EVOLVING GUIDELINES FOR
`INTRA VITREOUS INJECTIONS
`
`UDYD P. AIELLO, MD,1 ALEXANDER J. BRUCKER, MD,2 STANLEY CHANG, MD,3
`EMMETT T. CUNNINGHAM, JR., MD, PHO, MPH,4 DONALD J. D'AMICO, MD,5
`8
`6
`.
`.
`.
`l
`7
`HARRY W. FLYNN, JR., MD, LISA R. GRILLONE, P1-1D, STE\ E JIDTCHERSON,
`JEFFREY M. LIEBMANN, MD.9 TERRENCE P. O'BRIEN, MD,10
`INGRID U. SCOTT, MD, MPH,6 RICHARD F. SPAIDE, MD. 11
`CHRISTOPHER TA. MD, 12 MICHAEL T. TRESE. MD 13
`
`lntravit reous (IVl} injection is increasingly being incorporated into t he management of
`ocular diseases. While only fomivirsen sodium (VitraveneTM) is c urrently approved by the Food
`and Drug Administration as an IVT injection, the number of approved IVT injections indications
`is anticipated to grow on the basis of promising results from ongoing clinical studies. Despite
`the potential benefits that may be derived from intraocular injections of different agents, no
`guidelines have been published previously for 1\/T injection. The purpose of t his document is
`to identify specific strategies for the delivety of IVT injection that may reduce risks and improve
`outcomes. Consensus was sought among a panel of investigators, surgeons experienced with
`this technique, and industry representatives. Objective evidence was sought for all guidelines,
`but consensus was accepted where evidence remains incomplete. In the absence of either
`evidetnee or consensus, the current manuscript identifies outstanding issues in need of further
`investigation. It is anticipated that more complete guidelines will evolve over t ime, poten1ially
`altering some of the guidelines included here, based on new applications of IVT injection,
`additional clinical experietnee, and results of clinical trials.
`RETINA 24:S3-819, 2004
`
`Guidelines Synopsis
`
`T he following 1:,>Uidelines were based on round-table
`
`deliberations conducted after a review of published
`and tmpu blished studies and case series. The published
`database includes data on more than 15,000 intravitreous
`
`From the 1Bee1ham Eye Institute & Joslin Diabetes Cen1e.r,
`Harvar<l Me<lical School, Boston, Massachusetts; 2Unive.rsity of
`Pennsylvania, Philaddphia, Pennsylvania; 3Columbia University
`Me<lical Center, New York, NY; 4Eyetech Pharmaceuticals, lnc,
`New Yo1x, NY; 'Massachusetts Eye an<l Ear Infirmary, Boston,
`Massachusetts; 6 Bascom Palmer Eve Institute, Miami, Flori<la;
`71ST A Phannaceuticals, Inc., Irvine, California; 3Cyckux Kt<l,
`KKC, Rjchmon<l, Virginia; 9NewYork University M.e<lical Center,
`Manhattan Eye, Ear & Throat Hospital, New York, NY; 1°The
`Wilmer Ophthalmological Institute, Johns Boykins University
`School of Me<licine, Lutherv ille, Mai.yl.and; 1 Vitreous Retina
`Macul Consultants, New York, NY; 12Stanfor<l Eye Center, Stan(cid:173)
`for<l, California; 13Privale Practice, Ro}-al Oak, Michigan.
`This research WdS supporte<l by an mre.strictix.l ix.lu.-ational grant from
`E-yetcch'Pfi7..er, Oph1hamics. New Yolk, USA.
`A<l<lress correspondence an<l reprint requests to: Alexan<ler J.
`Bmcker, MD, RETINA<l', P.O. Box 67, G la<lwyne, PA 19035.
`brucker@retinajournal.com
`
`(]VT) injections, most of which were abstracted from
`clinical studies conducted over the past IO years. 1 Al(cid:173)
`though published studies conducted specifically to com(cid:173)
`pare aspects of peri-procedure care on outcome have
`been uncommon, IVT injection studies have generated
`useful infonm1tion regan:ling risks. Tl1e guidelines pre(cid:173)
`sented in this document are relevant to the basic princi(cid:173)
`ples ofIVT injection and, therefore, generally applicable
`for broad indications. However, caveats are included for
`specific indications when appropriate.
