Dr Szilárd Kiss

home

authors

dr-szilard-kiss

Today, more than 50% of patients with wet age-related macular degeneration (AMD) are treated off-label with repackaged intravenous bevacizumab (Avastin) that was formulated and packaged for oncologic use. This anti-VEGF chemotherapy agent is approved for systemic administration in multiple cancers but has no approved indications in ophthalmology, despite its widespread use in treating a variety of retinal diseases.

Other anti-VEGF therapies that are US Food and Drug Administration (FDA)-approved specifically to treat retinal diseases—including ranibizumab (Lucentis), aflibercept (Eylea), brolucizumab-dbll (Beovu), and faricimab-svoa (Vabysmo)—are much more expensive than off-label bevacizumab. The result: Many clinicians are forced by insurance companies to use the much-less-costly systemic bevacizumab for many of their patients.

Because bevacizumab is not intended or packaged for intravitreal injection, it must be obtained from compounding pharmacies to be used in the eye. These pharmacies repackage very small quantities of oncologic bevacizumab into syringes for intravitreal injection for conditions such as wet AMD, diabetic macular oedema, and branch retinal vein occlusion.

Although these repackaged bevacizumab syringes appear to satisfy an urgent clinical and financial need for patients with a variety of retinal disorders, they are known to be associated with considerable public health concerns due to the risks posed to patients from compounding pharmacies’ lack of compliance with a variety of FDA requirements. This article will examine some of the dynamics of repackaging bevacizumab into syringes for intravitreal use and suggest a way to eliminate these risks to allow physicians to continue to use bevacizumab for their patients.

What is repackaging, and why does the FDA allow it?

Pharmacy compounding, including repackaging, is permitted under FDA regulations when a physician prescribes medication for an individual patient that is unavailable commercially in the dosage and/or form needed by that individual patient. Examples of compounding include creating liquid formulations of medications that a baby or older patient cannot swallow in solid form. Bulk compounding of medications is not legal if the medication is commercially available (eg, FDA approved) in a form or dosage that is appropriate to treat the patient.

In the case of repackaged systemic bevacizumab, with no approved ophthalmic formulation, the only way for retina specialists to use the drug for intraocular injection is through off-label pharmacy repackaging. Compounding pharmacies aliquot small doses to create prefilled syringes of bevacizumab from a large vial for intraocular injection. Through this mechanism, retina physicians have relied on repackaged systemic bevacizumab for nearly 15 years to provide a cost-effective anti-VEGF therapy to their patients.

Although repackaged bevacizumab has helped millions of patients maintain and even improve vision for a variety of previously blinding retinal disorders, the approach may, nonetheless, unavoidably put patients at risk. This situation is largely due to the process of drawing up multiple syringes from a single vial, as well as to the fact that bevacizumab—developed and packaged for oncologic use—is not formulated to meet the FDA’s specific standards for ophthalmic injectables. The agency’s chemistry manufacturing and controls standards are an integral part of the FDA requirements for any drug approval, and the syringes that contain aliquoted bevacizumab have not undergone this rigorous review and vetting.

Typically, 70 to 80 separate aliquots are taken from one bevacizumab vial and repacked for intraocular use. This repetitive process opens the door to contamination; one of the most serious risks from contamination is bacterial endophthalmitis. Unfortunately, cases of endophthalmitis caused by repackaging of bevacizumab have been reported.

Other problems can also present. The repackaging process relies on human judgment as to the quantity of drug aliquoted into each syringe, and given that only a tiny amount is needed, even a small variation due to human error can significantly affect the actual dosage that a retina patient eventually receives. Studies

 have shown that prefilled syringes vary in terms of how much bevacizumab is provided, with underdosing being common; the impact of underdosing, of course, is that patients may appear not to be responding appropriately to treatment, when in fact they simply may be receiving a subtherapeutic dose of the anti-VEGF medication. 

Other risks derive from lack of FDA-reviewed analytical methods, specifications, drug stability data, unknown quantities of particulates or bacterial endotoxins, unverified FDA-approved pH levels, or even the temperatures at which the syringes are filled, stored, and shipped. Faulty performance along any of these dimensions can damage the molecule and compromise its safety and efficacy.

The syringes used to draw up an aliquot of bevacizumab can also introduce problems, including precipitating agglomerations of the molecule’s proteins such that the osmolarity of the drug solution in the aliquoted vial is compromised.

