INCREASED INCIDENCE OF STERILE
`ENDOPHTHALMITIS AFTER
`INTRA VITREAL TRIAMCINOLONE
`ACETONIDE IN SPRING 2006
`
`KIMBERLY E. STEPIEN, MD,* ALEXANDER M. EATON, MD,t
`GLENN J. JAFFE, MD,+ JANET L. DA VIS, MD,* JUNAID RAJA, BS,:I:
`WILLIAM FEUER, MS*
`
`Purpose: To compare the incidence of sterile endophthalmitis after intravitreal triam(cid:173)
`cinolone acetonide injections during a 6 month period in 2006 to the same period in 2005
`and determine the incidence after switching to intravitreal preservative-free triamcinolone
`acetonide.
`Methods: Retrospective multicenter interventional case series in which patients receiv(cid:173)
`ing intravitreal triamcinolone acetonide at three institutions from March 2005 to August
`2005 and from March 2006 to August 2006 and intravitreal preservative-free triamcinolone
`acetonide from late summer 2006 through February 2007 were reviewed for the develop(cid:173)
`ment of sterile endophthalmitis.
`Results: From March 2005 to August 2005, the rate of sterile endophthalmitis was 0%
`at all institutions. From March 2006 to August 2006, a statistically significant increase in
`sterile endophthalmitis was seen at all institutions with frequencies of 3.5% to 6.3% (P <
`0.001 ). With transition to preservative-free triamcinolone acetonide, sterile endophthalmitis
`over the next 6 months decreased to 0% at two sites and to 2.5% (from 5.5%) at the third
`institution (P < 0.009).
`Conclusions: A statistically significant increase in the rate of sterile endophthalmitis
`after intravitreal triamcinolone acetonide was seen in a 6 month period in 2006 when
`compared with the same period in 2005. Transition to preservative-free triamcinolone
`acetonide produced a frequency of sterile endophthalmitis similar to 2005.
`RETINA 29:207-213, 2009
`
`I ntravitreal triamcinolone acetonide (TA) is rou(cid:173)
`
`tinely used in the treatment of macular edema from
`various conditions including venous occlusive dis(cid:173)
`ease, refractory diabetic macular edema, uveitis, and
`cystoid macular edema. 1- 4 Additionally, intravitreal
`TA is used as an adjunctive therapy in the treatment of
`
`proliferative diabetic retinopathy and age-related mac(cid:173)
`ular degeneration. 5,6 Increased intraocular pressure
`and cataract progression are the most common adverse
`effects associated with intravitreal TA.7 Other rarer
`complications include retinal detachment, vitreous
`hemorrhage, pseudohypopyon, and endophthalmitis.
`
`From the *Bascom Palmer Eye Institute, University of Miami
`School of Medicine, Miami; tRetina Health Center, Fort Myers,
`Florida; and +Duke University Eye Center, Duke University Med(cid:173)
`ical Center, Durham, North Carolina.
`Supported by an unrestricted grant from Research to Prevent
`Blindness and NEI Core Center Grant P30 EY014801.
`
`No author has any proprietary interests.
`Presented at the American Academy of Ophthalmology Meet(cid:173)
`ing, New Orleans, LA, November 2007.
`Reprint requests: Alexander M. Eaton, MD, Retinal Health Cen(cid:173)
`ter, 1567 Hayley Lane, Suite 101, Fort Myers, FL 33907; e-mail:
`ame@retinaliealthcenter.com
`
`Copyright© by Ophthalmic Communications Society, Inc. Unauthorized reproduction of this article is prohibited.
`
`207
`
`Novartis Exhibit 2293.001
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`208
`
`RETINA, THE JOURNAL OF RETINAL AND VITREOUS DISEASES • 2009 • VOLUME 29 • NUMBER 2
`
`Additionally, charts of all patients who received in(cid:173)
`travitreal PFT A from August or early September 2006
`through February 2007 were reviewed. Patients who
`received intravitreal TA as an adjunct to a surgical
`procedure or who had undergone a surgical procedure
`within the 30 days preceding injection were excluded
`from the study.