`These guidelines are organized according to preinjec(cid:173)
`tion, peri-injection, and postinjection risk management
`\Vhile the conclusions reached for each of the variables
`considered during the roundtable discussion have been
`summarized, the panel discussions and comments them(cid:173)
`selves were instructive. We have included, therefore, not
`only the evidence on which each guideline is based, but
`also selected quotes from panel membeis to reveal the
`tone of specific deliberations.
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`Novartis Exhibit 2020.001
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`Clinical experience with IVT injection has provided
`important lessons for safe administration that should be
`made available to clinicians who plan to use this method
`of tberapy. In characterizing the conclusions in this doc(cid:173)
`mnent, the expe.1t panel has selected the term "guide(cid:173)
`lines'' over the term "reconU11e11dations" due to the sub(cid:173)
`stantial number of conclusions that depend on consensus
`suppo1t in the absence of objective evidence. While
`appropriate application of these guidelines may yield
`significant opportunities to improve outcome, they also
`outline areas where fi.uther investigation is needed and
`provide a foundation upon which more rigorous stan(cid:173)
`dards can be developed.
`I. Guidelines for Care and Prophylaxis Before
`Injection
`A . Disorders ,vith the potential to increase risk
`from IVT injection should be managed be(cid:173)
`fore treatment.
`l. Preexisting glaucoma
`- Patients with glaucoma should receive
`IVT
`appropriate
`treatment
`before
`injection.
`--JVT injection should not be denied or
`withheld from patients with a history of
`glaucoma if such therapy is deemed im(cid:173)
`portant to preservation of central vision.
`- Before perfonning IVT injection, phy(cid:173)
`sicians should conduct a thorough risk
`assessment based on standard medical
`practice. This should include the moni(cid:173)
`toring of intraocular pressure before and
`after inje..-:tion.
`-·Anterior chamber paracentesis is not
`the treatment of choice for the manage(cid:173)
`ment of transient injection-related rises
`in intraocular pressure.
`2. Allergies to povidone iodine
`- Since true contact allergy to povidonc
`iodine is quite rare, a reported history of
`povidonc iodine allergy should be veri(cid:173)
`fied by applying a skin patch test before
`use of topical povidone iodine.
`3. Active external
`infection,
`including
`marked blepharitis
`-·Postpone injection unti l after active in(cid:173)
`fection is effectively treated.
`4. Eyelid abnormalities
`- Consider eyelid abnormalities as a risk
`factor for endophthalmitis.
`
`B . Gloves and draping
`
`l. As part of universal precautions and for
`
`the safety of physicians who may be ex(cid:173)
`posed to blood, gloves arc- appropriate.
`2. Draping of the periorbital region and
`eyelashes may be employed b ut is not
`essential
`C. Prophylactic antibiotics
`l. Physicians may consider using preinjec(cid:173)
`tion topical antibiotics.
`Caveat: Limited data suppott preinjec(cid:173)
`tion use of antibiotics.
`Caveat: Data also indicate that antimi(cid:173)
`crobia 1 resistance may be more likely to
`occur with antibiotic treatment.
`2. Lid scrnbs
`-Excessive !id manipulation is to be
`avoided.
`3. Preinjection globe softening
`- While not believed to be necessary in most
`instances. if globe softening is desired, pres(cid:173)
`sure should be applied directly to the globe
`so as to avoid eyelid manipulation.
`4. Pressure should not be applied to the
`eyelids, eyelid margins, or the adnexa.
`II. Guidelines for Peri-Injection Management
`A. Pupi llary dilation
`Dilation is prefon-cd for adequate visualiza(cid:173)
`tion after the injection is given, unless oth(cid:173)
`erwise contraindicated.
`B. Topical anesthetic
`Topical anesthetic should be applied as in(cid:173)
`dicated by standard medical practice.
`C. Supplemental subconjtmctiva] anesthetic in
`addition to topical anesthetic may be con(cid:173)
`sidered.
