Drug shortages arise frequently in retina care. Across ophthalmology, the US Food and Drug Administration lists 10 current shortages and 9 that have recently been resolved, in addition to the discontinuation of 15 medications.¹ Included in those shortfalls are numerous drugs considered critical to the diagnosis and treatment of retinal conditions.

Not surprisingly, these gaps in availability — sparked by manufacturing or supply interruptions — create barriers to effective patient care. For example, a 2022 survey^2,3 of key opinion leaders flagged a worldwide shortage of Visudyne (verteporfin for injection; Bausch + Lomb) as a serious problem in ophthalmic care, reporting that it may have led to irreversible vision loss in some patients. Moreover, a report by the American Society of Health-System Pharmacists⁴ indicates that drug shortages, including those involving ophthalmic products, continue to crop up even as older ones persist, affecting patients and organizations on a large scale.

Fortunately, repeated navigation of these emergencies in the clinic has helped identify some best practices for the management of drug shortages. With these workarounds in mind, retina specialists and general ophthalmologists can offer their patients the highest possible standard of care in the face of fluctuating drug availability.

GRAPPLING WITH SHORTAGES AND DISCONTINUATIONS

A look at the US Food and Drug Administration’s list of drugs affected by shortages or discontinuations¹ underscores how much the availability of key retina medications has fluctuated in recent months.

• Triesence (triamcinolone acetonide injectable suspension; Harrow) is in the midst of a shortage, creating a barrier to the preservative-free treatment of cystoid macular edema, sympathetic ophthalmia, and uveitis.
• Fluorescein was in shortage until very recently, and the generic dye may still be difficult for ophthalmologists to obtain, interfering with their ability to perform angiograms for the diagnosis of retinal diseases.
• Visudyne has also emerged from a recent shortage, opening the door once again to the use of photodynamic therapy (PDT) for conditions including central serous chorioretinopathy, polypoidal choroidal vasculopathy, and angiomatous tumors.
• Avastin (bevacizumab; Genentech) was at the center of a nationwide shortage a few years ago, creating a challenge for ophthalmologists and their uninsured or underinsured patients who needed an affordable antiangiogenic treatment to treat wet AMD. Avastin still periodically disappears from portions of the eye-care market when compounding pharmacies — which allocate the medication into individual-dose syringes — decline to release batches that fail to meet sterility standards. Issues around silicone oil droplets and other particulates in the syringes have also disrupted supply chains.

The discontinuation of some drugs has also created hardships for ophthalmologists and their patients.

• Polytrim (polymyxin B sulfate and trimethoprim sulfate solution; Allergan), a standard antibacterial drop for administration after retinal surgery, has been added to the discontinued list.
• Intron A (interferon alfa-2b; Merck) was, by far, the most effective drug for ocular squamous cell cancer, but after its discontinuation by Merck in February 2022, patients with this condition now receive less optimal medications or surgery. While interferon isn’t a retina treatment, its absence has created a significant gap in the care of patients with ocular surface neoplasia by our anterior segment colleagues.

FEW SUPPLIERS, FREQUENT DELAYS

Why are these gaps in availability so common? In general, shortages of retina drugs can be attributed to restricted production capacity or quality control issues on the part of manufacturers or suppliers.

Manufactured Products

When it comes to manufactured retina drugs, a key obstacle to availability is a lack of diversity among suppliers. Often, these drugs are made in a single facility, meaning that any production interruption could result in a shortage. An example is Visudyne, which is manufactured exclusively in 1 South Carolina factory and has been on intermittent back order since 2020 due to production issues.³ Similarly, Triesence has traditionally been manufactured in a limited number of plants, with problems at any of those facilities restricting its availability.

Because drug makers face myriad pricing pressures, particularly for drugs that lack patent protection, many are unable to shoulder the expense of setting up a second manufacturing plant, especially to produce medications that do not generate large profits. Rather, many companies are moving in the opposite direction by abandoning their eyecare drugs altogether. Novartis plans to leave the ocular space by mid-2023 and has been selling off its products, including Vigamox (preservative-free moxifloxacin), Maxidex (dexamethasone), and Triesence, all of which will now be available through Harrow, formerly known as Imprimis, which offers both manufactured and compounded drugs.^5,6 Another challenge arose when Akorn Pharmaceuticals recently declared bankruptcy, interrupting access to fluorescein and a host of other eyecare drugs.⁷

Compounded Products

Similarly, Avastin’s availability is limited by the small number of compounding pharmacies that prepare it for ophthalmic use. However, quality control issues constitute the primary reason for shortages of this and other compounded retina drugs.

In some cases, a compounding pharmacy may temporarily shut down to resolve a contamination issue. However, with Avastin, a more frequent scenario is that a pharmacy will decline to release a batch that fails a sterility test. In addition, compounding pharmacies sometimes recall a batch of Avastin after release if its use is associated with eye infections.

IMPLEMENTING WORKAROUNDS

To weather these fluctuations, doctors must keep abreast of both current and resolved shortages so they can find ways to cope with the absence of some drugs while reincorporating others into practice. Stockpiling drugs affected by shortages or buying them from other practices for use in the office, surgical suite, or clinical trials is one such strategy, but there are others:

Use alternative therapies during shortages whenever possible.

