Keeping an Eye Out: Safety Recalls Impact Over-the-Counter Eye Drops

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Reports of eye infection and enucleation related to OTC eye drops concerned the eye care community in 2023 and drove increased vigilance towards ensuring safer ophthalmic products.

Safety signals related to over-the-counter eye drops captivated both the eye care community and the public, as this year delivered a series of extremely concerning reports and a resulting increased vigilance toward ensuring safe, effective ophthalmic products.

The whirlwind of eye drop-related safety reports exploded in the first months of 2023 when a bacterial outbreak in artificial tears led to upwards of 80 cases of eye infections, including 4 reports of enucleation and at least 4 deaths, and an immediate recall. Since then, further warnings from the US Food and Drug Administration (FDA) and Centers for Disease Control and Prevention (CDC) have led to warnings over unapproved ophthalmic products and a nationwide voluntary recall of products sold from leading brands, including CVS Health, Rite Aid, and Target.

These updates and the rush of recalls have left both consumers and practitioners unsure of how to fully parse the situation and often, left feeling like they’re in the dark. The problem may particularly arise when a consumer asks their healthcare provider for advice on the best artificial tear for their dry eye—a clinician may rely on their own anecdotal evidence, given a lack of consistent empirical evidence on safety and efficacy related to eye drops.

“I think what is difficult about this situation is, we still don’t have a good sense of how broad the problem is. I would imagine 99% of everything out there is completely safe,” Timothy Janetos, MD, MBA, of the department of ophthalmology at Northwestern University Feinberg School of Medicine, told HCPLive. “But, because there’s not a system in place that requires inspections of facilities, or pre-approval of drops coming to market, there’s not currently a good way of tracking these problems.”

Keeping an Eye Out: Safety Recalls Impact Over-the-Counter Eye Drops

FDA Regulations

The FDA does not require prior approval before OTC drugs are brought to market, so long as the drug meets the requirements of the agency’s designated OTC monograph. An OCT monograph includes specifications based on active ingredients, indications, dosages, routes of administration, labeling, and testing. The responsibility then falls on the manufacturer to follow the guidance of the monograph, rather than the agency’s job to enforce these rules.

The agency’s strict regulation for quality standards, known as Current Good Manufacturing Practice, are maintained for both new drug applications and those matching OTC monographs. Part of the regulation guidelines usually include an inspection of manufacturing facilities to ensure the FDA’s standards are being met.

However, the FDA’s in-person inspections of manufacturing facilities outside the US were limited between March 2020 to February 2022 due to the COVID-19 pandemic. As in-person inspections resumed, they occurred at a far reduced rate compared to pre-pandemic levels.

“The FDA has a very strict guideline for manufacturing procedures, and it is the exact guideline for OTC medications as for drugs that are going through the pre-market approval pathway,” Janetos said. “The difference is, no one is checking OTC products before they get to market. Products can be distributed in the US, and the FDA may never have inspected a facility, or the facility may not have provided notice that they are making this product.”

Once the product reaches the market, monitoring is reliant on the manufacturers required to report any serious adverse events and those using the product, who are encouraged to report adverse events to the FDA through the Adverse Event Reporting System (FAERS). Based on these events reported in the FAERS, the agency may issue safety communications—however, the reporting party is responsible for related details of the claim, without further independent verification of the claim.

In cases when consumer safety concerns are reported, the agency remains unable to mandate the recall of drugs. Instead, the FDA’s authority to intervene is limited to recommending a recall or implementing seizure of the drug products, seeking injunctions, and/or pursuing other legal action.

“When we go and inspect these facilities, there are often blatant violations of FDA guidelines,” Janetos said. “At that point, the FDA has no authority to recall an OTC medication, but it sends out a warning letter and most companies will voluntarily withdraw their products from the market. But it’s an after-the-fact discovery, rather than a pre-distribution discovery.”

EzriCare Artificial Tears

In February, a health advisory from the CDC warned clinicians and patients to immediately discontinue the use of EzriCare Artificial Tears and Delsam Pharma’s Artificial Tears, after a cluster of bacterial infections were found to be associated with the drops.

The CDC issued a Health Alert Network Health Advisory about infections related to an extensively drug-resistant strain of the bacterium, Pseudomonas aeruginosa. Clinicians were advised to monitor signs and symptoms of infection and perform culture and antimicrobial susceptibility testing when clinically indicated.