`D. Povidone iodine
`.Povidone iodine should be applied directly
`to the eyelid margins, eye lashes, and con(cid:173)
`j W1ctival ocular surface before the injection
`via a sterile applicator, drops, or a flush. Lid
`scrnbs arc not to be perfom1ed.
`E. Speculum
`A speculum is generally recommended to
`avoid needle contact with lids and lashes.
`Once the speculum is in place, additional
`drops of povidone iodine should be applied
`to the ocular surface at the intended site of
`injection.
`F. Site of injection
`The injection is placed through the pars
`plana in the inferotemporal quadrant 3.5 to
`4 mm posterior to the limbus for a pseu(cid:173)
`dophakic and phakic eye, respectively.
`G. Needle size
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`

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`EVOLVING GUIDELINES FOR INTRAVITREOUS INJECTIONS co AIELLO Ef AL
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`S5
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`Use a needle of 27 gauge or smaller with a
`length of 0.5 to 0.62 inches.
`Insert the needle at least 6 nun toward the
`center of the eye.
`H. Injection
`A moderately slow injection should be used
`to place the drng gently into the vitreous
`cavity. Rapid injection causes excessive dis(cid:173)
`persion of the drng into the vitreous cavity
`and can cause the needle to come off the
`synnge.
`After injection, the needle should be care(cid:173)
`fully removed from the eye, and consider(cid:173)
`ation should be given to using a sterile cot(cid:173)
`ton-tip applicator to prevent reflux of both
`the therapeutic agent and vitreous.
`[. Protocol: Sequence of events
`An appropriate sequence of steps for IVT
`injection is to:
`1) apply topical anesthetic;
`2) apply povidone iodine to eyelid margins,
`eyelashes, and conjunctiva[ surface;
`3) inse1t speculum:
`4) apply additional drop of povidone iodine
`to site of injection;
`5) inse1t needle:
`6) gently inject therapeutic agent;
`7) rc.111ove needle.
`Ill. Guidelines for Postinjection Management
`A. Postinjection antibiotics
`Physician may consider use of postinjection
`topical antibiotics.
`Risks of promoting antimicrobial resistance
`should guide drug selection and dosage.
`B. lntraocular pressure
`Monitor intraocular pressure after injection.
`Provide therapy when elevated intraocular
`pressure. warrants treatment. This usually
`occurs in the context of increased intraocu(cid:173)
`lar pressure to the extent that the central
`retinal artery remains closed and the pa(cid:173)
`tient has no light perception for more than
`l to 2 minutes. Transient graying or ob(cid:173)
`scuration of vision following injection,
`however, is expected and should not be
`treated.
`C. Post:inject:ion reperfusion of the optic nerve
`Visualize the optic nerve to verify repe1fo(cid:173)
`sion of the central retinal artery in the im(cid:173)
`mediate postinjection period.
`Verify iutravitreous location of therapeutic
`agent when possible.
`
`Verify that the retina is attached and that
`there is no new intraocular hemorrhage.
`D. Discharge
`No special precautions are required before
`discharge of a patient who has had an un(cid:173)
`eventful recovery from IVT injection, but
`patients and/or caregivers should be edu(cid:173)
`cated to avoid rubbing the eye and to rec(cid:173)
`ognize the signs and symptoms of endoph(cid:173)
`thalmitis, reti.nal detachment, or intraocular
`hemorrhage; these are eye pain or increased
`discomfo1t, increased redness of the eye
`(compared to immediately after injection),
`blurred or decreased vision, and increased
`ocular sensitivity to light.
`Patients should be infonned that some blur(cid:173)
`ring of vision is common post-injection,
`which is often described as seeing spots
`floating in the eye. The floaters usually re(cid:173)
`solve after a few days or weeks.
`IV. Guidelines for Follow-Utl
`The patient should be contacted by the phy(cid:173)
`sician's office within one week of the pro(cid:173)
`cedure. Further follow-up should be dic(cid:173)
`tated by the specific needs of the patient.