`Patients were included in the study if they experi(cid:173)
`enced symptoms of sterile endophthalmitis within 7
`days of injection. Sterile endophthalmitis was defined
`as presence of inflammation in the anterior chamber
`and/or vitreous cavity within 7 days after intravitreal
`TA or PFT A with the absence of organisms on gram
`stain and negative intraocular cultures, if obtained. If
`cultures were not obtained, patients were defined as
`having sterile endophthalmitis if there was clearance
`of inflammation and improvement in vision with no
`treatment or with only topical medication treatment
`within the next 30 days. Clinical exam findings, ocular
`history, indication for intravitreal TA or PFTA, time
`to presentation and treatment were recorded.
`Injections of intravitreal TA or PFT A were per(cid:173)
`formed by multiple physicians at all sites. Injections
`were performed according to accepted techniques 14
`and included topical or subconjunctival anesthesia un(cid:173)
`der aseptic technique, disinfection by instillation of
`5% povidone-iodine in the conjunctiva! sac, and a
`sterile lid speculum. Four milligrams of TA in 0.1 mL
`was injected into the vitreous cavity 3.5 to 4 mm
`posterior to the limbus. In the spring of 2005 and
`2006, single-use vials of Kenalog-40 (Bristol-Myers
`Squibb, Princeton, NJ) were used at all three sites.
`Kenalog-40 contains 0.99% benzyl alcohol, 0.75%
`carboxymethylcellulose sodium, and 0.04% polysor(cid:173)
`bate 80 for buffering and isotonicity. Supernatant was
`neither routinely removed from the TA, nor was the
`TA filtered. Perfusion and intraocular pressure were
`monitored after injection. Patients were instructed to
`use a topical antibiotic 3 to 4 days after the procedure
`at all three sites.
`PFTA (New England Compounding Pharmacy,
`Framingham, MA) was injected in an identical man(cid:173)
`ner after summer 2006 at two sites (BPEI and Duke).
`One site (Retinal Health Center) removed supernatant
`from the PFTA before injection. Crystals of PFTA
`were allowed to precipitate out in the syringe against
`the plunger and clearer supernatant was discarded
`before injection. This was done to reduce the amount
`of any other substance other than triamcinolone from
`the injection.
`Upon presentation with signs of sterile endoph(cid:173)
`thalmitis, patients were treated according to the dis(cid:173)
`cretion of their physician. Patients were either closely
`observed with or without topical corticosteroid and/or
`
`Fig. 1. Sixty-eight year old female presenting with sterile endoph(cid:173)
`thalmitis 48 hours after an intravitreal injection of triamcinolone ace(cid:173)
`tonide. Vision had decreased to hand motions from 20/300. A vitreous
`tap with injection of intravitreal antibiotics was preformed. Cultures
`were negative. Vision returned to baseline 5 days after initial injection.
`
`Noninfectious or sterile endophthalmitis has been re(cid:173)
`ported after intravitreal TA.8 - 13 Patients present with an
`acute inflammatory reaction shortly after injection (Fig(cid:173)
`ure 1 ). In most cases, visual acuity is significantly de(cid:173)
`creased but patients rarely complain of pain or discom(cid:173)
`fort. Cultures, if taken, are negative and most patients
`improve quickly with good visual prognosis. Whether
`sterile endophthalmitis is an inflammatory reaction to the
`drug or its vehicle or if it represents a true infection with
`negative cultures remains unclear. Rates of sterile en(cid:173)
`dophthalmitis have been reported from 0.87% to 7.3%.8,9
`In the spring of 2006, the authors noted an increas(cid:173)
`ing occurrence of sterile endophthalmitis in their prac(cid:173)
`tices and switched to intravitreal compounded preser(cid:173)
`vative-free triamcinolone acetonide (PFTA) towards
`the end of summer of 2006. Herein, we determined the
`incidence of sterile endophthalmitis after intravitreal
`TA during a 6 month period in 2006 to the same time
`period in 2005. Additionally, we examined the inci(cid:173)
`dence of sterile endophthalmitis after switching to
`intravitreal PFT A.
`
`Methods
`
`This multicenter retrospective review was carried
`out at three clinical centers (Bascom Palmer Eye In(cid:173)
`stitute, University of Miami, Miami, FL; Duke Uni(cid:173)
`versity Eye Center, Duke University Medical Center,
`Durham, NC; Retina Health Center, Fort Myers, FL)
`after receiving Institutional Review Board approval.
`The sites were selected because of large volume of
`intravitreal TA done by multiple physicians at these
`locations, increasing sample size and reducing bias.