Soon after, the FDA joined the CDC in warning against the purchase and urging the immediate discontinuation of both ophthalmic products due to potential bacterial contamination. The OTC products were manufactured by Global Pharma Healthcare Private Limited, and the company initiated a voluntary recall at the consumer level of all unexpired lots.

The recall was recommended due to identified current good manufacturing practice violations, including lack of appropriate microbial testing and lack of proper controls related to tamper-evident packaging. Formulation issues were further identified, as the agency noted the company manufactures and distributes ophthalmic products in multi-use bottles without an adequate preservative. As a result, the FDA placed the company on import alert for providing an inadequate response to a records request and for not complying with CGMP requirements.

At the time, clinicians expressed their concern with the severity of the outbreak and its link to a ubiquitous OTC product such as artificial tears, particularly when patients are experiencing dry eye due to the local climate and seasons.

“If confirmed, I think this link is concerning for several reasons. First and foremost, the severity of the infections seems to be alarming,” Veeral Sheth, MD, the director of clinical trials at University Retina, told HCPLive. “The second concern is that artificial tears are so ubiquitous with countless patients using them this time of year when the air is cooler and drier in many parts of the country."

As of May 15, 2023, the CDC identified 81 patients across 18 states with VIM-GES-CRPA, a rare strain of Pseudomonas aeruginosa. At that time, the agency identified infections from the bacteria strain that led to at least 4 deaths, vision loss in 14 individuals, and 4 cases of enucleation. The FDA additionally warned consumers to discontinue the use of an eye ointment manufactured by Global Pharma because of potential contamination.

The lack of facility inspections may have impacted the outbreak of eye infections in Global Pharma Healthcare’s manufacturing facility, as data showed the facility had not been inspected before the investigation in early 2023.

“It looks like the main source of the problem is poor manufacturing processes and the bare minimum, to me, is we should have manufacturers tell the FDA they are going to be distributing products, before they go on the market, giving the FDA time to inspect the facilities,” Janetos said.

Further Recalls

In late October, the FDA provided a warning to consumers to not purchase and immediately discontinue the use of 26 OTC eye drop products, including products from CVS, Target, and Rite Aid, due to the potential risk of eye infection.

Manufacturers were recommended to recall all lots, owing to unsanitary conditions found in the manufacturing facility and positive bacterial test results from environmental sampling of “critical” drug production areas. At that time, the FDA did not announce any adverse event reports of infection related to the ophthalmic products.

By mid-November, the now 27 eye drop products were voluntarily recalled by manufacturer Kilitch Healthcare India Limited. The recalled ophthalmic products were nationally distributed through the product distributor, Velocity Pharma, who were said to have informed all wholesalers and retailers of the recall and arranged for the return of impacted products.

At that time, Kilitch Healthcare India Limited reported no reports of adverse events related to the recall. The FDA continued to urge those with any recalled product to cease use of the product and report any related negative effects or quality concerns with any medicine to the FAERS.

Also, in November, the FDA’s Center for Drug Evaluation and Research issued a warning letter to Amazon.com, Inc. regarding unapproved new ophthalmic drug products. Addressed to Andrew Jassy, chief executive officer of Amazon, the letter indicated the company is responsible for the introduction or delivering for introduction into commerce of 7 eye drop products.

These products were not recognized as safe and effective for their referenced uses, including pink eye, dry eye, eye strain, and floaters. According to the FDA, the claims on the labels and labeling provide evidence of the intended use of these products as drugs. Short of certain exceptions, a new drug is unable to be introduced or delivered for introduction into commerce without an approved application from the agency.

Shortly after the warning, Amazon announced it was removing the 7 eyedrops from the website. The FDA had given the company 15 days after receipt of the letter to define what steps it had taken to address the violation and ensure it does not sell unapproved new drug products for eyes in the future.

Previously, in September, the FDA provided warning letters to 8 companies for manufacturing unapproved ophthalmic drug products in violation of federal law, including CVS Health and Walgreens. Companies addressed in the letter were said to have illegally marketed eye products to treat conditions including conjunctivitis, cataracts, and glaucoma.