`
`Background
`
`After a long period of experimentation and devel(cid:173)
`opment, IVT injection has become an accepted tool in
`the management of ophthalmologic diseases. Al(cid:173)
`though the regulatory approval of the first drng to be
`delivered by IVT injection was granted nearly 100
`years after clinical studies with IVT injection were
`initiated,1 a broad and rapid expansion of clinical
`applications is expected on the basis of evidence that
`the benefits of access to the vitreous through injection
`are achieved with acceptable safety.
`There arc substantial potent1al advantages of IVT
`injection over alternative routes of drug delivery.
`These include highly targeted activity with the poten(cid:173)
`tial to provide an increase in therapeutic effect with
`reduced systemic toxicity. For delive1y of gases, as in
`pneumatic repair of retinal detachment, IVT injection
`has the potential to lessen the risks of more invasive
`procedures. The lessons of safe access to the vitreous
`cavity leamed from IVT injections may also be rele(cid:173)
`vant to diagnostic procedure.s, including needle aspi(cid:173)
`ration, vitreous biopsy, or vitreous sampling.
`The large clinical experience with IVT injections
`bas provided a reassuring record of safety. In a com(cid:173)
`prehensive review of published clinical studies that
`included nearly 15,000 IVT injections, the overall rate
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`of endophthalmitis was 0.3% per injection. 1 This rate
`decreased to 0.2% per injection, however, when non(cid:173)
`infectious cases of pseudoendophthalmjtis associated
`with the off-label use of triamcinolone acetonide were
`exluded. Moreover, even this 0.2% per injection rate
`may be somewhat over-inflated for IVT injections as a
`whole, since infoctious endophthalmitis appears to be
`more common following IVT triamcinolone acetonide
`injections, where an overall prevalence of 0.6% per
`injection has been reported.1
`A.dditional complications associated with IVT i11-
`jection such as retinal detachment, intraocular hemor(cid:173)
`rhage, uveitis/iritis, sustained ocular hypertension, and
`hypotony, were reported to be even less common, and,
`in the case of uveitis/iritis and ocular hypertension,
`tended to be related more to the agent injected than the
`injection procedure.1
`The apparent safety of JVT injections in clinical
`trials may result from prudent application of appropri(cid:173)
`ate precautions as well as from the inherent safety of
`this technique. Needles introduced into the vitreous
`space through the pars plana fortunately do not phys(cid:173)
`ically threaten vulnerable strnctures of the eye but arc
`associated with the attendant risks of other invasive
`procedures, pat1icularly infection. In addition to en(cid:173)
`dophthalmitis, serious injection-related adverse events
`have included traumatic cataract, retinal detachment,
`intraocular hemorrhage, uveitis/iritis, and hypopyon.
`Although these events have not been commonly re(cid:173)
`ported, it is important to recognize that clinical tiials
`are typically conducted by investigators with expertise
`in the procedure under evaluation.
`Published s rudies of IVT injection date to 191 J,
`,vhen this approach was first evaluated as a method of
`employing air to tamponade detached retinas.3 In the
`early 1940s, studies were published evaluating [VT
`injection of sulfanilamide and penicillin for treatment
`of endophthalmitis.4•-'•6 Further studies of IVT injec(cid:173)
`tion for treatment of retinal detachment and endoph(cid:173)
`thalmitis conducted over the ensuing decades corrob(cid:173)
`orated that IVT injection was feasible. However, these
`applications remained experimental due to inconsis(cid:173)
`tent clinical benefits and concern about safety.
`In 1987, a published case report described benefit
`from delivery of ganciclovir sodium (Cytovine) via
`IVT injection to a patient with opportunistic cytomeg(cid:173)
`alov irus (CMV) infection as a complication of ac(cid:173)
`quired inununodeficiency syndrome (AIDS).7 Due to
`a poor response to alternative methods of treatment,
`IVT injection for CMV retinitis was pursued. In 1998,
`fomivirsen sodium (VitraveneTM) was licensed by the
`U.S. Food and Drng Administration for IVT injection
`in the treatment ofCr.1V retinitis, the fmn approval for
`a drug to be administered by IVT injection.