In patients with chronic central serous chorioretinopathy (CSC), photodynamic therapy (PDT) can be swapped out for micropulse laser therapy or a trial of eplerenone or NSAID drops⁸; lifestyle modification involving observation, stress reduction, and/or the omission of oral steroids or other offending medications can also be recommended for patients. In patients with polypoidal choroidal vasculopathy, any anti-VEGF agent is a good alternative to Visudyne.⁹ For patients with rare ocular tumors, such as choroidal hemangioma or retinal hemangioblastoma, other lasers, surgical therapies, or medication can be used.^10,11

If Triesence is in short supply, an alternative treatment for inflammation is Kenalog given by subconjunctival or sub-Tenon injection, although injecting this drug into the vitreous comes with an increased risk of inflammation and/or pseudoendophthalmitis, and some hospitals and ambulatory surgery centers will not allow its off-label use. Other choices are Ozurdex (dexamethasone intravitreal implant; Allergan) or the suprachoroidally delivered Xipere (triamcinolone acetonide injectable suspension, Bausch).

When a specific anti-VEGF agent is in shortage, other drugs in the class are available to fill the gap. Samples or medications provided through patient assistance programs can be used for patients who are underinsured or uninsured.

Select the minimum viable dose of hard-to-find medications to stretch supplies.

Although 5 mL of fluorescein is standard for an angiogram, doses as small as 1.25 mL can be used with similar results. Similarly, when treating CSC, an effective option is reduced-strength PDT,¹² which can be achieved by halving the fluence, the dose, or the treatment time. While ophthalmologists typically opt for half fluence, data on the effectiveness of half-dose administration are just as strong.

Establish relationships with several compounding pharmacies.

By working with several compounding pharmacies, ophthalmologists provide themselves with a backup plan in case a pharmacy is unable to release a batch of Avastin or needs to recall one.

Be cognizant of shortages when overseeing clinical trials.

Frustrations with drug shortages can reach a high for physician investigators involved in clinical trials, because swapping scarce drugs for more plentiful ones is not an option in that setting. It’s important for investigators to keep a close eye on supply issues that could interrupt treatment for trial participants, because when a study drug becomes difficult to find, the best course of action is to stop enrolling patients until the shortage has been resolved. Sometimes, the study sponsor or contract research organization can help source these medications.

CONCLUSION

Ophthalmologists can expect drug shortages to remain a challenge in retina care. Paying careful attention to shifts in drug availability may help physicians predict deficits so they can stock up on affected drugs — although a careful balance is necessary, as the hoarding of supplies will only complicate shortages across the field.

When medicines become hard to find, ophthalmologists can swap preferred agents for safe and effective substitutes, administer the lowest viable minimum dose of scarce medications, and establish relationships with several compounding pharmacies to protect against treatment interruptions.

These lessons are not only pertinent to ophthalmologists, but to the pharmaceutical companies that market retina drugs. Although pricing pressures are valid concerns, drug companies that rely on single-source manufacturing risk jeopardizing not only patient care but their own reputations and profits. These factors should be part of the conversation as government, industry, and medicine collaborate to prevent future shortages of critical ophthalmology medications. RP

REFERENCES

1. US Food and Drug Administration. FDA drug shortages. Accessed April 25, 2023. https://www.accessdata.fda.gov/scripts/drugshortages/default.cfm
2. Amsterdam University Medical Centers. The impact of the shortage of ophthalmalogical drug verteporfin. June 2, 2022. Accessed April, 25, 2023. https://amsterdamumc.org/en/about/organization/the-impact-of-the-shortage-of-ophthamalogical-drug-verteporfin.htm
3. Sirks MJ, van Dijk EHC, Rosenberg N, et al. Clinical impact of the worldwide shortage of verteporfin (Visudyne®) on ophthalmic care. Acta Ophthalmol. 2022;100(7):e1522-e1532. doi:10.1111/aos.15148
4. American Society of Health-System Pharmacists. Drug shortages statistics. ASHP: Pharma cists Advancing Healthcare. Accessed June 12, 2023. https://www.ashp.org/drug-shortages/shortage-resources/drug-shortages-statistics?loginreturnUrl=SSOCheckOnly
5. White, DE. Exiting, slowly, stage left: Novartis sheds more minor drugs. Healio Ophthalmology. February 3, 2023. Accessed April 25, 2023. https://www.healio.com/news/ophthalmology/20230203/blog-exiting-slowly-stage-left-novartis-sheds-more-minor-drugs
6. Pharmaceutical Technology. Harrow to acquire US rights to Novartis’ ophthalmic products. December 15, 2022. Accessed April 25, 2023. https://www.pharmaceutical-technology.com/news/harrow-novartis-ophthalmic-products/
7. Becker’s Hospital Review. 5 weeks later, Akorn’s closure racks up 14 swelling drug shortages. Updated April 4, 2023. Accessed April 25, 2023. https://www.beckershospitalreview.com/pharmacy/5-weeks-later-akorns-closure-racks-up-13-swelling-drug-shortages.html
8. Porter, D. What is central serous chorioretinopathy? American Academy of Ophthalmology. September 21, 2022. Accessed April 25, 2023. https://www.aao.org/eye-health/diseases/what-is-central-serous-retinopathy
9. Taylor, R. Polypoidal choroidal vasculopathy, part 2: treatment. American Academy of Ophthalmology. February 2022. Accessed April 25, 2023. https://www.aao.org/eyenet/article/polypoidal-choroidal-vasculopathy-part-2-treatment
10. Drugs.com . Choroidal hemangioma. Updated April 2, 2023. Accessed April 25, 2023. https://tinyurl.com/y22bjj44
11. Cleveland Clinic. Hemangioblastoma. Updated April 12, 2022. Accessed April 25, 2023. https://my.clevelandclinic.org/health/diseases/22738-hemangioblastoma
12. Nicolò M, Desideri LF, Vagge A, Traverso CE. Current Pharmacological Treatment Options for Central Serous Chorioretinopathy: A Review. Pharmaceuticals (Basel). 2020;13(10):264. Published 2020 Sep 23. doi:10.3390/ph13100264