Clinical Ophthalmology
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`REVIEW
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`Prefilled syringes for intravitreal drug delivery
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`This article was published in the following Dove Medical Press journal:
`Clinical Ophthalmology
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`
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`T h é r‘é S e M S a S sal O S I
`Yan n is M Pau I u s l -2
`
`Abstract: [ntravitreal injections of anti-vascular endothelial growth factor (VEGF) medications
`play an increasingly critical role in numerous retinal vascular diseases. initially, anti-VEGF
`
`'Department of Ophthalmology
`and Visual Sciences,W.K. Kellogg
`Eye Center, UniverSltY 0f MlChlganv
`Ann Arbor, MI, USA; 2Department of
`Biomedical Engineering, University
`of Michigan,Ann Arbor, MI, USA
`
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`medications came in Vials that had to be drawn up by the phySiCian into a syringe for admims-
`tration. In 2018, the US Food and Drug Administration (US FDA) approved tie ranibizumab
`
`0.3 mg prefilled syringe (PFS), and in October 2016, the US FDA approved tie ranibizumab
`0.5 mg PFS. This article discusses the advantages of the PFS, including reduced injection time,
`possible reduced risk of endophthalmitis, reduction in intraoeular air bubbles and silicone oil
`droplets, and improved precision in the volume and dose ofintravitreal ranibiztu‘nab administered,
`along with possible disadvantages. implications of the innovation of the PFS on intravitreal
`injection technique and clinical practice pattern are discussed and reviewed.
`Keywords: intravitreal injection, intravitreous injection, anti—VEGF, ranibizumab, prefilled
`syringe, diabetic retinopatliy
`
`Introduction
`
`The advent and ubiquity of anti-vascular endothelial growth factor (anti-VEGF)
`injections have led intravitreal injections to become an increasingly common and
`effective method of delivering many types of medications into the vitreous cavity.l
`Anti—VEGF medications are designed to bind to and inhibit VEGF, which is thought
`to play a critical role in the formation of new blood vessels and vascular permeability
`of these vessels. The number of intravitreal injections being performed is increasing
`at epidemic proportions, with over 4 million intravitreal injections performed in the
`USA in 2013 and rising to an estimated 5.9 million patients receiving intravitreal
`injections in 2016 in the USA.2 Anti-VEGF injections have become a cornerstone in
`the treatment of retinal diseases.
`
`Furthennore, randomized clinical trials have demonstrated the efficacy of anti-
`VEGF intravitreal injections in the treatment of retinal diseases including exudative
`age—related macular degeneration, diabetic retinopathy, and retinal vein occlusions?7
`In these studies, patients demonstrated the efficacy of anti-VEGF therapy not only in
`avoiding visual loss but also in improving visual acuity}11
`There are currently three anti-VEGF agents commonly used in retina practices
`in the USA: Avastin® (bevacizumab; Genentech, Inc., South San Francisco, CA,
`
`USA), Lucentis® (ranibizumab; Genentech, inc), and Eylea® (aflibercept; Regeneron,
`
`Tarrytown, NY, USA). In March 2018, the US Food and Drug Administration (US
`Correspondence: Yannis M Paulus
`FDA) approved the ranibizumab 0.3 mg prefilled syringe (PFS) as a new method of
`Department of Ophthalmology and Visual
`Sciences, W.K. Kellogg Eye Center,
`administering intravitreal injections for the treatment of diabetic retinopathy and dia-
`University of Michigan,
`IOOO Wall Street,
`betic macular edema.”13 The ranibizumab 0.5 mg PFS was cleared by the US FDA in
`Ann Arbor, MI 48 I 05, USA
`.
`.
`.
`.
`.
`.