`
`The efficacy of IVT injection for viral retinitis is
`credited with renewed in'lcrest in IVT injections as a
`viable approach to deliveri.ng therapy to the interior of
`the eye. Other applications evaluated dm;ng this era
`include administration of 5-fluorouracil to prevent
`postvitrectomy fibroblast proliferation inpatients with
`proliferative retinopathy,8 a<lministration of dexa(cid:173)
`methasonc to conlTOl diabetic retinopathy after vitrec(cid:173)
`tomy,9 and administration of tissue plasminogen acti(cid:173)
`vator
`(t-PA)
`for management of submacular
`hemonhage.to Of these three examples, only IVT in(cid:173)
`jection of t-PA was associated with benefit in the
`initial clinical studies, but each experience reinforced
`the safety and tolerability of this method of drug
`delive1y and encomaged forther trials.
`Early clinical studies of ovine hyaluronidase (Vit(cid:173)
`rase) have suggested efficacy in the lTeatment of vit(cid:173)
`reous hemorrhage.i 1 Among the most promising d:tugs
`in current trials are biologic compounds, such as ran(cid:173)
`dibizumab
`(LucentisTI',~ and pegaptanib sodium
`(MacugenTM), which
`inhibit vascular endothelial
`growth factor (VEGF). Potential applications include
`treatment of exudative age-related macular degenera(cid:173)
`t ion, diabetic macular edema, and retinal vein occlu(cid:173)
`sion. The advanced clinical studies with these and
`other agents anticipate continued expansion of IVT
`injection as a method of drug delivery.
`It is important to confirm the safety and tolerability
`of each compound introduced into the vitreous by
`injection. However. it is also important to apply the
`lessons of clinical n·ials in identifying common 1isks
`of IVT injection. Regardless of therapy, IVT injection
`is an invasive technique for which it is reasonable to
`presume that the protocol for administration will ex(cid:173)
`ercise an important i.nfluence on outcome. ln particu(cid:173)
`lar, minimizing the risk of infection, circumventing an
`inflammatory response, and avoiding damage to ocu(cid:173)
`lar strnctures play a critical role in preserving a favor(cid:173)
`ab le benefit-to-risk ratio.
`Extensive clinical experience with lVT injection
`has provided clinicians with an outline of avoidable
`risks through empirical experience. As safe delivery
`of IVT injections plays a critical role in clinical ben(cid:173)
`efit, specific protocols are needed to guide clinicians
`attempting to reproduce the benefits of IVT injection
`in individual patients. To date., many of the steps
`purported to contribute to safe IVT technique have
`not been evaluated in a clinical trial. Until such
`studies are perfom1ed, controversies arc likely to
`persist. However, there is evidence on wl1ich to
`endorse some measures of risk management. In
`additiou, there is broad conseusus among experts on
`the value of several steps, and continued c<mtro(cid:173)
`versy about other steps, not fonnally validated in
`
`Novartis Exhibit 2020.004
`Regeneron v. Novartis, IPR2021-00816
`
`

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`EVOLVING GUIDELINES FOR INTRAVITREOUS INJECTIONS co AIELLO Ef AL
`
`S7
`
`clinical trials. It is essential to collate this informa(cid:173)
`tion to guide clinical decision-making in routine
`patient management.
`In this document, the goal is to outline steps for safe
`delivery of IVT injection by establishing where there
`is evidence, where there is consensus, and where there
`is controversy. These guidelines facilitate a best prac(cid:173)
`tice approach to IVT injection but also outline areas in
`which further investigation is wan·anted. Although
`more experience with IYT injection may modify or
`alter the guidelines within this document, a practical
`outline of current understanding of risk management
`is needed as the application of IVT injection expands
`in routine clinical managen1ent.
`
`I. Guidelines for Care and Prophylaxis Before
`Injection
`
`GUIDELINE: Screen patients for disorders, condi(cid:173)
`tio11s, or abnormalities with the potential to increase
`risks associated vvilh ff;T injection. Specific guidelines
`for common complicating.factors follow.
