EBLING LIBRARY
`UNIVERSITY OF WISCONSIN
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`OCT 2 6 2004
`
`750 Highland Avenue
`Madison, WI53705
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`y ‘
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`):$
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`R3025 |
`214
`
`NGUISHING FEATURES OF NONTRAUMATIC AND TRAUMATIC
`RETINAL DIALYSES
`Hollander, Irvine, Poothullil, Bhisitkul
`RISKS OF INTRAVITREOUS INJECTION: A COMPREHENSIVE REVIEW
`Jager, Aiello, Patel, Cunningham,Jr.
`MINIMIZING THE RISK OF ENDOPHTHALMITIS FOLLOWING
`INTRAVITREOUS INJECTIONS
`Ta
`CHARACTERISTICS OF SIXTY MYOPIC EYES WITH PRE-LASER IN SITU
`KERATOMILEUSIS RETINAL EXAMINATION AND POST-LASER IN SITU
`KERATOMILEUSIS RETINAL LESIONS
`Chan, Arevalo, Akbatur, Sengiin, Yoon, Lee, Tarasewicz, Lin
`CHARACTERISTICS AND OUTCOMES OF CHOROIDAL
`NEOVASCULARIZATION OCCURRING AFTER MACULAR HOLE
`SURGERY
`Tabandeh, Smiddy, Sullivan, Monshizadeh, Rafiei, Cheng, Freeman
`VITREOUS SURGERY WITH AND WITHOUT INTERNAL LIMITING
`MEMBRANE PEELING FOR MACULAR HOLE REPAIR
`Kumagai, Furukawa, Ogino, Uemura, Demizu, Larson
`SURGERY FOR EPIMACULAR MEMBRANE: IMPACF OF RETINAL
`INTERNAL LIMITING MEMBRANE REMOVAL ON FUNCTIONAL
`OUTCOME
`Bovey, Uffer, Achache
`TRYPAN BLUE-ASSISTED VITRECTOMY
`Vote, Russell, Joondeph
`SURGICAL REMOVAL OF PERIPAPILLARY CHOROIDAL
`NEOVASCULARIZATION ASSOCIATED WITH OPTIC NERVE DRUSEN
`Mateo, Moreno, Lechuga, Addn, Corcdéstegui
`RISK FACTORS FOR RETENTION OF SUBRETINAL PERFLUOROCARBON
`LIQUID IN VITREORETINAL SURGERY
`Garcia-Valenzuela, Ito, Abrams
`COMPARISON OF RETINAL OUTCOMES AFTER SCLERAL BUCKLE OR
`LENS-SPARING VITRECTOMY FOR STAGE 4 RETINOPATHY OF
`PREMATURITY
`Hartnett, Maguluri, Thompson, McColm
`SEROUS MACULAR DETACHMENT SECONDARY TO DISTANT RETINAL
`VASCULAR DISORDERS
`Otani, Yamaguchi, Kishi
`OUTCOME OF CHOROIDAL NEOVASCULARIZATION IN ANGIOID
`STREAKS AFTER PHOTODYNAMIC THERAPY
`Menchini, Virgili, Introini, Bandello, Ambesi-Impiombato, Pece, Parodi,
`Giacomelli, Capobianco, Varano, Brancato
`
`
`
`
`
`
`Apotex Exhibit 1033
`Apotex Exhibit 1033
`Page 1 of 25
`Page 1 of 25
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`

`

`
`
`THE JOURNAL OF RETINAL AND VITREOUS DISEASES
`EDITOR-IN-CHIEF
`ALEXANDER J. BRUCKER
`Philadelphia, PA
`
`Abstract Editor
`MARK S. BLUMENKRANZ
`Stanford, CA
`
`
`
`SECTION EDITORS
`Book Review Editor
`CHARLES P. WILKINSON
`Baltimore, MD
`
`Diagnostic and Therapeutic Editor
`H. RICHARD McDONALD
`San Francisco, CA
`Photo Essay Editor
`LEE M. JAMPOL
`Chicago, IL
`
`CME Editor
`RICHARD F, SPAIDE
`New York, NY
`
`EDITORIAL BOARD
`
`TIMOTHY G. MURRAY
`JAMES C. FOLK
`GARY W. ABRAMS
`Miami, FL.