`Charts of all patients who received intravitreal TA
`between March to August 2005 and March to August
`2006 as identified by ICD-9 codes were reviewed.
`
`Novartis Exhibit 2293.002
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`INCREASED INCIDENCE OF STERILE ENDOPHTHALMITIS • STEPIEN ET AL
`
`209
`
`Table 1. Sterile Endophthalmitis After lntravitreal Triamcinolone Acetonide (March 2006-August 2006) Patient
`Characteristics
`
`Patient Age Lens
`(yrs) Status
`No.
`
`Time to
`Indication
`For IVTA Presentation (h) Hypopyon
`
`Treatment
`
`Past Ocular History
`
`Return to
`Initial VA
`
`1
`2
`3
`4
`5
`6
`7
`8
`9
`10
`11
`12
`13
`14
`15
`16
`17
`18
`19
`20
`21
`22
`23
`
`24
`
`25
`26
`27
`
`72 PCIOL cme
`68 ACIOL cme
`67 PCIOL cme/dme
`79 PCIOL dme
`NR PCIOL cme
`78 PCIOL cme/amd
`77 PCIOL cme
`76 PCIOL cme
`59 PCIOL hypotony
`NR PCIOL cme
`55 PCIOL uveitic cme
`76 Phakic cme
`48 PCIOL cme
`47 Phakic cme
`NR Phakic dme
`NR Phakic uveitic cme
`58 PCIOL cme
`57 PCIOL cme
`91 PCIOL brvo
`100 PCIOL amd
`74 PCIOL erm
`57 PCIOL cme
`54 PCIOL cme
`
`46 PCIOL uveitic cme,
`hypotony
`58 PCIOL cme
`NR PCIOL cme
`51 Phakic uveitic cme
`
`12-24
`48-72
`12-24
`72-96
`24-48
`48-72
`24-48
`24-48
`24-48
`24-48
`12-24
`12-24
`24-48
`48-72
`24-48
`12-24
`12-24
`12-24
`>96
`24-48
`72-96
`24-48
`12-24
`
`>96
`
`24-48
`48-72
`12-24
`
`Yes
`Yes
`Yes
`Yes
`Yes
`No
`Yes
`Yes
`Yes
`No
`Yes
`No
`Yes
`Yes
`No
`No
`Yes
`Yes
`No
`No
`No
`Yes
`Yes
`
`No
`
`Yes
`No
`Yes
`
`gtts
`Yes
`trauma
`tap & inj
`Yes
`pseudophakic cme
`tap & inj
`Lost to F/U
`dme/cme
`gtts
`Yes
`dme
`gtts
`Yes
`rd repair retinoschisis
`Yes
`amd
`gtts
`nvg, crvo
`gtts
`Yes
`coag pseudophakic cme Yes
`gtts
`trauma, rd repair
`gtts
`No
`ppv-scheduled sickle cell retinopathy
`Yes
`tap & inj
`uveitic cme
`No
`gtts
`post op ppv
`No
`gtts
`trauma, rd repair
`Yes
`gtts
`post op ppv
`Yes
`gtts
`dme
`Yes
`gtts
`uveitic cme
`Yes
`gtts
`rd repair
`Yes
`tap & inj
`rd repair
`No
`gtts
`brvo
`Yes
`tap & inj
`amd
`Yes
`gtts
`erm
`Yes
`tap & inj
`post op cme
`No
`tap & inj
`macular translocation
`Yes
`surgery, POHS
`uveitis, hypotony
`
`gtts
`
`Yes
`
`tap & inj
`diamox
`gtts
`
`Yes
`coag, post op trab
`retinal degeneration, cme Yes
`uveitis
`Lost to F/U
`
`VA, visual acuity; PCIOL, posterior chamber intraocular lens; ACIOL, anterior chamber intraocular lens; NR, not recorded; cme, cystoid
`macular edema; dme, diabetic macular edema; amd, age-related macular edema; rd, retinal detachment; nvg, neovacular glaucoma;
`brvo, branch retinal vein occlusion; crvo, central retinal vein occlusion; trab, trabeculectomy; erm, epiretinal membrane; POHS,
`presumed ocular histoplasmosis; coag, chronic open angle glaucoma; ppv, pars plana vitrectomy; gtts, topical medication drops; tap
`& inj, tap and injection; F/U, follow-up.
