Acta Ophthalmologica 2010
`
`Letter to the Editor
`
`Intravitreal silicone oil
`droplets following
`pegaptanib injection
`
`Selim Kocabora, Kemal
`Mehmet
`Turgay Ozbilen and Kubra Serefoglu
`
`Retina Unit, Vakif Gureba Education
`and Research Hospital, Ophthalmology
`Clinic, Istanbul, Turkey
`
`doi: 10.1111/j.1755-3768.2008.01336.x
`
`Editor,
`
`I ntravitreal
`
`injection has recently
`gained in popularity for the treat-
`ment of many retinal diseases. Pegap-
`tanib is an agent used in intravitreal
`injection to treat choroidal neovascu-
`larizations
`by
`repeated
`injections
`administered every 6 weeks. Presumed
`intraocular migration of silicone oil
`droplets caused by intravitreal pegap-
`tanib injections was reported previ-
`ously (Freund et al. 2006).
`We report three cases of intravitreal
`silicone oil droplets following pegapta-
`nib injection for
`the treatment of
`subretinal choroidal neovascular mem-
`branes.
`In July 2007, pegaptanib
`became the first anti-vascular endothe-
`lial growth factor (anti-VEGF) agent
`to be approved for ocular use in Tur-
`key. The medication is distributed in
`prefilled
`glass
`syringes
`containing
`0.3 mg pegaptanib in 0.09 ml solution.
`Of 22 eyes
`injected intravitreally
`with pegaptanib between October
`2007 and April 2008,
`three were
`observed to contain presumed intra-
`vitreal silicone oil droplets. The drop-
`lets were firstly noticed occasionally
`during routine ophthalmological exam-
`ination in one patient’s eye. Conse-
`quently, we undertook a
`careful
`examination of all pegaptanib-injected
`patients and we found intravitreal oily
`droplets in two eyes of
`two other
`patients. None of the three patients
`with intravitreal oily droplets com-
`plained of floaters
`in their visual
`fields. The intravitreal droplets were
`small,
`spherical,
`translucent
`foreign
`bodies. Under biomicroscopic exami-
`nation, the droplets resembled silicone
`
`e44
`
`for the presence of silicon (Si) in two
`used and one unused pegaptanib-filled
`syringe. Inductively coupled plasma-
`MS is a highly sensitive method
`routinely used to determine trace ele-
`ments. We demonstrated the presence
`of Si in used and unused syringes and
`also in the pegaptanib solution itself
`(Fig. 3). These findings support
`the
`hypothesis that oily intravitreal drop-
`lets
`following pegaptanib injection
`may be silicone oil
`that originated
`from syringes used to inject pegapta-
`nib.
`Siliconization of the inner syringe
`wall and outer plunger surface serve
`to decrease friction for piston move-
`ment and minimize protein absorption
`to prolong drug stability. Because sili-
`cone oil has a relatively low cohesive-
`ness, it may migrate into the syringe
`and contaminate the drug. The release
`of silicone oil from disposable syringes
`during insulin expulsion has been
`reported to result
`from mechanical
`abrasion and flushing actions on the
`siliconized plastic surfaces of the syr-
`inge barrel and plunger (Chantelau
`et al. 1986). Almost all ophthalmic
`viscosurgical devices (OVDs) injected
`into the anterior chamber were found
`to contain small amounts of silicone
`oil, which is used as a lubricant for
`the prefilled OVD syringe (Ohrstrom
`et al. 2004).
`Pegaptanib, ranibizumab and bev-
`acizumab are the current anti-VEGF
`agents used intravitreally, but bev-
`acizumab is not approved for intra-
`vitreal delivery and thus its use is
`off-label.
`Intravitreal
`injection
`of
`VEGF inhibitors as an invasive proce-
`dure carries the risk of blinding com-
`plications
`such as
`endophthalmitis
`and retinal detachment; moreover,
`potential systemic side-effects include
`arterial hypertension, thromboembolic
`events and gastrointestinal bleeding
`(la Cour 2007).
