News|Articles|October 31, 2026

Q&A: Phentolamine for presbyopia: a non-miotic route to near vision

Author(s)Alice Epitropoulos, MD, Lynda Charters

Key Takeaways

Phentolamine 0.75% (Ryzumvi, Opus Genetics/Viatris), just approved to treat presbyopia, works according to a distinct mechanism not a bigger effect. The drug narrows the pupil by blocking the iris dilator rather than by acting on the sphincter or ciliary body and avoids the brow-ache, myopic shift, and dim vision linked to cholinergic miotics.
Evening dosing may help adherence. A single bedtime dose facilitates near-vision benefit the next day, which separates the drug’s effects from daytime activities and simplifies the regimen.
Treatment is an adjunct not a replacement. The best candidates are motivated early-to-moderate presbyopes, roughly in their mid-40s to mid-50s, with good distance vision who want to rely less on readers.

The FDA approved the Supplemental New Drug Application for phentolamine 0.75% (Ryzumvi, Opus Genetics/Viatris) to treat presbyopia.

The FDA approved the Supplemental New Drug Application for phentolamine 0.75% (Ryzumvi, Opus Genetics/Viatris) to treat presbyopia on October 16, 2026. This treatment is an alpha-1 and alpha-2 adrenergic antagonist that binds the receptors on the iris dilator muscle with a resultant reduction in pupil diameter. The pupil dynamics are modulated through a sympatholytic mechanism that avoids engaging the ciliary muscle.

This latest approval extended the indications for phentolamine 0.75%, which had been approved previously in September 2023 for pharmacologically induced mydriasis caused by adrenergic agonists or parasympatholytic agents.

In this Q&A, Alice Epitropoulos, MD, FACS, director of the Dry Eye Center of Excellence, The Eye Center of Columbus in Columbus, OH, speaks with Ophthalmology Times about this recent approval of phentolamine 0.75% to treat presbyopia and the benefit it offers patients. While presbyopic drops are not replacements for spectacles or contact lenses in this patient population, according to Epitropoulos, she believes that the non-miotic, non-accommodative mechanism of phentolamine may be attractive to some patients. She discusses what led up to its extended indication and which patients might benefit most.

Ophthalmology Times: The approval of phentolamine 0.75% was based on the phase 3 VEGA-2 and VEGA-3 trials. What did the study results show? How clinically meaningful are these results, and how do they compare with what you see in practice with currently available presbyopia drops?

Alice Epitropoulos, MD, FACS: Both trials met their primary and key secondary endpoints for near vision without meaningful loss of distance vision.Both trials evaluated the proportion of patients who gained three or more lines (15 or more letters) of distance-corrected near acuity under mesopic conditions without losing more than one line of distance vision. That threshold was chosen because it reflects a change that patients actually notice and not just a difference large enough to reach statistical significance; three lines is the difference between a patient squinting at a menu and actually reading it and at the same time leaving the distance vision alone is exactly what patients ask for. In VEGA-3,¹ for instance, 27.2% of patients on phentolamine hit that mark at 12 hours versus 11.5% on placebo, the effect also showed up at earlier time points, and it was maintained through 6 weeks.

What this tells me is that pharmacologically shrinking the pupil can deliver a meaningful near-vision benefit without touching the accommodative apparatus or sacrificing distance vision. This provides a meaningful benefit for a subset of patients, not a drop that retires reading glasses for everyone. That caveat applies to every pharmacologic approach to presbyopia, because patients differ so much in the baseline near demand, degree of presbyopia, pupil behavior, ocular surface status, and tolerance for visual side effects.

When I counsel patients, I base the conversation on what the currently marketed drops have delivered, and it is worth laying out the full US menu, because until recently, every approved option was a cholinergic miotic. There are now four FDA-approved option in the US: pilocarpine 1.25% (Vuity, AbbVie), the first FDA-approved presbyopia drop; pilocarpine 0.4% (Qlosi, Orasis), a lower concentration, preservative-free formulation, the chief selling point of which is a much lower headache rate (roughly 7%); aceclidine 1.75% (Vizz, LENZ Therapeutics), targeting the sphincter while minimizing ciliary muscle activation; and the one fixed-dose combination, Yuvezzi (carbachol 2.75%/brimonidine tartrate 0.1%, Visus Therapeutics), a once-daily dual-agent drop.

The pilocarpine 1.25% GEMINI trials showed pooled analysis of around 33% versus a 12% three-line responder advantage over vehicle²; the pilocarpine 0.4% NEAR-1 and NEAR-2 trials³ cleared the same three-line bar with a friendlier tolerability profile, and aceclidine 1.75% posted some of the strongest responder numbers of the class. In the phase 3 CLARITY-1 and CLARITY-2 trials,^4,5 65% of aceclidine patients vs 12% on brimonidine, and 71% vs 8% on vehicle, gained three or more lines of distance-corrected near visual acuity without losing a line of distance vision at day 1, hour 3. Yuvezzi used the identical three-line responder endpoint under mesopic conditions, with a peak effect in BRIO-II of about 38% vs 4% on vehicle at 1 hour, tapering over the dosing day.