`
`Evidence for Guideline.- Infection within the eye,
`although uncommon, is the most likely and most dev(cid:173)
`astating complication of IVT injection. In experimen(cid:173)
`tal studies, there was a higher rate of infection in the
`vitreous than in the anterior chamber when each was
`inoculated ,:vitb the same number of bacteria.12 It is
`reasonable to anticipate a reduced 1isk of infection
`from treatment of exist ing predisposing diseases, i.e.,
`blepharitis, and screening for obstacles to effective
`prophylaxis.
`
`Discussion
`
`Scott: There are few absolute contraindications to
`IVT injection. Even in patients with glaucoma or
`cataracts, IVT injection may be appropriate if the risk
`of failing to treat is persistent or continuing loss of
`central vision. Clearly, treatable conditions should be
`treated to facilitate injection, but I think the bcnefit(cid:173)
`to-risk ratio of delaying [YT injection should also be
`considered.
`Ta: Active external i.nfcction needs to be treated.
`However, it is imp011ant to distinguish between
`chronic disease and active infection. There arc gray
`areas. Blepharitis, for example, is extremely common
`and may be culture positive, but it should not be a
`contraindication to IVT injection in patients who
`might benefit from this procedure. It is, however, a
`relative contraindication for an elective procedure.
`
`Glaucoma
`
`GUIDELINE: 1) Patients with preexisling glau(cid:173)
`coma should be managed by un ophthalmologist ac(cid:173)
`cording lo clinical practice guidelines.fbr appropriate
`ireatment; 2) IVT injection should not be denied or
`withheld from patients ,vith a hislaty of gl.aucoma t(
`such therapy is deemed important to preservation of
`Cf..'ntral vision; 3) Bf.((ore pe1forming !VT i11;ection, phy(cid:173)
`sicians should conduct a ihorough rLvk assessment based
`on standard medical practice and monitor intruocular
`pressure bej(1re and after i11iection; and .J) Anterior
`chamber paraceniesis is not the treatment ~f choice .for
`patien£5 with transient injection-related inlraocular pres(cid:173)
`sure rises.
`
`Evidence for G11tdeiine.- Preexisting glaucoma may
`pose a risk of developing increased intraocular pres(cid:173)
`sure following IVT injection. Although the risks of a
`complication from IYT injection in a patient with
`uncontrolled glaucoma may be outweighed by the
`potential benefits when central vision is at risk, cau(cid:173)
`tion should be exercised. There are no controlled trials
`on whicl1 to base the risk-to-benefit ratio of IVT
`injection in patients with glaucoma.
`
`DL~cussion.- Leihmann: Most ofmy colleagues man(cid:173)
`age the patient with the goal of preserv·ing central
`vision. A patient with severe glaucoma will need to be
`managed for that condition before injection. Physi(cid:173)
`cians should use individual discretion in making treat(cid:173)
`ment decisions.
`Flynn: If a patient has baseline intraocular pressure
`~35, this should be treated first, before getting the
`injection. [VT injection should not be denied or with(cid:173)
`held from patients with a history of glaucoma.
`D 'Amico: You need to check intraocular pressure
`because the risk of adverse events is increased when it is
`chronically elevated > 30. lntraocular presstll'e should be
`monitored at least once after you give the injection.
`Certainly, these rises in pressure can be treated.
`Liebmann: The overriding concern for patients and
`physicians should be the preservation of central vi(cid:173)
`sion, and pre-existing glaucoma should be managed
`app.ropriately before IVT. Treatment for acute eleva(cid:173)
`tion in intraocular pressure includes a -2 adrenergic
`agonists such as brimonidine and apraclonidine, {3-ad(cid:173)
`renergic antagonists such as timolol, and oral or top(cid:173)
`ical carbonic anhydrase inhibitors. Surgical therapy
`includes paracentes is.
`Cunningham: Bm paracentesis should be used only
`in extreme circumstances when the degree of pressure
`elevation poses an imminent and in·eversible threat to
`vision. I think we all agree on this point.