`lowa City, IA
`Detroit, MI
`DAVID H. ORTH
`WILLIAM R. FREEMAN
`LLOYD P. AIELLO
`Chicago, IL
`La Jolla, CA
`Boston, MA
`ARNALL PATZ
`J. DONALD M. GASS
`GEORGE W. BLANKENSHIP
`Baltimore, MD
`Nashville, TN
`Hershey, PA
`GHOLAM A. PEYMAN
`KURT GITTER
`NEIL M. BRESSLER
`New Orleans, LA
`New Orleans, LA
`Baltimore, MD
`INGRID SCOTT
`W. RICHARD GREEN
`SUSAN B. BRESSLER
`Miami, FL
`Baltimore, MD 3
`Baltimore, MD
`CAROL L. SHIELDS
`STANLEY CHANG
`coe
`blir MD
`eo
`:
`TEVEN T. CHARLES
`Philadelphia, PA
`eeFe JABS
`Memphis, TN
`LAWRENCE J. SINGERMAN
`:
`D. JACKSON COLEMAN
`Cleveland, OH
`a Aste
`New York, NY
`urna,
`JASON S. SLAKTER
`:
`GABRIEL J. COSCAS
`New York, NY
`MARK W. JOHNSON
`Paris, France
`PAUL STERNBERG,JR.
`Ane Arbor, AE
`DONALD J. D'AMICO
`Nashville, TN
`ANSELM KAMPIK
`Boston, MA
`YASUO TANO
`Munich, Germany
`EUGENE DE JUAN,JR.
`Osaka, Japan
`HARVEY A. LINCOFF
`Los Angeles, CA
`FELIPE |. TOLENTINO
`New York, NY
`FREDERICK L. FERRIS,Ill
`Boston, MA
`MAUREEN G. MAGUIRE
`Bethesda, MD
`CYNTHIA A. TOTH
`Philadelphia, PA
`STUART L. FINE
`Durham, NC
`BROOKS W. McCUEN
`Philadelphia, PA
`GEORGE A. WILLIAMS
`Durham, NC
`GERALD A. FISHMAN
`Royal Oak, MI
`RONALD G. MICHELS*
`West Chester, IL
`LAWRENCE A. YANNUZZI
`Baltimore, MD
`HARRY W. FLYNN, JR.
`
`*1943-1991 New York, NY
`Miami, FL
`
`|
`MANAGING EDITOR: TERRY ROTHSTEIN BRUCKER
`RETINA® The Journal of Retinal and Vitreous Diseasesis indexed in Biological Abstracts, EMBASE/Excerpia Medica, Index Medicus, and Current Contents.
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`RISKS OF INTRAVITREOUS INJECTION:
`A COMPREHENSIVE REVIEW
`
`RAMA D. JAGER, MD, MBA,* LLOYD PAUL AIELLO, MD, PuD,* SAMIR C. PATEL, MD,7
`EMMETT T. CUNNINGHAM, JR., MD, PHD, MPH}
`
`Purpose: To evaluate the prevalence of the most common serious adverse events
`associated with intravitreous (IVT) injection.
`Methods: A systematic search of the literature via PubMed from 1966 to March 1, 2004,
`was conductedto identify studies evaluating the safety of IVT injection. Data submitted in New
`Drug Applications to the U.S. Food and Drug Administration for drugs administered into the
`vitreous were included where available. Serious adverse events reported in each study were
`recorded, and risk per eye and risk per injection were calculated for the following serious
`adverse events: endophthalmitis, retinal detachment,
`iritis/uveitis,
`intraocular hemorrhage,
`ocular hypertension, cataract, and hypotony. Rare complications also were noted.