`
`antibiotic drops or underwent a vitreous tap with in(cid:173)
`travitreal antibiotics. In one case, a patient underwent
`a pars plana vitrectomy; however, this procedure was
`previously scheduled before the injection as a result of
`other retinal pathology. Patients were then followed at
`intervals determined by their treating physician.
`A vial of Kenalog-40 from the same lot as a vial
`known to cause a case of sterile endophthalmitis in a
`patient in this study was forwarded to Arjun Srinivasan,
`MD, at the Centers for Disease Control and Prevention,
`Atlanta, GA and tested for the presence of endotoxin.
`Statistical analysis was performed with the exact Man(cid:173)
`tel-Haenszel chi-square test, stratifying by clinic.
`
`Results
`
`In the 6 month period between March 2005 and
`August 2005, 445 injections of intravitreal TA were
`performed and no cases of sterile endophthalmitis
`
`were identified. From March 2006 to August 2006,
`532 injections were performed and 27 cases of sterile
`endophthalmitis occurred. Use of PFT A began in late
`August-early September 2006 at all three sites. A
`total of 308 intravitreal PFT A injections were admin(cid:173)
`istered through February 2007 and four cases of sterile
`endophthalmitis were found.
`Twenty-seven eyes of 27 patients developed sterile
`endophthalmitis after an intravitreal injection of TA
`during the period of March to August 2006 (Table 1).
`The rate of sterile endophthalmitis after intravitreal
`TA was 6.3% at Retinal Health Center, 5.5% at Bas(cid:173)
`com Palmer Eye Institute, and 3.5% at Duke Univer(cid:173)
`sity Eye Center. This increase was found to be statis(cid:173)
`tically significant when compared with the same time
`period I year previous (P < 0.001) (Figure 2). The
`rate of sterile endophthalmitis with data combined
`from all three sites was 5.1 %, which was statistically
`
`Copyright© by Ophthalmic Communications Society, Inc. Unauthorized reproduction of this article is prohibited.
`
`Novartis Exhibit 2293.003
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`210 REnNA, THE JOURNAL OF REnNAL AND VITREOUS DISEASES• 2009 • VOLUME 29 • NUMBER 2
`
`Number of
`Cases
`
`20
`
`18
`
`16
`
`14
`
`12
`
`10
`
`8
`
`6
`
`4
`
`2
`
`0
`
`5.5%
`
`□ Retina Health Center
`m Bascom Palmer
`
`■ Duke
`
`Fig. 2.
`Incidence of sterile
`endophthalrnitis by site.
`
`0%
`
`0%
`
`0%
`
`TA - March 2005-
`August2005
`
`TA - March 2006-
`August 2006
`
`PFTA - Late Summer
`2006- February 2007
`
`Time periods
`
`TA - Triamcinolone Acetonide, PFTA - Preservative-free Triamcinolone Acetonide
`
`significant (P < 0.001). Ages ranged from 46 to 100
`years old and there were 13 males and 14 females.
`One patient had an anterior chamber intraocular lens,
`21 patients had a posterior chamber intraocular lens
`and 5 were phakic. Treatment with intravitreal TA
`was given for cystoid macular edema in 19 patients,
`four of whom had uveitic cystoid macular edema, for
`diabetic macular edema in three patients, for age(cid:173)
`related macular degeneration in two patients, and for
`an epiretinal membrane, a branch retinal vein occlu(cid:173)
`sion and hypotony in one patient each. Hypopyons
`were present in 17 eyes at presentation. Anterior
`chamber inflammation could be seen in 26 eyes and
`greater than 1 + vitreous haze was noted in 26 eyes.
`Seventeen eyes were treated with close observation
`and topical medications, eight patients underwent vit(cid:173)
`reous tap with intravitreal antibiotic injection, one
`patient was treated with topical medications and then
`underwent a pars plana vitrectomy with epiretinal
`membrane removal 4 days after injection as was pre(cid:173)
`viously scheduled before the injection, and one patient
`with retinal degeneration was followed with close
`observation and continuation of oral acetazolamide.
`All gram stains and cultures obtained were negative.
`Twenty of the patients returned to at least preinjection
`
`visual acuity, five patients did not return to preinjection
`vision and two patients were lost to follow-up. In those
`five patients whom preinjection vision was not obtained,
`their poorer vision was thought to be due to their under(cid:173)
`lying ocular pathology and not inflammatory causes.