Many of the letters cited quality issues related to product sterility. The warning was noted as being per an agency-wide effort to protect citizens from harmful ophthalmic products.Ophthalmic products intended for administration into the eye can pose an increased risk of harm to users, as they bypass many of the human body’s natural defenses.

“Most of the time, we as ophthalmologists, don’t think about asking if they’re taking artificial tears and most of the time, patients don’t report that they’re taking OTC products, because they’re considered benign,” Janetos said. “This year alone has shown that most are probably safe, but they do have the potential to cause real harm, including blindness and death.”

Solutions

Ophthalmologists often recommend popular brands of artificial tears, but these tears may not provide substantial benefit over generics. Ultimately, cost may play the largest role in consumer selection. Although most drops are presumed to be safe, clinicians may feel unequipped to make a recommendation based on empirical evidence, given these outbreaks.

“A lot of it has to do with manufacturing guidelines and the stringent methods that different companies follow,” Hani Salehi-Had, MD, of the Retina Associates of Southern California, told HCPLive. “With the formulations that are done in the proper facilities, we don’t see much of this.”

To provide more transparency on common eye care products, Janetos and colleagues advocate for an open-source, centralized database with information on product characteristics and reported adverse events. He noted the FDA’s adverse event reporting system is underutilized and lacks proper accessibility for patients and clinicians alike.

“The idea behind this was to make a Wikipedia-type database of the top 100 brands out there, to search for any sort of allergies and brands, and it will link to any reported adverse events,” Janetos said. “And, hopefully, it can be updated by a community of ophthalmologists.”

But, despite these concerning reports, ophthalmologists and eye care professionals stress that most eye drop products are completely safe and have a long-standing history of providing benefits for patients, without increasing the risk of infection.

“If you consider how long we’ve used eye drops, and how few cases we’ve had of these outbreaks, it goes to show you they are still a very safe route of delivery,” Salehi-Had said.

References

  1. Iapoce C. FDA announces recall of eye drops from leading brands over safety concerns. HCP Live. November 29, 2023. Accessed December 27, 2023. https://www.hcplive.com/view/fda-announces-recall-eye-drops-leading-brands-safety-concerns.
  2. Iapoce C. FDA issues warning to Amazon over unapproved ophthalmic products. HCP Live. November 14, 2023. Accessed December 27, 2023. https://www.hcplive.com/view/fda-issues-warning-amazon-unapproved-ophthalmic-products.
  3. Iapoce C. FDA warns against eye drops from major brands due to infection risk. HCP Live. October 30, 2023. Accessed December 27, 2023. https://www.hcplive.com/view/fda-warns-against-eye-drops-major-brands-infection-risk.
  4. Iapoce C. CVS, Walgreens among companies to receive FDA warning for marketing unapproved eye drops. HCP Live. September 12, 2023. Accessed December 27, 2023. https://www.hcplive.com/view/cvs-walgreens-among-companies-to-receive-fda-warning-for-marketing-unapproved-eye-drops.
  5. Iapoce C. FDA joins CDC, issues warning over EzriCare artificial tears. HCP Live. February 3, 2023. Accessed December 27, 2023. https://www.hcplive.com/view/cdc-issues-health-advisory-infection-outbreak-related-artificial-tears.
  6. Younessi DN, Lin JC, Janetos TM. Regulatory and Informational Gaps in the Over-the-Counter Eye Care Product Industry—Over the Counter, Under the Radar. JAMA Ophthalmol. Published online November 02, 2023. doi:10.1001/jamaophthalmol.2023.4961
  7. Center for Drug Evaluation and Research. CDER alert. U.S. Food and Drug Administration. November 16, 2023. Accessed December 27, 2023. https://www.fda.gov/drugs/drug-safety-and-availability/fda-warns-consumers-not-purchase-or-use-certain-eye-drops-several-major-brands-due-risk-eye#eyedrops.
  8. Outbreak of extensively drug-resistant pseudomonas aeruginosa associated with artificial tears. Centers for Disease Control and Prevention. May 18, 2023. Accessed December 27, 2023. https://www.cdc.gov/hai/outbreaks/crpa-artificial-tears.html.
  9. Center for Drug Evaluation and Research, US Food and Drug Administration. OTC drug review process: OTC drug monographs. February 3, 2023. Accessed December 27, 2023. https://www.fda.gov/drugs/otc-drug-review-process-otc-drug-monographs
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