`Results: Data from 14,866 IVT injections in 4,382 eyes were analyzed. There were 38
`cases of endophthalmitis (including those reported as pseudoendophthalmitis) for a prev-
`alence of 0.3% perinjection and 0.9% per eye. Excluding cases reported specifically as
`pseudoendophthalmitis, the prevalence of endophthalmitis was 0.2% per injection and
`0.5% per eye. Retinal detachment, iritis/uveitis, ocular hypertension, cataract, intraocular
`hemorrhage, and hypotony were generally associated with IVT injection of specific com-
`pounds and wereinfrequently attributed by the investigators to the injection procedure
`itself. Retinal vascular occlusions were described rarely in patients after |VT injection, and
`it was unclear in most cases whether these represented true injection-related complica-
`tions or chance associations.
`Conclusion: The risk of serious adverse events reported after IVT injection is low.
`Nevertheless, careful attention to injection technique and appropriate postinjection mon-
`itoring are essential because uncommoninjection-related complications may be associ-
`ated with permanentvision loss.
`RETINA 24:676-698, 2004
`
`ver the last 2 decades, the use of intravitreous
`(IVT) injection has gained increasing acceptance
`in the therapeutic management of many intraocular
`
`From *the Beetham Eye Institute, Joslin Diabetes Center and
`Department of Ophthalmology, Harvard Medical School, Boston,
`Massachusetts;
`the tDepartment of Ophthalmology and Visual
`Science, University of Chicago, Chicago,Illinois; and the {Depart-
`ment of Ophthalmology, New York University School of Medi-
`cine, New York, New York.
`Samir C, Patel and Emmett T. Cunningham,Jr., are employees
`of Eyetech Pharmaceuticals, Inc., New York, NY.
`Although the term “intravitreal” is used colloquially quite often,
`we have used “intravitreous” as the grammatically correct and
`preferred term in this review.
`Reprints: Dr. Emmett T. Cunningham, Jr., Eyetech Pharmaceu-
`ticals, Inc., 3 Times Square, 12th Floor, New York, NY 10036;
`e-mail: emmett.cunningham @eyetech.com
`
`diseases, particularly disorders affecting the posterior
`segment. A highly effective and frequently used
`means of administering antiviral agents in the treat-
`ment of cytomegalovirus (CMY)retinitis, direct in-
`jection of antiviral agents into the vitreous of patients
`with acquired immunodeficiency syndrome maxi-
`mizes intraocular drug levels while minimizing the
`risk of toxicity associated with systemic administra-
`tion of these agents.!“!! In addition, IVT injection of
`various gases has been used as a less-invasive alter-
`native to scleral buckling for the managementofret-
`inal detachment
`in the setting of pneumatic reti-
`nopexy!?-!4 and for
`the administration of
`tissue
`plasminogen activator ([TPA] Retavase; Centocor,
`Malvern, PA)!5:!6 in the treatment of submacular hem-
`
`676
`
`
`
`
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`RISKS OF IVT INJECTION « JAGER ET AL
`
`677
`
`orrhage and acute central retinal vein occlusion. Nee-
`dle aspiration of the vitreous—procedurally similar to
`IVT injection—is used routinely to biopsy the vitre-
`ous. In addition to the long-standing practices of vit-
`reous Gram staining, microbial culture, and sensitivity
`analysis in the setting of suspected endophthalmitis, !”
`vitreous sampling may also be used to obtain DNA for
`polymerase chain reaction—based analyses for patients
`suspected of having necrotizing herpetic retinitis!*-??
`or toxoplasmic retinochoroiditis.?>
`Recent investigations into the treatment ofretinal
`neovascularization, retinal edema, and posterior seg-
`ment inflammation have led to the development of
`new biologic and pharmacologic agents that are opti-
`mally administered directly into the vitreous.
