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Silicone deposits in repackaged anti-VEGFs may cause permanent IOP spikes

Issue: February 25, 2011

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Malik Y. Kahook

IOP spikes in patients receiving intravitreal injections may be linked to silicone oil deposits leaching into repackaged vials of anti-VEGF agents, a speaker said.

At Hawaiian Eye 2011, Malik Y. Kahook, MD, discussed increased IOP related to the injection of Avastin (bevacizumab, Genentech) and Lucentis (ranibizumab, Genentech).

Bevacizumab has a high safety profile overall but has been associated with complications, Dr. Kahook said.

"The main complication ... is an increase in IOP. I'm not talking about a brief increase in intraocular pressure that happens from a volume effect. This was a sustained increase in intraocular pressure," he said.

Researchers theorized that IOP spikes might be related to inflammation, toxicity or concentrations, but no significant associations were reported, Dr. Kahook said.

In 2006, Genentech issued a notification letter concerning reports of 32 patients who had experienced uveitis or sterile endophthalmitis related to intravitreal Avastin. The adverse events were traced to a single batch of the product, Dr. Kahook said.

In 2010, a study published in Investigative Ophthalmology and Visual Science showed that refreezing anti-VEGF, storing it longer than 2 weeks or exposing it to sunlight may cause silicone to leach from the syringe and into the vial.

Orientation of syringes in relation to ice packs in shipment may also play a role, Dr. Kahook said.

Compounding pharmacies should insert freeze watch cards into drug samples. If a card freezes, it colors the backing paper and shows clinic personnel that the product was frozen.

Practices should investigate sources of repackaged bevacizumab, determine whether syringes are stored longer than 2 weeks, refrigerate syringes until injections are administered, check for frozen syringes in product shipments, purchase their own vials and monitor patient's IOP, Dr. Kahook said.

• Disclosure: Malik Y. Kahook, MD, disclosed financial interests in Alcon Laboratories, Allergan, Actelion, Genentech, Heidelberg Engineering, Merck and Shape Ophthalmics.

Hawaiian Eye and Retina 2012 will be held January 15-20 at the Grand Wailea Resort & Spa in Maui. Learn more at OSNHawaiianEye.com or RetinaMeeting.com.

Intravitreal Lucentis (ranibizumab, Genentech) and Avastin (bevacizumab, Genentech) have dramatically improved our treatment outcomes in eyes with neovascular age-related macular degeneration. While ocular adverse events including intraocular inflammation, retinal tears, vitreous hemorrhage and endophthalmitis do occur with these therapies, fortunately, these occurrences are rare. Several recent reports suggest that another ocular adverse event, sustained ocular hypertension, can occur in a small percentage of eyes receiving intravitreal ranibizumab or bevacizumab therapy. The cause of these sustained IOP elevations remains elusive, but several potential mechanisms have been considered. The drugs could have a direct pharmacologic effect on aqueous outflow through effects on the trabecular meshwork, uveoscleral pathway, Schlemm canal or episcleral venous pressure. Alternatively, repeated transient IOP spikes related to the volume of drug introduced could also alter aqueous outflow pathways. Another theory is mechanical obstruction to outflow due to byproducts of pharmacologic compounding or issues related to shipping and storage of pre-filled bevacizumab syringes such as high-molecular-weight protein aggregates and/or microdroplets of silicone oil. The barrels, plungers and needles of nearly all syringes are lubricated with dimethicone (polymethylsiloxane) to reduce friction, and small droplets of silicone oil are frequently observed in the anterior vitreous of eyes receiving intravitreal injections of any agent. As silicone droplets have not yet been described in the aqueous or anterior chamber angle in eyes that have developed sustained ocular hypertension, it is premature to conclude that this mechanism is the primary cause of this adverse event. Also, sustained IOP elevations have been reported in eyes that have received only intravitreal ranibizumab, which is not supplied in pre-filled syringes. In summary, retina specialists should be cognizant of this uncommon but important phenomenon. Further research to establish the relationship between anti-VEGF therapy and sustained ocular hypertension is necessary.

– K. Bailey Freund, MD
Clinical Associate Professor, New York University School of Medicine
Disclosure: Dr. Freund receives research support from Genentech and has served on Scientific Advisory Boards for Genentech, Alimera, Alcon and Allergan.

References:

• Adelman RA, Zheng Q, Mayer HR. Persistent ocular hypertension following intravitreal bevacizumab and ranibizumab injections. J Ocul Pharmacol Ther. 2010;26(1):105-110.
• Bakri SJ, et al. Persistent ocular hypertension following intravitreal ranibizumab. Graefes Arch Clin Exp Ophthalmol. 2008;246(7):955-958.
• Bakri SJ, Moshfeghi DM, Rundle A, et al. IOP in eyes treated with monthly ranibizumab: A post hoc analysis of data from the MARINA and ANCHOR trials, Presentation at the AAO Annual Meeting, October 17, 2010; Chicago, Ill.
• Freund, KB, et al. Silicone oil droplets following intravitreal injection. Retina. 2006;26(6):701-703.
• Good TJ, et al. Sustained elevation of intraocular pressure after intravitreal injections of anti-VEGF agents. Br J Ophthalmol. 2010.
• Kahook MY, et al. Sustained elevation in intraocular pressure associated with intravitreal bevacizumab injections. Ophthalmic Surg Lasers Imaging. 2009;40(3):293-295.
• Kahook MY, et al. High-molecular-weight aggregates in repackaged bevacizumab. Retina. 2010;30(6): 887-892.
• Liu L, et al. Silicone oil microdroplets and protein aggregates in repackaged bevacizumab and ranibizumab: effects of long-term storage and product mishandling. Invest Ophthalmol Vis Sci. 2010.
• Tseng JJ, Della Torre KE, Cooney MJ, et al. Sustained increased intraocular pressure related to intravitreal anti-vascular endothelial growth factor therapy for neovascular age-related macular degeneration. J Glaucoma. 2011. In Press.