`One vial of Kenalog-40 from the same lot as a vial
`that had caused a sterile endophthalmitis reaction in a
`patient in our study was forwarded to the Centers for
`Disease Control and Prevention and tested by Dr.
`Arjun Srinivasan for presence of an endotoxin. Levels
`in the sample were found to be negative to less than 2
`EU/mL which is the lowest level that can be detected
`in a solution of TA. The Food and Drug Association
`has set a limit of 0.5 EU/mL for endotoxins in inject(cid:173)
`able solutions. However, because of its opacities, the
`solution of TA can only be analyzed accurately for the
`presence of endotoxins to levels of 2 EU/mL. (Arjun
`Srinivasan, personal communication).
`In late August 2006 or early September 2006, all
`three sites began using PFTA. Two of the three sites
`had no further cases of sterile endophthalmitis during
`the next 6 month period. One site had four cases of
`sterile endophthalmitis in 4 eyes of 4 patients or a rate
`of 2.5% at this institution (Table 2). This site pre(cid:173)
`formed 53% of the reviewed injections with PFTA
`
`Table 2. Sterile Endophthalmitis After Preservative-Free Triamcinolone Acetonide Patient Characteristics
`
`Patient
`No.
`28
`29
`30
`31
`
`Age
`(yrs)
`
`77
`58
`73
`71
`
`Lens
`Status
`
`PCIOL
`PCIOL
`PCIOL
`PCIOL
`
`Indication
`For IVTA
`
`cme
`cme
`cme
`cme
`
`Time to
`Presentation (h) Hypopyon
`48-72
`24-48
`24-48
`24-48
`
`No
`Yes
`No
`Yes
`
`Treatment
`
`Past Ocular
`History
`
`Return to
`Initial VA
`
`gtts
`gtts
`gtts
`gtts
`
`coag brvo
`angioma, rd repair
`rd repair
`rd repair
`
`Yes
`No
`No
`Yes
`
`PCIOL, posterior chamber intraocular lens; cme, cystoid macular edema; gtts, topical medication drops; coag, chronic open angle
`glaucoma; brvo, branch retinal vein occlusion; rd, retinal detachment; IVTA, intravitreal triamcinolone acetonide; VA, visual acuity.
`
`Copyright© by Ophthalmic Communications Society, Inc. Unauthorized reproduction of this article is prohibited.
`
`Novartis Exhibit 2293.004
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`INCREASED INCIDENCE OF STERILE ENDOPHTHALMITIS • STEPIEN ET AL
`
`211
`
`and did not remove supernatant before injection with
`PFf A. The reduction in sterile endophthalmitis was
`statistically significant (P = 0.009) when compared
`with the previous 6 month period from March 2006 to
`August 2006. When compared with the March to
`August 2005 time period, this increase with PFT A
`was statistically significant (P = 0.013). Ages ranged
`from 58 to 77 years and there were two males and two
`females. All patients had posterior chamber intraocu(cid:173)
`lar lens and all had received treatment for cystoid
`macular edema. All presented within 24 to 72 hours
`after injection with symptoms. Hypopyons were
`present in two of the patients. Three of four patients
`had anterior chamber cell and significant vitreous haze
`was present in three of the four patients. All were
`followed with close observation and topical medica(cid:173)
`tions. Half regained preinjection vision. All four pa(cid:173)
`tients had undergone previous intraocular surgery with
`three having retinal detachment repair and one with
`recent glaucoma surgery.
`
`Discussion
`
`Intravitreal TA is used to treat retinal pathology of
`many etiologies.1- 6 Endophthalmitis is a potential
`complication of intravitreal TA and has been described
`in three forms; infectious endophthalmitis, noninfectious
`or sterile endophthalmitis, and pseudoendophthalmitis.