`[VT
`injection of these compounds is being investigated,
`both as a method of achieving vitreous concentrations
`beyond those obtainable with systemic administration
`and as a meansof avoiding potential systemic adverse
`effects. Several of these investigational agents, such as
`the therapeutic aptamer oligonucleotide pegaptanib
`sodium (Macugen; Eyetech Pharmaceuticals, New
`York, NY)?*-6 and the monoclonal antibody frag-
`ment ranibizumab (Lucentis; Genentech, San Fran-
`cisco, CA),?’?8 are currently undergoing clinical eval-
`uation for the treatment of neovascular age-related
`macular degeneration (AMD) and, in the case of pe-
`gaptanib sodium,for diabetic macular edemaand ret-
`inal vein occlusion. In addition, the off-label use of
`IVT triamcinolone acetonide (Kenalog; Bristol-Myers
`Squibb, New York, NY) injection is under investiga-
`tion for a number of disorders,
`including macular
`edema??*9 and retinal neovascularization.*!34
`Because the potential advantages of [VT injection
`have become more widely appreciated and the number
`of possible applications has grown, questions have
`arisen regarding risks associated with this route of
`administration. Several potential complications of
`IVT injection, such as endophthalmitis, retinal detach-
`ment, traumatic cataract, and intraocular hemorrhage,
`can be vision threatening. A sufficient body of litera-
`ture now exists to support a thorough review of the
`risks associated with IVT injection in managing ocular
`diseases. To that end, as background, we present a
`brief historical overview of the use of IVT injection in
`humans over the last century and a synopsis of re-
`cently published studies on the pharmacokinetic prop-
`erties of agents administered directly into the vitreous.
`Wethen present the results of a comprehensive, sys-
`tematic review of the literature from which we calcu-
`lated prevalence estimates for the most common com-
`plications associated with [VT injection.
`- The analyzed reports of IVT injection varied con-
`siderably in size, design, and indication, and in most
`
`instances, the reported rates of the various complica-
`tions were quite low. Although efforts were made to
`distinguish the risks associated with the specific
`agents being administered from therisks related to the
`IVT injection procedure per se, in some instances,
`such distinctions were difficult to make. Together,
`these factors limit to some extent the generalizability
`of cross-study comparisons and analyses. Despite
`these inherent shortcomings, to our knowledge,this re-
`view represents the most extensive assessment of the
`risks associated with [VT injection compiled to date.
`
`A Historical Perspective on the Use of IVT
`Injection
`
`IVT injection has been used in the treatment of
`human ocular disease for nearly a century. Figure
`124.25,27,28,34—-48 presents a timeline of important ad-
`vances in the use of this technique from its earliest
`therapeutic application through the present. Although
`this timeline is intended to highlight some of the major
`achievements in the development of [VT therapeutics,
`it is not meant to be an exhaustive compilation or to
`acknowledge the many excellent investigative studies
`that served as a foundation for these advances. Ini-
`tially reported in 1911 by Ohm? as a meansto intro-
`duce air for retinal tamponade and repair of detach-
`ment,
`the
`IVT administration of pharmaceutical
`agents was pioneered in the mid-1940s with the use of
`penicillin to treat endophthalmitis.*°3” Unfortunately,
`at that time drug administration often was delayed for
`days or even weeks after the infection became estab-
`lished, making mostof these early attempts unsuccessful.
`The technique wasused infrequently, therefore.
`; During the 1950s and 1960s, the use of IVT injec-
`tion still was limited to the administration of air3® or
`silicone oi]?° in the treatment of retinal detachment.
`By the 1970s,
`the advent of newer antimicrobial
`agents, combined with the continued poor success of
`alternative treatment options, led to renewed interest
`in IVT therapy for endophthalmitis. Animal studies
`demonstrating the safety of this route of administra-
`tion*?5° were followed by the publication of two case
`series describing successful
`treatment of endoph-
`thalmitis using IVT injection in patients.4°*! Although
`still considered experimentalat that time,>! wider use
`of IVT injection to treat endophthalmitis was being
`advocated due to the poor treatment outcomes re-
`ported with systemic administration of antibiotics,
`which generally produced suboptimal drug levels in
`the vitreous.>*
`The development of IVT injection for the treatment
`of ophthalmic conditions other than endophthalmitis
`and retinal detachment lagged even further behind,
`
`
`
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`678
`
`RETINA, THE JOURNAL OF RETINAL AND VITREOUS DISEASES * 2004 ® VOLUME 24 * NUMBER 5
`
`1910
`
`1911 IVT injection of air was first used to promote retinal detachmentrepair.