`
`Fig. 1. Slit-lamp biomicroscopy demonstra-
`ting three oily droplets in the mid-vitreous
`cavity.
`
`oil remnants such as those commonly
`observed in the vitreous cavity of vit-
`rectomized eyes following silicone oil
`removal. By contrast with the vitrec-
`tomized eyes,
`the droplets in these
`three patients’ eyes were embedded in
`the vitreous gel and changed position
`with vitreous after-movements (Fig. 1).
`These small oily bubbles were more
`easily detectable on ocular echography
`(Fig. 2) because of
`their apparently
`exaggerated echogenicity
`and size
`caused by the typical ‘Rayleigh’ scat-
`tering of ultrasound from the vitre-
`ous–oil
`interface,
`as
`reported by
`Spaide et al. (2005).
`We used inductively coupled plasma
`mass spectrometry (ICP-MS) to test
`
`Fig. 2. B-scan ultrasonography of the same
`eye as in Fig. 1 demonstrates a typical scat-
`tering with three hyperechogenic opacities.
`
`Fig. 3. Silicon (atomic weight 29 g ⁄ mol) shown by the continuous red line detected in trace
`amounts in the pegaptanib solution by inductively coupled plasma mass spectrometry analysis.
`(Other lines are blank.)
`
`Novartis Exhibit 2008.001
`Regeneron v. Novartis, IPR2020-01317
`
`

`

`In our experience with intravitreal
`bevacizumab injection over 2 years,
`we have not observed a single case
`of
`intravitreal
`silicone oil droplets.
`Ranibizumab is not yet approved or
`commercially
`available
`in Turkey
`and therefore we have no experience
`with it.
`By contrast with pegaptanib, neither
`ranibizumab nor bevacizumab are
`stored in prefilled syringes. We think
`that intravitreal contamination by sili-
`cone oil droplets is most likely associ-
`ated with the use of prefilled syringes.
`The functional and clinical conse-
`quences of
`intravitreal
`silicone oil
`droplets are unknown, but their occur-
`rence could be avoided by using new-
`generation prefilled syringes that do
`not have an internal silicone coating.
`
`Acta Ophthalmologica 2010
`
`Acknowledgements
`We thank Professor Ahmet Kasgoz
`from the Department of Chemical
`Engineering, University of
`Istanbul
`for
`providing
`inductively
`coupled
`plasma mass spectrometry analysis for
`this study.
`
`Ohrstrom A, Svensson B, Tegenfeldt S,
`Celiker C & Lignell B (2004): Silicone oil
`content in ophthalmic viscosurgical devices.
`J Cataract Refract Surg 30: 1278–1280.
`Spaide RF, Chung JE & Fisher YL (2005):
`Ultrasound detection of silicone oil after its
`removal
`in retinal reattachment surgery.
`Retina 25: 943–945.
`
`References
`Chantelau E, Berger M & Bo¨ hlken B (1986):
`Silicone oil released from disposable insulin
`syringes. Diabetes Care 9: 672–673.
`la Cour M (2007): Intravitreal VEGF-inhibi-
`tors: is Avastin a generic substitute for Lu-
`centis? Acta Ophthalmol Scand 85: 2–4.
`Freund KB, Laud K, Eandi CM & Spaide
`RF (2006): Silicone oil droplets following
`intravitreal injection. Retina 26: 701–703.
`
`Correspondence:
`M. Selim Kocabora
`Sanatcilar Sitesi
`27 E Blok Daire: 12
`Tarabya-Sariyer
`34457 Istanbul
`Turkey
`Tel: + 90 212 534 6900
`Fax: + 90 212 621 7580
`Email: kocabora@gmail.com
`
`e45
`
`Novartis Exhibit 2008.002
`Regeneron v. Novartis, IPR2020-01317
`
`