`Tl+|7347644l82
`2016. This PFS (Figure l) is packaged in a Single-use, sealed sterile tray, thus allow-
`F; H 734 936 38 I 5
`Email ypaulus@med.umich.edu
`ing physicians to eliminate a number of steps in the preparation and administration
`
`
`70'
`Clinical Ophthalmology 20l9:l3 70l—706
`“mm" l’m‘”“‘*""’9"“PL
`© 10” lassalos and Paulus.This work is published and licensed by Dove Medical Press Limitedlhe lull terms at this litense are available at littpsa’lwwwdovepress.com/teiriis.php
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`Figure I Photograph of ranibizumab PFS,
`Abbreviation: PFS, prefilled syringe.
`
`of intravitreal ranibizumab. This review summarizes the
`literature on the administration of ranibizumab via the PFS
`
`and the implications of this innovation on intravitreal injec-
`tion technique and clinical practice pattern (Table 1).
`
`Ranibizumab PFS injection technique
`and ease of administration
`
`Typical ranibizumab injection setup requires the physician/
`assistant to remove the vial cap, disinfect the drug vial top
`often with an isopropyl alcohol 70% swab, attach a filter
`needle to a sterile syringe, draw the medication into a sterile
`syringe, remove the filter needle, replace this needle with a
`smaller gauge sterile injection needle (often a 30 G or 32 C
`1/2 inch needle), remove air bubbles, and adjust the volume
`of the medication prior to administration. In contrast, the
`ranibizumab 0.3 mg PFS is made of borosilicate glass and
`is packaged in a single-use, scaled sterile tray. Therefore,
`using the PFS, the physician simply removes the syringe
`cap, attaches the injection needle, and adjusts the dose prior
`
`Table I Overview of the advantages and disadvantages of the
`PFS for intravitreal drug delivery
`Characterization of
`Proposed advantages]
`disadvantages
`evidence
`Reduced injection time Strongly supportive
`
`
`Reduction in endophthalmitis risk Theoretical
`Reduction in intraocular air bubbles
`Theoretical, of possible
`
`and silicone oil droplets clinical significance
`Accuracy and precision of intravitreal
`Supportive
`ranibizumab doses
`
`
`Theoretical
`Disadvantages of a sterile syringe/
`drug assembly
`Abbreviation: PFS, prefil led syringe.
`
`to administration. Retina specialists and ophthalmic medical
`personnel have successfully performed both simulated-use
`and actual—use usability studies (with the PFS) with reported
`ease and without any critical errors. ‘4 Reduction in these steps
`in the administration of intravitreal injections comes With
`some advantages which are detailed in the following sections.
`
`Reduced injection time
`By eliminating a number of steps in the previous injection
`preparation, reduced injection time is a significant advantage
`to using the ranibiz umab PFS. Souied et al15 demonstrated a
`270/073 9% reduction in syringe preparation time when using
`the PFS rather than the standard ranibizumab vial. Likewise,
`a previous multicenter study comparing preparation times
`using traditional syringes vs the PF S revealed that the use
`of a PFS saved an average of 25.5 seconds.16 Although this
`figure may appear modest when considering a single injec-
`tion, when taken in the context of a busy retina practice
`performing multiple injections in a day, a physician using
`a PFS could save substantial time using a PFS compared to
`conventional injection vials.
`
`Endophthalmitis
`The most visually devastating risk of intravitreal injections
`is infectious endophthalmitis (Figure 2). Regardless of the
`clinical setting or drug injected, this risk is rare, occurring
`on average in approximately one in 2,000 injected eyes.”23
`Although there are regional and global differences in aseptic
`intravitreal injection technique, the use of povidone—iodine
`remains a critical agent to reduce bacterial colonization and
`the risk of endophthalmitis.
`The use of PFSs effectively eliminates a number of
`steps in (aseptic) injection preparation, thus decreasing the
`risk of iatrogenic contamination due to suboptimal drug/
`device handling. 1““ Although a recent report on an ongoing
`multicenter study has suggested that the odds of endophthal-
`mitis with conventional intravitreal injections were higher
`than those using ranibizumab PFS, there are currently no
`comparative trials to confimi the validity ofthis hypothesis.25
`
`Reduction in intraocular air bubbles
`
`and silicone oil droplets
`The occurrence of intraocular air bubbles during intravitreal
`anti—VEGF injection has been well described?“27 Although
`intravitreal air bubbles typically resorb spontaneously within
`3 days, they can produce unexpected and disturbing symp-
`toms as well as a risk for patients during air travel. 3" Thought
`to be a result of the physician inadvertently drawing up
`
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`Figure 2 Endophthalmitis: 66-year-old male with aggressive endophthalmitis resulting in enucleation. (A) External photograph demonstrating conjunctival iniection and
`hypopyon. (B) Slit-beam photo demonstrating hypopyon and l<eratic precipitates.