`
`1943-1947 Initial reports describing treatment of endophthalmitis with the use of IVT
`antibiotics were published.’*"”
`
`
`
`1950
`
`1952 The use of IVT injection ofair to treat retinal detachmentin a large series ofpatients
`was reported.”*
`
`1970
`
`1980
`
`1962 IVT injection ofsiliconeoil to treat retinal detachment was tested in a series of
`patients.”*
`
`1976-1978 Thefirst studies were published in which IVT antimicrobial agents were
`successful in treating endophthalmitis."
`
`1982 IVT injection of 5-flucrouracil was tested for postvitrectomy fibroblast
`proliferation”?
`
`1987 IVT ganciclovir was effective in treating cytomegalovirus retinitis in a patient with
`
`acquired immunodeficiency syndrome.”
`
`1991 Thefirst case series evaluating the use of IVT dexamethasonefor treatment of
`diabetic retinopathy was published.
`
`1995 Results ofa pilot study demonstrating efficacy of IVT injection oftriamcinolone
`
`acetonide for treating exudative macular degeneration were published.
`
`1997 IVT injection of methotrexate was effective in treating ocular lymphoma in a small
`series of patients.‘*
`
`1998 The U.S. Food and Drug Administration (FDA) approved the use of [VT fomivirsen
`
`for treatment of cytomegalovirus retinitis.
`
`1999 Thefirst study reporting successful treatment ofsubmacular hemorrhage by IVT
`injection oftissue plasminogen activator was published.”
`
`2002 Data were submitted to the FDA supporting the efficacy and safety of [VT ovine
`hyaluronidase in the managementofvitreous hemorthage.“*
`
`2002-2003 Results oftrials evaluating IVT injection of pegaptanib sodium for treatment of
`age-related macular degeneration were published."
`
`2003 Early results were published from a trial evaluating the [VT administration of
`
`ranibizumab forthe treatment of neovascular age-related macular degeneration.*”*
`
`Fig. 1. A timeline of important advances in the use of intravitreous (IVT) injections to treat human ocular diseases.
`
`perhaps because of perceived risks related to the pro-
`cedure and because endophthalmitis and retinal de-
`tachment generally have the greatest
`likelihood for
`acute and irreversible vision loss. Although [VT in-
`jection of corticosteroids was evaluated in an animal
`model ofocular inflammation in the early 1980s,53>4
`there were no publications describing the use of IVT
`corticosteroids in humans until the 1990s. The first
`new application for IVT injection was nottried until
`
`1982, when a pilot study assessing the efficacy and
`safety of 5-fluorouracil delivered as an IVT injection
`for the prevention of postvitrectomy fibroblast prolif-
`eration in patients with proliferative retinopathy was
`initiated.42 This was followed in 1987 by the use of
`IVT ganciclovir sodium (Cytovine; Roche Pharma-
`ceuticals, Nutley, NJ) in the treatment of CMV reti-
`nitis in a patient with acquired immunodeficiency
`syndrome.*3
`
`
`
`
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`RISKS OF IVT INJECTION « JAGER ET AL
`
`679
`
`The gradually increasing confidence in the safety of
`IVT injection that emerged as a result of these studies
`led to the evaluation of [VT administration of a num-
`ber of other agents throughout the 1990s. Blanken-
`ship** demonstrated in 1991 that dexamethasone was
`well tolerated but of no therapeutic value for postvit-
`rectomy treatment of diabetic retinopathy. Penfold et
`al34 in a pilot study demonstrated that triamcinolone
`acetonide, a longer-acting corticosteroid, was well tol-
`erated in patients with exudative AMD. Other novel
`applicationsof IVT injection in the 1990s included the
`use of methotrexate for treatment of ocular lympho-
`ma*> and the injection of TPA for the management of
`submacular hemorrhage.*? In 1998, fomivirsen so-
`dium (Vitravene; Isis Pharmaceuticals, Carlsbad, CA),
`an antisense compound used to treat active CMV
`retinitis, was the first compound to be approved spe-
`cifically for IVT injection by the U.S. Food and Drug
`Administration, representing a milestone achievement
`in the use of IVT therapy (Fig. 1).*¢
`The pace of development of new applications for
`IVT injection continues to accelerate, with three new
`investigational drug products in clinical trials in the
`early 2000s. These include the vascular endothelial
`growth factor inhibitors ranibizumab?’and pegaptanib
`sodium?+~°6 for the treatment of neovascular AMD
