For two decades, off-label bevacizumab has been a cheap and widely effective mainstay of the ophthalmologist’s toolbox for the treatment of retinal diseases.

The FDA changed that paradigm in July when it approved a new formulation of bevacizumab made specifically for the eye for the treatment of neovascular age-related macular degeneration (nAMD), but not for any of the other retinal diseases for which the drug has been used.

The off-label bevacizumab ophthalmologists use has been repackaged from vials for cancer injections into syringes for injections into the vitreous of the eye. Compounding pharmacies do that repackaging with varying degrees of consistency, according to retina specialists who have used the drug. Off-label bevacizumab costs a fraction of the on-label drugs used for the same indications — up to $75 per injection compared with $255 to almost $2400 for branded agents. So Medicare and commercial payers have embraced off-label bevacizumab.

‘It’s Complicated’

With the approval of the branded version, called Lytenava, ophthalmologists can get an eye-ready formulation of bevacizumab directly from the manufacturer, Outlook Therapeutics. But switching is not straightforward.

“It’s complicated,” Baruch Kuppermann, MD, PhD, chair of the of Department of Ophthalmology and Visual Sciences and director of the Gavin Herbert Eye Institute at the University of California, Irvine, told Medscape Medical News. Kuppermann said he plans to convert to the new formulation for his patients with nAMD when it becomes available, which may not be until next year based on the Outlook Therapeutics’ schedule for getting a reimbursement code.

Other retina specialists expressed reservations. “Off-label, compounded bevacizumab quietly has been the backbone of retina treatment for a lot of physicians in our field,” said Jayanth Sridhar, MD, who practices in Miami. “Now that there is an on-label approved bevacizumab, it raises interesting medicolegal questions: What does it mean to you?”

Bevacizumab is a recombinant humanized monoclonal antibody that inhibits VEGF, a major contributor to the neovascularization characteristic of nAMD, diabetic macular edema, diabetic retinopathy, and macular edema associated with retinal vein occlusion. Clinicians use off-label bevacizumab for all of these conditions.

The branded anti-VEGF drugs — Lucentis (ranibizumab), Eylea (aflibercept) and Eylea HD, and Vabysmo (faricimab), which also targets angiopoietin-2, another known culprit of exudative retinal disease — are approved for the same indications. Lytenava is approved only for nAMD.

Cost Complications

Cost is what makes this dynamic so complicated. Outlook Therapeutics has not yet listed a price for its treatment; however, off-label bevacizumab is considerably cheaper than its branded competitors. The July 2026 Medicare Part B update allows payment limits of $75 for bevacizumab 10 mg, $255 for ranibizumab 0.5 mg, $1487 for aflibercept 2 mg, $2389 for aflibercept 8 mg, and $1943 for faricimab 6 mg. The fee for the intravitreal injection procedure itself is separate, and all fees carry a 20% coinsurance coverage.

Outlook CEO Bob Jahr told Medscape Medical News the company is taking into account the price of off-label bevacizumab in pricing Lytenava, which already is available in the UK and EU. The list price in Germany is about $800, according to Sanicare Apotheke, a German drug price estimator website. A UK formulary lists Lytenava at around $637.

But Jahr cautioned against using those prices as benchmarks for the US figure because they do not include all “tenders” — competitive purchasing contracts drug makers negotiate with payers in Europe.

FDA approval does not always mean Medicare will automatically cover the drug, but Jahr said he’s confident the program will ultimately pay for Lytenava. In an investor conference call this month, he said the company will apply for a permanent Healthcare Common Procedure Coding System code to enable reimbursement and expects to have a permanent J code for the drug itself in April 2027.

Compounded vs Manufactured Bevacizumab

Ophthalmologists who have advocated for an eye injection-ready bevacizumab have said such a product would avoid problems that have come with compounded drugs.

Compounded bevacizumab has been linked to two notable outbreaks in the US of endophthalmitis, a potentially sight-threatening complication, or intraocular inflammation. In 2011, 12 patients in Florida developed endophthalmitis from syringes prepared at a single compounding pharmacy. In 2013, four patients in Georgia and one in Indiana developed acute endophthalmitis after injections of repackaged bevacizumab traced to the same compounding pharmacy in Georgia, which had distributed the product to 11 clinics in four states.

Other clusters have been reported internationally. Ophthalmologists in Mexico City reported 10 cases in 2014, and similar clusters were reported in Iran and China around the same time.

Large studies found rates of endophthalmitis were similar across different types of anti-VEGF drugs. A 2016 study of 503,890 injections reported the rate of endophthalmitis for compounded bevacizumab was 0.039% vs 0.035% for both ranibizumab and aflibercept.

However, a study of clinics in Switzerland, New Zealand, and Australia found significantly higher rates of endophthalmitis associated with bevacizumab: 0.081% (eight in 9931 injections) vs 0.005% (three in 54776) for ranibizumab and none in 23425 injections of aflibercept.

The syringes used for repackaged bevacizumab may also, in some instances, contain silicone oil droplets, which can cause floaters in the field of vision. A single-practice study in 2019 reported 23 such cases in 5 months compared with one in the previous decade. Another single-practice study reported the phenomenon in 60 patients, linking it to a possible change in the manufacturing of the insulin syringes used in the repackaging process.

Rishi Singh, MD, chair of the Department of Ophthalmology at Mass General Brigham and Harvard Medical School in Boston, called the “failure modes” of compounded bevacizumab “real and recurrent.”

“Day to day, the issues are batch inconsistency, supply interruptions, and recalls, and slow outbreak investigation because traceability is fragmented,” Singh said. “The frequency is low.” However, the consequence — endophthalmitis — can be “catastrophic and avoidable,” he said.

“My view is that the field has been more comfortable with this risk than it warrants largely because the economics were so favorable,” Singh added.

“We all know that there can be variability when the bevacizumab comes in a big bottle…and it’s fractionated, compounded by the compounding pharmacy,” Kuppermann said. “There is a surprising amount of variability in the dose, and I don’t like that.”

What About Step Therapy?

Up to three quarters of commercial payers and Medicare Advantage plans use step therapy protocols for treatment of retinal disease, according to a 2025 study. Most require providers use bevacizumab as the first-line drug before moving on to or stepping up to, more expensive treatments. The idea met great resistance from retina specialists when it was first floated in 2019, but many payers adopted step therapy nonetheless.

So where would Lytenava fit in? “That’ll be a decision by the insurers,” said Kuppermann, whose university practice limits step therapy. “Will they mandate in their step therapy that you need to start with off-label, compounded bevacizumab when you have an on-label product?”

Payers “may be pushing for off-label,” Sridhar said. Another factor could be the price of ranibizumab biosimilars, four of which have been approved by the FDA. “If Lytenava is priced the same or equivalent, who’s to say what that will look like?” he said.

“It was inevitable that we were going to have an on-label standardized option for the most-used drug in the field,” Sridhar added. “We all should want what’s best for our patients. I hope that pricing doesn’t shift behavior away from what’s most appropriate for that individual treatment.”

Kuppermann and Singh are consultants to Outlook Therapeutics. Jahr is an employee of Outlook. Sridhar reported no relevant financial relationships.

Richard Mark Kirkner is a medical journalist based in the Philadelphia area.