`Patients with acute infectious endophthalmitis present
`with decreased vision and pain at a median of 7 .5 days
`after intravitreal T A. 15 This devastating complication
`usually has a prolonged recovery time, poorer visual
`outcomes and is estimated to occur at an incidence of
`0.43% to 0.87%. 11 ,15 In contrast, pseudoendoph(cid:173)
`thalmitis is caused by migration of TA crystals into
`the anterior chamber, not infection. Patients present
`with no pain, minimal visual symptoms and are more
`likely to be pseudophakic or aphakic with a peripheral
`iridotomy. Symptoms resolve without treatment and
`within a few days.16•17
`Patients with noninfectious or sterile endophthalmi(cid:173)
`tis present with an acute inflammatory reaction shortly
`after injection of intravitreal TA or PFf A. Visual
`acuity is usually significantly decreased but patients
`rarely complain of pain or discomfort. Cultures, if
`taken, are negative. Patients improve quickly with
`good visual prognosis. Sterile endophthalmitis rates
`have been reported from 0.87% to as high as 7 .3% as
`reported by Maia et al. 8,9 It should be noted that
`patients in the study reported by Maia et al received
`intravitreal TA from two different manufacturers,
`Ophthalmos Laboratories, San Paulo, Brazil and Bris(cid:173)
`tol-Myers Squibb, Princeton, NY.9 Patients in this
`
`study were treated with intravitreal TA from Bristol(cid:173)
`Myers Squibb only.
`There are several possible explanations for the inflam(cid:173)
`matory changes associated with sterile endophthalmitis
`we observed in the present study. The commercially
`prepared TA, Kenalog-40, has 0.99% benzyl alcohol,
`0.75% carboxymethylcellulose sodium, and 0.04% poly(cid:173)
`sorbate 80 in its suspension and is buffered with so(cid:173)
`dium hydroxide or hydrochloric acid to a pH of 5.0 to
`7.5. Benzyl alcohol is a bacteriostatic preservative that
`has been theorized to be a potential cause of an in(cid:173)
`flammatory response, prompting some providers to
`decant supernatant or filter the TA before injec(cid:173)
`tion.18,19 Sterile endophthalmitis can still occur, how(cid:173)
`ever, as Carrero et al recently reported sterile endoph(cid:173)
`thalmitis cases despite removal of 90% of benzyl
`alcohol by filtration before injection.20 The role of pH
`of the intravitreal solution is uncertain. Although the
`range of pH in Kenalog-4O is broad, nonphysiologic
`pH is present in some approved intravitreal medica(cid:173)
`tions such as ranibizumab (Lucentis, Genentech, Inc.,
`South San Francisco, CA) which has a pH of 5.5.21
`The preservative-free formulation of triamcinolone
`uses United States Pharmacopeia micronized triam(cid:173)
`cinolone suspended in a buffered polyethylene glycol
`solution. Although cases of sterile endophthalmitis still
`occurred in our study after treatment with preservative
`free triamcinolone, rates were lower. Sterile endoph(cid:173)
`thalmitis has also been reported after PFf A by Maia et
`al.9 As sterile endophthalmitis can occur despite removal
`of almost all benzyl alcohol20 or in preservative-free
`formulations,9 it is unlikely that the preservative is the
`sole cause of sterile endophthalmitis.
`Sterile solutions can contain bacterial endotoxins
`that may incite an inflammatory response. An epi(cid:173)
`demic outbreak of diffuse lamellar keratitis after
`LASIK was found to be caused by endotoxins released
`by gram negative biofilms in a sterilizer.22 A bacterial
`endotoxin contaminant could persist in the vehicle or
`vial of a drug and induce an inflammatory response,
`despite preparation of the drug under sterile condi(cid:173)
`tions. One vial of Kenalog-4O from the same lot as a
`vial that had caused a sterile endophthalmitis reaction
`in a patient in our study was forwarded to the Centers
`for Disease Control and Prevention and was found to
`be negative for endotoxin to the extent of detection in
`an opaque solution; however, this level is still higher
`than the limit set by the Food and Drug Association
`for injectable solutions (Arjun Srinivasan, personal
`communication). If endotoxins were the cause of ster(cid:173)
`ile endophthalmitis, one would expect cases to be
`clustered nearer to each other as medications from the
`same lots or lots produced close together were used.
`As all three centers were located in the southeast, it is
`
`Copyright© by Ophthalmic Communications Society, Inc. Unauthorized reproduction of this article is prohibited.
`
`Novartis Exhibit 2293.005
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`212
`
`REnNA, THE JOURNAL OF REnNAL AND VITREOUS DISEASES• 2009 • VOLUME 29 • NUMBER 2
`
`possible that all three sites were receiving product
`from the same lot or lots manufactured very close to
`each other. This could explain the increased incidence
`seen between the two 6 month periods in which IVT A
`was used in our study. A similar clustering of cases
`was reported by Roth et al in which seven cases of
`sterile endophthalmitis occurred within a 5 week pe(cid:173)
`riod between January 16, 2002 and February 19th,
`2002.23 Although lot numbers were not noted as part
`of this study, one author (AME) can confirm that his
`patients who developed sterile endophthalmitis did
`receive intravitreal TA from different lots.