`and ovine hyaluronidase (Vitrase; ISTA Pharmaceuti-
`cals, Irvine, CA),*® which was recently approved by
`the U.S. Food and Drug Administration as a disper-
`sion agent for other injected drugs andis still seeking
`approval for the treatment of vitreous hemorrhage.>>
`The use of IVT injection as a method for localized
`adenovirus vector—mediated gene transferto treat ret-
`initis pigmentosa and AMD is
`also being ex-
`plored.5°>? With numerous novel ophthalmic thera-
`pies currently poised to enter into clinical trials, it is
`likely that the numberof drugs under developmentfor
`IVT injection will continue to increase rapidly.
`
`Pharmacokinetic Characteristics of Compounds
`Injected Into the Vitreous
`
`Drug concentrations in the vitreous are determined
`not only by the amount of drug given but also by the
`distribution and clearance of such compounds.*®°? As
`with other routes of drug administration, pharmacoki-
`netic characteristics are dependent on both the ana-
`tomical and physiologic features at the site of admin-
`istration>*-© and the physicochemical properties of
`the agent administered.°!? Although several investi-
`gators have explored the pharmacokinetic properties
`of the [VT injection of selected compounds in animal
`models5#-%.62.63 and to a limited extent
`in hu-
`
`mans®*~-®6 over the past 2 decades, this topic remains
`complex and incompletely understood.
`The composition of the vitreous is uniquein thatit
`is a highly hydrated, avascular, gelatinous body con-
`taining 98% water. Vitreous structural elements com-
`posed of type II collagen and hyaluronic acid occupy
`<1% ofthe total volume.*! The human eye contains 3
`mL to 4 mL of vitreous humor.®? The vitreous can
`move during eye motion, particularly in the elderly
`who normally have a more liquefied vitreous than
`younger individuals.®! By 80 years of age, approxi-
`mately one half of the vitreous in most people is
`estimated to exist in a liquid state.6* Althoughlittle is
`known about the effect of age on the disposition of
`compounds administered directly into the vitreous,
`such age-related changes in vitreous characteristics
`merit consideration because many indications for [VT
`injection affect elderly patients disproportionately.
`Although there is a relative barrier between the
`anterior and the posterior segments of the eye, injected
`substances move throughoutthe vitreous fairly readily
`by either diffusion or bulk flow. Whereas bulk flow
`tends to be the primary means of movement when the
`vitreous is formed, when the vitreous body is partly
`removed, degenerated, or collapsed,
`the exchange
`movement tends to be due largely to diffusion. Gra-
`dients exist in both directions between the vitreous
`and plasma. These gradients are a result of several
`mechanisms, including diffusion and bulk flow pro-
`cesses within the vitreous body as mentioned above,
`the presence of physiologic blood—ocular barriers vis-
`a-vis active and passive transport, and metabolism
`within the eye itself.%
`Alterations of the normal anatomy and physiology
`of ithe eye and the size of the administered compound
`have been demonstrated to be factors that impact the
`distribution and elimination of drugs from the vitreous
`in animal studies. A history of vitrectomy, aphakia, or
`pseudophakia has been shownto increase the rate of
`distribution and clearance of amphotericin B, for ex-
`ample. Radiolabeled amphotericin B elimination from
`aphakic, vitrectomized rabbit eyes occurred in 1.8
`days compared with 15.1 days for normal
`rabbit
`eyes.°? A similarly rapid clearance of triamcinolone
`acetonide in aphakic, vitrectomized rabbit eyes (6.5
`days) compared with clearance from aphakic, nonvit-
`rectomized eyes (16.8 days) and normal, phakic, non-
`vitrectomized eyes (41 days) was reported by Schin-
`dler et al.®° In this latter study, high-performance
`liquid chromatography was unable to detect the drug
`in 5 of 6 normal rabbit eyes at 21 days after [VT
`injection. Uptakeoftriamcinolone acetonide by ocular
`tissues is apparently quite slow, because <1% of the
`compound was found in the iris ciliary body, lens,
`
`
`
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`680
`
`RETINA, THE JOURNAL OF RETINAL AND VITREOUS DISEASES « 2004 * VOLUME 24 * NUMBER 5
`
`retina, pigmentepithelium,and sclera at 72 hours after
`injection.