`
`Novartis Exhibit 2020.005
`Regeneron v. Novartis, IPR2021-00816
`
`

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`Allergy to Povidone Iodine
`
`GUIDEUNE: Due to the rarity<?/ serious povidone
`iodine allergy, consider a skin patch test before ruling
`out use of this agent, even in patients who report a
`hisiory ()f this allergy.
`Evidence .for Guideline.- A history of an allergy to
`povidone iodine is commonly reported but uncom(cid:173)
`monly documented. As povidone iodine is a usefol
`tool for prevention of infection, a skin patch test may
`be appropriate i.n patients whose claim of an allergy is
`not substantiated by medical records. Skin tests are a
`reliable method of identifying a serious allergy with
`the potential for significant complications, such as
`anaphylactic shock. There are no controlled studies
`documenting that a skin test is an effective method for
`screening for povidone iodine allergies before IVT
`injection.
`Discussion.- Flynn: Patients occasionally come to us
`with a histo1y of allergy to povidone iodine, and in
`such circumstances, we may conduct a skin test to
`determine if there is a reaction. A history of systemic
`iodine allergy usually does not translate to allergy
`with povidone iodine.
`0 'Brien: The majority or allergic reactions are to
`iodine contrast, and this should not be confused with
`a reaction of povidone iodine. There are very few
`cases of anaphylaxis to povidone-iodine.
`Spaide: People get povidone iodine on their skin,
`and 12 or 24 hours later they take off the bandage and
`have some skin irritation because they didn't wash off
`the agent. The irritation may also be clue to the tape
`from the bandage. Neither of these are "allergies" that
`should prevent the use of poviclone iodine for ocular
`procedures.
`Brucker.· If the patient's skin becomes red after
`receiving the povidone iodine patch test, should the
`physician still use povidone iodine? My answer is yes,
`absolutely. Go ahead and use the povidone iodine. I
`don't want the patient to develop endophthalmitis, and
`I have not seen a patient have an anaphylactic reaction
`from a drop of povidone iodine.
`Scoa: One may consider conducting a patch test in
`the waiting room or in the holding area before surgeiy.
`
`Active External Infection, Including Blepharitts
`
`GUIDELINE Postpone injection and treat with
`antibiotics. lltiection can be administered ajier the
`infection clears.
`Evidence .fiw Grtideline.-One of the most serious
`complications of IVT injection is infection of the
`vitreous. Rigorous precautions to reduce this risk arc
`warranted. There are no controlled data demonstrating
`
`a reduced risk of fVT injection with treatment of
`external infections before IVT injection, hut this ap(cid:173)
`proach is consistent with good medical practice.
`Discussion.- This recommendation was accepted
`without discussion.
`
`Eyelid Abnormalities
`
`GUIDELINE: Consider eyelid abnomwlities as a
`risk factor for endoplllhalmitis.
`
`Evidence for Guide/ine.- Data indicate that eyelid ab(cid:173)
`nonnalities such as blcpharitis appear to contribute to the
`risk of endophthalmitis in patients after sec<mdary in(cid:173)
`traocular lens (IOL) transplantation. 13 These data can be
`extrapolated to IVT injection. In a study evaluating the
`risk of endophthalmitis after secondary IOL implantation
`relative to other intraocular surgeries, endophthalmitis
`was associated with pre.operative eyelid abnom1alities, as
`well as diabetes mellitus, mmsscleral suture fixation of
`posterior chamber IOLs, polypropylene haptics, re-entry
`of eye through a previow; wound, and postinjection
`wound defects. Most cases were caused by Swphylococ(cid:173)
`cus epidermidis.
`
`Discussion.- Ta: Patients w ith active [extemal] infec(cid:173)
`t ion should receive pretreatment with an antibiotic to
`decrease 1heir risk of infection dm·ing the procedure.
`Three or 4 days of antibiotics might be appropriate.
`Brucker: If the patient has an active infection, for
`example blepharitis, and the physician is concerned
`about it being a risk factor, the injection should not be
`given immediately. The patient can be treated with
`antibiotics and then con1e back for the IVT injection.
`
`U. Guidelines for Peri-Injection .Management
`
`Gloves and Draping
`
`GUIDELINE: 1) As part of universal infection con(cid:173)
`trol practice, gloves are appropriate; 2) Draping may
`be employed but is not essential.