 Moreover, the prefilled syringes themselves often do not meet the FDA’s standards for ophthalmic injectables, may contain silicone lubricant that can be expelled into the eye and cause permanent visual obstruction and increases in intraocular pressure,

 or are not ophthalmic syringes at all but rather ones created for other uses (such as insulin injection). There are no standards or guidelines for the syringes containing repackaged bevacizumab.

When the FDA approves a drug for commercial marketing, in addition to establishing safety and efficacy, it also reviews and regulates the actual manufacturing process, the specific manufacturing equipment employed, and the packaging that will be used for the finished drug product. Current Good Manufacturing Process, or cGMP, is the global gold standard for pharmaceutical manufacturing and a threshold that must be met to secure FDA approval. The FDA demands that manufacturers of approved medications comply with all cGMP protocols. Repackaging pharmacies may not abide by cGMP standards when individual syringes are drawn for intraocular use.

In the interests of providing their patients with a proven anti-VEGF therapy at a more workable pricepoint than is possible with the currently approved anti-VEGF retinal therapies, physicians have long relied on repackaged bevacizumab from compounding pharmacies—and indeed the molecule has proven itself a valuable therapy for many years. But a solution to the risks that repackaging entails, as delineated above, would be a bevacizumab molecule that is specifically developed and optimized to meet all the FDA’s rigorous requirements for an ophthalmic injectable, manufactured in a cGMP facility, packaged with a vial or syringe specifically designed for ophthalmic use, and introduced into the market via the established supply chain.

Such a product would bring retina physicians and their patients a safe and effective FDA-approved option, using a trusted and well-understood molecule, that mitigates the risks they currently face from repackaged bevacizumab from compounding pharmacies.

Szilárd Kiss, MD, is the Bob and Dolores Hope–Robert M. Ellsworth, MD, Distinguished Associate Professor in Ophthalmology and director of clinical research in ophthalmology at Weill Cornell Medical College in New York, New York. His clinical interests include complex vitreoretinal surgery and treatment of age-related macular degeneration and diabetic retinopathy.

1. Gonzalez S, Rosenfeld PJ, Stewart MW, Brown J, Murphy SP. Avastin doesn’t blind people, people blind people.

. 2012;153(2):196-203.e1. doi:10.1016/j.ajo.2011.11.023

2. US Food and Drug Administration. FDA alerts health care providers and patients of the nationwide recall of all lots of sterile products distributed by Clinical Specialties Compounding Pharmacy. 

http://www.fda.gov/NewsEvents /Newsroom/PressAnnouncements/ucm345019

3. US Food and Drug Administration. Drugs: FDA alerts health care professionals of infection risk from repackaged Avastin intravitreal injections. 

http://www.fda.gov/Drugs/Drugsafety/ucm270296

4. Sheyman AT, Cohen BZ, Friedman AH, Ackert JM. An outbreak of fungal endophthalmitis after intravitreal injection of compounded combined bevacizumab and triamcinolone. 

2013;131(7):864-869. doi:10.1001/jamaophthalmol.2013.88

5. Hawe A, Hulse WL, Jiskoot W, Forbes RT. Taylor dispersion analysis compared to dynamic light scattering for the size analysis of therapeutic peptides and proteins and their aggregates. 

. 2011;28(9):2302-2310. doi:10.1007/s11095-011-0460-3

6. Chi EY, Krishnan S, Randolph TW, Carpenter JF. Physical stability of proteins in aqueous solution: mechanism and driving forces in nonnative protein aggregation. 

2003;20(9):1325-1336. doi:10.1023/a:1025771421906

7. Mahler HC, Friess W, Grauschopf U, Kiese S. Protein aggregation: pathways, induction factors and analysis. 

. 2009;98(9):2909-2934. doi:10.1002/jps.21566

8. Liu L, Ammar DA, Ross LA, Mandava N, Kahook MY, Carpenter JF. Silicone oil microdroplets and protein aggregates in repackaged bevacizumab and ranibizumab: effects of long-term storage and product mishandling. 

. 2011;52(2):1023-1034. doi:10.1167/iovs.10-6431

Articles

Although off-label repackaged bevacizumab syringes appear to satisfy an urgent clinical and financial need for patients with a variety of retinal disorders, they are known to be associated with considerable public health concerns due to the risks posed to patients from compounding pharmacies’ lack of compliance with a variety of FDA requirements.

Author | Dr Szilárd Kiss

Articles

Intravenous bevacizumab repackaged for intravitreal use: Making the sight-saving treatment safer