`The pharmacokinetic properties of compounds in
`the vitreous have been observed to change in the
`setting of inflammation or infection, such as endoph-
`thalmitis. Using a rabbit model, Cocoet al5* estimated
`that the half-life of vancomycin in normal, uninflamed
`eyes was ~62 hours, compared with 14 hours in eyes
`in which endophthalmitis had been experimentally
`induced by injecting Staphylococcus aureus into the
`vitreous, a >4-fold increase. The reverse wastrue for
`plasma concentrations. These data led the investiga-
`tors to suggest that the elimination of vancomycin was
`enhanced in the setting of inflammation or infection,
`most probably due to breakdown of the blood-tretinal
`barrier, which whenintactacts to limit drug clearance.>*
`The size of the administered compound has been
`shown to affect
`the half-life in the vitreous. Full-
`length radiolabeled humanized monoclonal antibodies
`(molecular weight, +150 kd)injected into the vitreous
`of rhesus macaques were found not to penetrate the
`inner limiting membraneofthe retina, while Fab an-
`tibody fragments (molecular weight, ~50 kd) diffused
`through the neural retina to the retinal pigment epi-
`thelial layer within 1 hour.S? Consequently, the half-life
`in the vitreous was 5.6 days for the full-length antibody
`and 3.2 days for the Fab antibody fragment.®
`Specific pharmacokinetic profiling of compounds
`administered into the vitreous in humans has been
`limited. Two studies have evaluated the duration of
`detectable concentrations of triamcinolone acetonide
`in aqueous humor samples.°®> Neither study at-
`tempted to identify the route of elimination of triam-
`cinolone acetonide from the eye or the levels of com-
`pound that could be achieved in various ocular
`compartments after IVT injection, Pharmacokinetic
`studies of pegaptanib sodium injected into the vitreous
`humor of rhesus monkeys have shown that vitreous
`humor and plasma concentrations were linearly re-
`lated to the dose administered with a half-life of ~4
`days. In addition, pegaptanib sodium sampled from
`the vitreous at 28 days was fully active.®7
`Recent computer simulations have suggested that
`both anterior and posterior routes of elimination may
`be important in the clearance of drugs from the vitre-
`ous.*! Although the crystalline lens is highly imper-
`meable to water and to many drugs, the anterior hya-
`loid membrane, which separates the vitreous from the
`aqueous, is thin and porous, offeringlittle resistance to
`diffusion. Because aqueous turnover is very rapid,
`with a residence time in the eye of ~2.5 hours,®! in
`aphakic and pseudophakic patients aqueous clearance
`can represent a major route of elimination of com-
`poundsinjected into the vitreous. In contrast, elimi-
`
`nation by the posterior route is facilitated by active
`unidirectional drug transport at the posterior vitreous
`surface, as demonstrated by studies in which fluores-
`cein movementthrough the vitreous was monitored.®
`The computer model predicts that a relatively small
`molecule will be quickly cleared from the vitreous by
`absorption through the retina or by release into the
`aqueous.®! In contrast, a larger molecule would dif-
`fuse more slowly, relying on bulk flow to transverse
`the vitreous, and clearance will occur primarily
`through the retina and not the aqueous.®! Although
`these findings are largely hypothetical in the absence
`of empirical data, they do suggest that the pharmaco-
`kinetic properties of compounds administered into the
`vitreous can be complex and influenced by a number
`of factors.