`
`Evidence.for Guideline.-- The use of gloves has been
`associated with a reduced risk of nosocomial infec(cid:173)
`tions i.n controlled trials. TI1ere are no controlled data
`confi.1111.ing the efficacy of wearing gloves in reducing
`the risk of i.nfection following IVT injection, but this
`is a reasonable extrapolation of the use of gloves in
`infection control practice. The association between
`draping of the eyelids and eye lashes and prophylaxis
`against postinjection infection is not well established,
`although this is a common practice at many institu(cid:173)
`t ions. Clinicians should consider draping optional.
`
`Novartis Exhibit 2020.006
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`EVOLVING GUIDELINES FOR INTRAVITREOUS INJECTIONS co AIELLO Ef AL
`
`S9
`
`Discussion.- Cunningham: In Eyetech Phannaceuti(cid:173)
`cals protocols for ongoing studies, investigators arc
`requi:red to use gloves to perfo1m IVT injection. The
`use of gloves in the protocols is considered to be part
`of good clinical practice.
`D 'Amico: I like to put on gloves. In the presence of
`the patient, it shows the pat ient that this is an operative
`procedure.
`Cunningham: Opinions regarding the use of a ster(cid:173)
`ile drape before IVT injections vary widely. The Eye(cid:173)
`tech protocols require both the use of a sterile drape
`and an eyelid speculum to help hold the lashes away
`from the surgical field. We provided small drapes to
`cover the eyelids only, which were generally well(cid:173)
`tolerated by the patients.
`Ta: One benefit of a lid drape is that it requires the
`physician and the staff to treat IVT injection as a
`serious procedure, and that is its greatest benefit. It
`helps practitioners to be more attentive in keeping the
`evelashe.s a\vav from the injection.
`, Chang: Usi;1g the drape depends on the eye of the
`patient ~nd on the person injecting. If the patient is
`cooperative and the injection can be done in 10 sec(cid:173)
`onds, [ don't think you need the drape. But in the real
`world there are going to be patients who will squee.ze as
`soon as you put the speculum in. This may result in a 2-
`or 3-minute delay, and during that time period, with the
`patient squeezing, bacteria can get into the eye.
`
`Preoperative Antibiotics
`
`GUIDELLVE: The physicia11 may consider using
`preoperative antibiotics at his or her discretion.
`Evidence for this Gutdeline.- In the absence of con(cid:173)
`trolled data to evaluate the risks or benefits of preop(cid:173)
`erative topical antibiotics, physician discretion is ad(cid:173)
`vised. While topical antibiotics clearly lower the
`number of bacteria that can be cultured from the eye
`lashes, the eyelid margins, and conjunctiva, there is no
`direct evidence that topical antibiotics lower the rate
`of endophthalmitis. If physicians choose to use pro(cid:173)
`phylactic antibiotics, antibiotics should be selected
`appropriately according to their likely coverage of
`potential pathogens, their tolerability, and their cost
`There are no randomized prospective trials, and data
`are often conflicting.
`CAVEAT: Some dala support use of preinfection
`use of antibiotics.
`While a review of the data 14 indicates that evidence
`for using prophylactic interventions, including pre(cid:173)
`operative topical antibiotics and antibiotic-conta in(cid:173)
`ing irrigating solutions, is weak and often conflict(cid:173)
`ing, S<)mc evi.dencc supports the use of prcinjcction
`use of antibiotics.
`
`Table 1. Sensitivity of Gram-Positive Organisms
`
`Antibiotic
`
`Vancornycin
`Gentamicin
`Ciprofloxacin
`Ceftazidime
`Cefazolin
`
`Adapted from Benz MS et al.' 5
`
`Sensitivity
`
`100%
`78.4%
`68.3%
`63.6%
`66.8%
`
`Although no single antibiotic is effective against the
`broad spectrum of organisms known to cause endoph(cid:173)
`thalmitis, vancomycin is usually effective against gram(cid:173)
`positive organisms, ·while amikacin and ceftazidime are