`
`non-sterile air from the standard drug vial (when preparing a
`drug for inj ection), air bubbles can prove difficult to eliminate
`once drawn into the syringe and can take significant addi—
`ti onal physician time to remove, particularly for aflibercept.
`The design features of the ranibizumab PFS include a
`latex-free. nonretractable plunger preventing inadvertent draw-
`ing of non-sterile air. Thus, by eliminating the need to draw
`up the medication and introducing a nonretractable plunger,
`the user is far less likely to inject intraocular air bubbles into
`the vitreous cavity (ifproper syringe ventilation is observed).
`In addition to intraocular air bubbles, recent reports have
`shown presumed silicone oil drops associated with intravit-
`real anti-VEGF injections. Specifically, a recent study dem-
`onstrated 1.73% ofpatients receiving bevacizmnab prepared
`with insulin syringes to have a complication of silicone oil
`droplets (Figure 3).29 The culprit for these silicone oil droplets
`
` m, man
`
`Figure 3 Silicone oil droplets post intravitreal injection of bevacizumabz78-year-old
`female with exudative age-related macular degeneration of the right eye who had
`been receiving intravitreal injections ofAvastin (bevacizumab) every I—2 months for
`4 years and 3 months demonstrating silicone oil droplets.Visual acuity was 20/60 on
`the initiation of anti-VEGF therapy and 20/25 at last follow-up on the acquisition of
`the photograph.
`Abbreviation: VEGF, vascular endothelial growth factor.
`
`is thought to be polydimethylsiloxane, a chemical used as
`lubrication to reduce the friction between the syringe barrel
`and plunger. Much like intraocular air bubbles, silicone oil
`droplets are thought to result in symptoms of droplet-related
`floaters. Although not yet substantiated by clinical data, there
`is also a concern for the theoretical development ofglaucoma
`due to retained oil droplets.30
`Among the design features of the PFS is included an
`optimized siliconization process whereby a silicone oil-in-
`water emulsion is spray coated to the syringe barrel’s inner
`surface and then heat fixed to minimize oil migration into
`the ranibizumab solution. This “baked silicone” process
`is thought to reduce the incidence of silicone-related
`complications from repeated intravitreal injections.Z4
`
`Accuracy and precision of intravitreal
`ranibizumab doses
`
`The established therapeutic doses of anti-VEGF medications
`are achieved by injecting an intraocular volume of 0.05 mL.
`One ranibizumab PFS contains 0.165 mL of ranibizumab,
`
`ensuring that one always has adequate volume to administer a
`single dose of 0.05 mL. Several studies have revealed consid-
`erable variability in the accuracy and repeatability achieved
`with typical syringes used for intravitreal injections.”35
`Most commonly used small—volume syringes tend to over
`deliver their target volume”)35 Furthermore, all syringes
`have unique surface markings (volume metrics) which can
`also lead to inaccuracies in volume dispensed. Finally, the
`presence of silicone oil and water deposits in the syringe can
`lead to deviations in volume.
`
`The accuracy of intravitreal injection volumes directly
`influences their therapeutic effect on the eye. Therefore,
`even small deviations from intended volumes can have
`
`significant implications with regard to therapeutic response,
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`drug toxicity, and lOP changes. Although formal comparative
`studies have yet to be published, the work by Loewenstein
`et a135 postulated that the accuracy of anti—VEGF injection
`volume was better achieved using a PFS compared to their
`conventional counterparts, although this study was not
`masked. They further projected that the ideal design for an
`intravitreal injection would consist of a low—volume, PFS
`with a low dead space plunger.35 The current design of the
`ranibizmnab PFS includes a small syringe barrel (0.5 mL)
`which is minimally siliconized with low void volumes. This
`syringe design helps to offer improved dose assurance.
