone: 3/61 eyes)	21
Moon et al., 2013^w80	Retrospective, chart review	IVR	—	AMD	220 eyes	“To analyze the incidence of…newly developed or increased macular hemorrhage…”	Macular hemorrhage: 18/220	17
Eghøj and Sørensen, 2012^w81	Retrospective, cohort	IVR	—	AMD	1,076 eyes	“…to investigate whether tachyphylaxis exists…”	Tachyphylaxis=20/1,076 eyes	18
Day et al., 2011^w82	Retrospective, case-control	IVP; IVR; IVB	No treated patients	AMD	Treated patients: 6,154; no treated patients: 6154	“This study examines the ocular complications of anti-VEGF injections…”	Treated vs. nontreated: endophthalmitis=38/6,154 patients vs. 6/6,154 patients; rhegmatogenous retinal detachment=41/6,154 patients vs. 40/6,154 patients; retinal tear=24/6,154 patients vs. 17/6,154 patients; uveitis=45/6,154 patients vs. 23/6,154 patients; vitreous hemorrhage=95/6,154 patients vs. 46/6,154 patients	21
Meyer et al., 2011^w83	Retrospective, cohort	IVR; IVB; rtPA+SF6-gas	—	BRVO; CRVO; AMD; retinal haemangioma; subretinal hemorrhages; Irvine-Gass syndrome; DME	35,942 injections	“…to present selected cases of RD after intravitreal drug applications”	RD=5/35,942 injections	17
Non-ocular adverse events
Mason et al., 2010^w84	Retrospective, cohort	IVR; IVB	—	Any therapeutic indication	Coumadin: 548 injections; plavix: 523 injections; coumadin+plavix: 33 injections; control (patients not anticoagulated): 2,002 injections; aspirin: 3,106 injections	“…to illuminate any hemorrhagic complications that may arise because of the intravitreal injections in patients on anticoagulant medication…”	Coumadin=0/548 injections; plavix=0/523 injections; coumadin+plavix=0/33 injections; control=0/2,002 injections; aspirin=0/3,106 injections	20
Bocco et al., 2008^w85	Retrospective, cohort	Triamcinolone; IVP; IVR	—	AMD; RVO; DME; membrane epirretinal; syndrome Irvine-Gass	1,236 patients	“To observe the tolerance of repeated intravitreous injections over the short and long term and to analyze their complications”	Endophthalmitis or pseudoenphthalmitis=4/1,236 patients; transitory hypertonicity=95/1,236 patients; cataract=9/1,236 patients; suprachoroidal hemorrhage=1/1,236 patients; macular hole=1/126 patients; intravitreal hemorrhage=2/1,236 patients	16
European epidemiologic cohort study^w86	Prospective	IVP; IVP+IVB; IVP+IVR; IVP+other AMD drugs	—	AMD	IVP: 403 patients; IVP+IVB: 16 patients; IVP+IVR: 75 patients; IVP+other AMD drugs: 7 patients	“Incidence of Pertinent Ocular Adverse Events…”	IVP vs. IVP+IVB vs. IVP+IVR vs. IVP+other AMD drugs (% per injection)—increased IOP: 1.34 vs. 2.19 vs. 0.48 vs. 2.50; vitreous hemorrhage: 0.10 vs. 0.73 vs. 0.0 vs. 0.0; traumatic cataract: 0.13 vs. 0.0 vs. 0.0 vs. 0.0; retinal detachment: 0.03 vs. 0.0 vs. 0.0 vs. 0.0; retinal tear: 0.03 vs. 0.0 vs. 0.0 vs. 0.0; endophthalmitis: 0.0 vs. 0.0 vs. 0.0 vs. 0.0	18
Non-ocular adverse events
Kemp et al., 2013^w87	Retrospective, cohort	IVB; IVR	PDT treatment; people without AMD (community)	AMD	IVB: 792 patients; IVR: 475 patients; PDT: 399 patients; community: 1,763 patients	“…to determine…increased risk of thromboembolic events…”	MI, stroke or GI bleeding—IVB: 19/792 patients; IVR: 15/475 patients; PDT: 6/399 patients; community: 28/1,763 patients	28
French and Margo, 2011^w88	Retrospective, case-control	IVB; IVR; IVB+IVR	No treated patients with dry AMD	Exudative AMD	Total treated exudative AMD: 3,210 patients; control: 117,364 patients	“…examined the 12-month all-cause mortality…”	Control: 5,309/117,364 patients died; exudative AMD: 127/3,210 patients died	28
Carneiro et al., 2011^w89	Retrospective, cohort	IVR; IVB	—	AMD	316 patients—IVB: 97 patients; IVR: 219 patients	“The present study compares the occurrence of ATEs…”	ATEs=15/316 patients (IVB: 12/97 patients; IVR: 3/219 patients)	21