`
`Assessment of Complications Associated With the
`Use of IVT Injection
`
`Methods
`
`A systematic review of the literature via PubMed
`from 1966 to March 1, 2004, using the search terms
`“intravitreous,” “intravitreal,” and “endophthalmitis”
`was conducted to identify studies and case series
`reporting the safety of IVT injection. The search was
`limited to primary reports published in English. Pub-
`lications also were retrieved using the “related arti-
`cles” function of PubMed, and bibliographies from all
`articles selected for analysis were reviewed to identify
`additional citations. More than 220 references were
`reviewed.
`The following types of reports were included:(a) all
`randomized, controlled human clinical
`trials using
`IVT injection; (b) prospective or retrospective case
`series that included =20 eyes; and (c) safety data from
`U.S. Food and Drug Administration New Drug Ap-
`plications for compounds not yet approved for use in
`the United States where adverse events related to [VT
`injection were reported. The following types were
`excluded: (a) reports in which compounds were ad-
`ministered into the vitreous through sclerotomyinci-
`sions during vitrectomy; (b) reports in which com-
`pounds were
`administered by IVT injection in
`conjunction with other ocular procedures, such as
`scleral buckling or vitrectomy; (c) reports in which
`IVT injections were administered in eyes as a treat-
`ment for endophthalmitis; and (d) reports that, in the
`opinion of the authors, lacked relevant data, provided
`data of unacceptable quality, or duplicated data sets
`found in more-comprehensive publications. There
`were no exclusions based on the length of the fol-
`low-up period.
`
`
`
`
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`RISKS OF IVT INJECTION e JAGER ET AL
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`681
`
`The following information was extracted from each
`report: (a) information on study design; (b) indication
`for IVT injection; (c) description, dose, and volume of
`substance injected; (d) injection procedure and any
`preinjection preparation, such as the use of topical
`antibiotics; (e) number of eyes in which IVT injec-
`tions were administered; (f) total numberof injections
`administered; (g) any complications or serious adverse
`events noted; and (h) duration of follow-up. The rate,
`or prevalence, of seven serious adverse events—en-
`dophthalmitis, retinal detachment,
`iritis/uveitis,
`in-
`traocular hemorrhage, ocular hypertension, cataract,
`and hypotony—was recorded. Both prevalence per
`eye and prevalenceper injection were then calculated.
`Other rare, but potentially serious, adverse events
`deemed by the reviewersto be possibly related to [VT
`injection also were noted.
`
`Results
`
`Publications identified via the literature search on
`IVT injection that met the study criteria outlined under
`Methods are summarized in Table 1,!-8.19.!1.79 Table
`2,29-34,71-and Table 3, 12-16,25,48,74-76 and results of
`combined analyses are presented in Table 4. CMV
`retinitis in patients with acquired immunodeficiency
`syndrome wasthe indication that yielded the greatest
`number of publications analyzed, with a total of 10
`(Table 1). The antiviral compoundscidofovir (Vistide;
`Gilead Sciences, Foster City, CA),4-’ ganciclovir
`(with or without intravenous foscarnet sodium [Fos-
`cavir; AstraZeneca Pharmaceuticals, Wilmington,
`DE]),!-39! and fomivirsen®7° were used in 909
`eyes. There were no reports describing [VT adminis-
`tration of foscarnet sodium alone with sufficient num-
`bers of eyes to meet
`the inclusion criteria for this
`review. Treatment of CMVretinitis entailed adminis-
`tering multiple [VT injections, usually once every
`week or every other week for extended periods, re-
`sulting in both the greatest numberof total injections
`(n = 10,839) and the greatest numberofinjections per
`eye. It should be noted, however, that patients with
`CMVretinitis are at greatly increased risk for retinal
`detachment due to the prese