`
`Disadvantages of a sterile syringel
`drug assembly
`Although there are several advantages to the syringe/drug
`complex in the PFS, one theoretical disadvantage would
`include the risk of drug loss due to a break in the sterile
`procedure. This includes the incidence of syringes which
`fall off the sterile injection tray or are contaminated prior to
`intravitreal injection. With the standard intravitreal injection
`procedure, the loss or contamination of a syringe (prior to
`drug aspiration) would simply involve replacement with a
`sterile syringe. A provider could incur financial loss (drug
`loss/replacement) from a PFS that is lost or contaminated
`prior to delivery to a patient.
`
`Is the PFS a compelling leap forward?
`With the advent of anti-VEGF treatment in the early 21st
`century, several landmark trials came which demonstrated
`not only the prevention of visual loss but also the significant
`increase in Visual acuity ofpatients in response to treatment for
`retinal diseases ranging from exudative macular degeneration,
`diabetic macular edema, to retinal vein occlusions.3640 Despite
`the marked success and widespread application of anti-VEGF
`treatment, there are a significant number of patients with
`macular edema and/or retinopathy who fail to respond to
`anti-VEGF treatment.“42 Furthermore, these treatments are
`invasive and often require frequent administration for thera-
`peutic effect. This has led to the evolution ofnovel treatments
`including corticosteroid—releasing implants, treatments target—
`ing the kinin—kallikrein system, NSAle, vitrectomy surgery,
`laser therapies, immuno suppressants, and antibiotics targeting
`the inflammatory characteristics of early disease.43 So, while
`not a great leap forward, the PFS represents an incremental
`step that significantly reduces injection preparation time
`and the risk of endophthalmitis, silicone oil droplets, and
`air injection while improving the accuracy of drug delivery.
`
`Conclusion
`
`The ranibiztunab PFS represents a novel method of adrnin—
`istering intravitreal anti—VEGF therapy for the treatment of
`retinal diseases including exudative macular degeneration,
`diabetic retinopathy, and retinal vein occlusions. The PFS
`features a small syringe barrel which is minimally siliconized
`with low void volLunes. In addition, the PFS totes a latex—
`
`free, nonretractable plunger and is packaged in a sin gle-use
`sterile tray. This syringe design helps to offer improved dose
`assurance, while eliminating a number of steps in the previ-
`ous injection preparation thus reducing injection times, risk
`of endophthalmitis, and administration of air or silicone oil
`droplets. In conclusion, the ranibizumab PFS improves the
`ease of administration to physicians for this very common
`intravitreal injection procedure.
`
`Acknowledgments
`This research was supported by a grant from the National
`Eye Institute 1K08EY027458 (YMP), unrestricted depart-
`mental support from Research to Prevent Blindness, and
`the Department of Ophthalmology and Visual Sciences,
`University of Michigan. The authors would like to thank
`Dr. Mark Johnson for generously allowing them to use
`photography from his patient for this article. Figures 1—3
`are original photographs performed at the Department of
`Ophthalmology and Visual Sciences, Kellogg Eye Center,
`University of Michigan, which have not been reproduced
`from any other published source. Written informed consent
`was obtained from the patients depicted in Figures 2 and 3
`to publish the content included in this manuscript.
`
`Author contributions
`
`TMS and YMP, contributed substantially to the conception
`and design of the manuscript. TMS wrote the initial draft of
`the manuscript, and YMP performed the critical revision of
`the manuscript for intellectual content. Both authors contrib-
`uted to data analysis, drafiing and revising the article, gave
`final approval of the version to be published, and agree to be
`accountable for all aspects of the work.
`
`Disclosure
`The authors report no conflicts of interest in this work.
`
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