`It is interesting that the majority of eyes in this
`study (30 of 31 identified) that developed sterile en(cid:173)
`dophthalmitis had a history of ocular surgery and/or
`uveitis. Patients with a history of uveitis, vitrectomy,
`or are pseudophakic may have an increased incidence
`of sterile endophthalmitis. 13,23 It is possible that in
`patients with a history of ocular surgery, toxins have a
`more direct access to ocular tissue, allowing a more
`acute inflammatory response to develop.23 Inflamma(cid:173)
`tory response seen in patients with a history of uveitis
`may be a result of immune hyperactivity. 13 The pa(cid:173)
`tients' history of ocular surgeries could have allowed
`more direct exposure of the TA and its vehicle to
`ocular tissue, increasing the likelihood of an inflam(cid:173)
`matory response. A history of inflammation may pre(cid:173)
`dispose the patient to increased immune hyperactivity
`that make them more susceptible to subtle changes in
`the formulation of the triamcinolone or its vehicle.
`The four patients in our study who developed sterile
`endophthalmitis after
`treatment with
`intravitreal
`PFTA had complicated ocular histories including in(cid:173)
`traocular surgery which could have made them very
`sensitive to any toxin that they come into contact due
`to increased immune hyperactivity and/or increased
`exposure of a toxin to ocular tissue.
`So what caused the increased incidence of sterile
`endophthalmitis in 2006 as found in our review? It is
`possible that the mechanism is multifactorial. The
`most likely explanation is that there was a change in
`the formulation or in the manufacturing of Kenalog-40
`that induced the inflammatory response. The presence
`of an endotoxin may have contributed to the develop(cid:173)
`ment of sterile endophthalmitis in these patients, al(cid:173)
`though this could not be confirmed. These patients
`may also have been predisposed to developing an
`inflammatory response due to their history of ocular
`surgery and/or uveitis. It is possible that the cohort
`receiving
`intravitreal
`triamcinolone from March
`through August of 2006 might have had more com(cid:173)
`plicated ocular histories than the cohort from the same
`time period in 2005, making them more predisposed
`
`to developing sterile endophthalmitis after intravitreal
`TA. The exact cause remains unknown.
`In summary, this study confirms that an increased
`incidence of sterile or noninfectious endophthalmitis
`after intravitreal TA occurred in March to August of
`2006 when compared with the same time period 1 year
`earlier. In our experience, switching to compounded
`PFTA significantly decreased the incidence of sterile
`endophthalmitis to rates similar to spring 2005. It is
`unclear if PFTA is less likely to cause an inflamma(cid:173)
`tory response than intravitreal TA with preservatives.
`A proinflammatory lot or lots in spring of 2006 cannot
`be excluded but other factors may also contribute to
`the development of sterile endophthalmitis. Clinicians
`who opt for off-label use of commercially available
`TA should be aware of potential for variation in lots of
`TA, especially in patients with risk factors for devel(cid:173)
`oping sterile endophthalmitis. PFTA may reduce the
`risk of developing sterile endophthalmitis; however,
`clinicians must also consider potential risks of infec(cid:173)
`tious endophthalmitis from preservative-free suspen(cid:173)
`sions. This retrospective review supports the need for
`further study of different formulations of TA and their
`potential risks of sterile and infectious endophthalmitis.
`Key words: glucocorticoids, intravitreal injections,
`macular edema, noninfectious endophthalmitis, retinal
`diseases, retrospective, sterile endophthalmitis, triam(cid:173)
`cinolone acetonide.
`
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`Copyright© by Ophthalmic Communications Society, Inc. Unauthorized reproduction of this article is prohibited.
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`Novartis Exhibit 2293.006
`Regeneron v. Novartis, IPR2021-00816
`
`

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`Copyright© by Ophthalmic Communications Society, Inc. Unauthorized reproduction of this article is prohibited.
`
`Novartis Exhibit 2293.007
`Regeneron v. Novartis, IPR2021-00816
`
`