Curtis et al., 2010^w90	Retrospective, cohort	IVP; IVR; IVB	PDT	AMD	IVP: 36,942 patients; IVR: 19,026 patients; IVB: 38,718 patients; control: 52,256 patients	“…to examine associations between therapies for neovascular age-related macular degeneration and risks of all-cause mortality, incident myocardial infarction, bleeding, and incident stroke”	PDT vs. IVP vs. IVB vs. IVR: all-cause mortality=1,648 vs. 1,052 vs. 1,324 vs. 647; incident myocardial infarction=567 vs. 312 vs. 378 vs. 170; bleeding=2,432 vs. 1455 vs. 1,719 vs. 943; incident stroke=847 vs. 482 vs. 659 vs. 289	18
Safety (both ocular and non-ocular adverse events)
Rakic et al., 2013^w91	Prospective	IVR	—	AMD	267 patients	“…to examine ranibizumab treatment patterns in “real-world” practice and clinical settings…”	SAEs=78 in 40 patients (5 deaths); AEs=77 in 34 patients; suspected to be related with ranibizumab=18 AEs, including 9 SAEs and 9 AEs, of a total of 14 patients; eye disorders: 13, of these 9 were known and listed in the SPC; cardiovascular events: 24 and none were listed in SPC	18
Finger et al., 2013^w92	Prospective	IVR	—	AMD	3,470 patients	“…to collect effectiveness and safety data…”	AEs: 505 in 225 patients; of these 320 were SAE (in 137 patients); eye disorders=133/3,470 patients; visual acuity reduced=86/3,470 patients; metamorphopsia=43/3,470 patients; cerebrovascular accident=14/3,470 patients; deaths=42/3,470 patients	18
Sharma et al., 2011^w93	Retrospective, cohort	IVR; IVB	—	AMD; DME; RVO	IVB: 173 patients; IVR: 351, of these 195 had been treated previously with IVB	“To compare the rate of serious ocular and systemic adverse effects of intravitreal bevacizumab and ranibizumab…”	Acute intraocular inflammation=IVB: 9/173 patients; IVR: 1/351 patients. Anterior chamber reactions=IVR: 1/351 patients. Retinal detachment=IVB: 0/173 patients; IVR: 0/351 patients; infectious endophthalmitis=IVB: 0/173 patients; IVR: 0/351 patients; vitreous hemorrhage=IVB: 0/173 patients; IVR: 0/351 patients; myocardial infarction=IVB: 2/173 patients; IVR: 0/351 patients; transient ischemic attack=IVB: 1/173 patients; IVR: 1/351 patients	18
Bakri et al., 2009^w94	Retrospective, cohort	IVR; IVB; IVB+triamcinolone; IVB+dexamethasone	—	AMD; DME; proliferative diabetic retinopathy; RVO; ME attributable to autoimmune retinopathy	35 patients	“…to evaluate the outcome of bilateral, simultaneous intravitreal injections”	Blurry vision: 4/35 patients; floaters: 2/35 patients; vitritis: 1/35 patients (IVB); small hypopyon: 1/35 patients. Stroke, cerebrovascular accident, or cardiovascular or thromboembolic event: 0/35 patients	17
Dayani et al., 2007^w95	Retrospective	IVP	—	AMD	31 patients	“…to evaluate the safety of intravitreal Macugen (pegaptanib sodium) injections among patients in whom warfarin anticoagulation was maintained throughout the treatment period”	Injection-related or immediate postinjection-related hemorrhagic complications=0/31 patients; Acute submacular hemorrhage=1/31 patients	14

Total quality score: ≥20, good; 15–19, fair; ≤14, poor.

Results are described as reported by the study authors.

AE, adverse event; AMD, age-related macular degeneration; ATE, arterial thromboembolic events; BRVO, branch retinal vein occlusion; CRVO, central retinal vein occlusion; DME, diabetic macular edema; GI, gastrointestinal; IOP, intraocular pressure; IVB, intravitreal injection of bevacizumab; IVP, intravitreal injection of pegaptanib; IVR, intravitreal injection of ranibizumab; MI, myocardial infarction; MQ, methodological quality; OHT, ocular hypertension; PDT, photodynamic therapy; PED, pigment epithelial detachment; PVD, posterior vitreous detachment; RD, rhegmatogenous retinal detachments; RPE, retinal pigment epithelial; RVO, retinal vein occlusion; SAE, serious adverse event; SPC, summary of product characteristics; VEGF, vascular endothelial growth factor.

Source: Appendix References.^w65-w95

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