However, we need to be cautious about comparing these percentages, not only with phentolamine but across all currently marketed presbyopia drops. The pivotal trials were conducted in different patient populations and under different protocols, so cross-trial comparisons do not support direct efficacy rankings.

What stands out to me about phentolamine, assuming the labeled claim holds, is not the size of the near-vision gain but how it gets there. The distinction matters because “non-ciliary” differentiates it from some competitors but not others. Pilocarpine contracts both the iris sphincter and the ciliary muscle, which is why it can produce accommodative brow-ache and a myopic shift. Yuvezzi likewise engages the ciliary apparatus: its carbachol component is a cholinergic agonist that constricts the iris sphincter and ciliary body, while the brimonidine component relaxes the iris dilator and tonic ciliary contraction to sharpen pupil selectivity and prolong the carbachol effect. Aceclidine is actually the exception among the miotics; its label describes it as a predominantly pupil-selective agent that contracts the iris sphincter with minimal ciliary muscle stimulation. Aceclidine also already spares the ciliary muscle. What makes phentolamine unique is the route it takes to the pupil: it is the only one of these agents that produces miosis purely sympatholytically, by alpha-blockade relaxing the iris dilator with no cholinergic action on the sphincter or ciliary body at all. Pair that with evening dosing and you have a genuinely distinct pharmacologic profile. This mechanism was seen early in the phase 2b ORION-1 study,⁶ in which an evening dose produced a sustained pupil reduction and a near-vision gain that hung on for well over a day.

It is important to recognize that no drops restore the eye’s natural accommodative ability. They all borrow the pinhole effect to deepen depth of focus. The real question for me is never the peak responder rate, it is tolerability and duration, because those are what decide whether a patient is still using the drop 6 months later.

OT: Phentolamine reduces pupil size by blocking the iris dilator muscle rather than stimulating the ciliary muscle, as miotic drops do. How might this difference, along with once-daily evening dosing, affect patient selection, tolerability, and adherence?

Epitropoulos: For me, the mechanism is the most interesting part of the story. Phentolamine is a non-selective alpha-1/alpha-2 blocker that shrinks the pupil by relaxing the iris dilator rather than contracting the sphincter or the ciliary body.

That is a genuinely different route to depth of focus, and it distinguishes phentolamine from pilocarpine and the other muscarinic agents, ciliary and sphincter activity of which drives the three complaints that limit the tolerability of daytime drops: the brow-ache and headache of accommodative spasm, myopic shift and blur, and dim vision that makes patients nervous about driving at night. Because phentolamine never engages the ciliary muscle, I would expect it to sidestep most of that, and in practice that matters most for the patient who wants a pharmacologic option but cannot tolerate or does not want the accommodative effects of a cholinergic miotic.

The bedtime, once-daily schedule is the other piece I like. Rather than remembering a drop in the morning and maybe a second dose during the workday, the idea is to dose in the evening and have the near-vision benefit ready the next day. That decouples the medicine from the very dimming and brow-ache that drive patients off daytime miotics, and once a day is simply easier to sustain. Both should help adherence, although real-world adherence will ultimately come down to how patients weigh the size of the benefit against any visual or surface symptoms. The ORION-1⁶ durability data make an overnight-dosed, all-day effect plausible to me.

That said, the trade-offs are different, not gone. I would not call phentolamine side effect-free. The reported effects are mostly local: instillation discomfort, conjunctival hyperemia, and a transient bad taste (dysgeusia), although in VEGA-3 the adverse events were predominantly mild and there were no treatment-related serious adverse events. Its sympatholytic mechanism makes systemic alpha-blockade worth a passing thought in patients already on oral alpha-blockers or prone to orthostasis, although this is not a labeled precaution, and systemic absorption from a topical drop is expected to be minimal. Because phentolamine produces miosis without contracting the ciliary muscle, it does not share the mechanistic pathway most often invoked for miotic-associated retinal detachment, and unlike the cholinergic presbyopia drops, its label carries no retinal-detachment precaution. That said, the retinal-detachment warning applied to the parasympathomimetics (pilocarpine, aceclidine, and the carbachol component of Yuvezzi) is the reason a dilated retinal examination is advised before starting those agents, consistent with American Academy of Ophthalmology guidance.⁷ Whether phentolamine's sympatholytic mechanism translates into a lower real-world detachment risk remains unproven.

OT: Which patients are the best candidates for phentolamine, and how might it fit alongside or in combination with existing presbyopia options, including glasses, contact lenses, and other drops?

Epitropoulos:The ideal candidate is likely a motivated reader-reluctant, early-to-moderate presbyope, typically in their mid-40s to mid-50s, with good baseline distance vision and a meaningful need for better unaided near vision. This is someone who wants the freedom to read without reaching for readers at every opportunity and is open to a topical treatment but would prefer to avoid directly stimulating the ciliary muscle. I would also consider patients' pupil characteristics, ocular surface status, visual demands, and tolerance for potential changes in visual quality when deciding whether this approach is appropriate.

I do not see any of these drops replacing glasses or contacts. I frame them as an adjunct and a lifestyle option, ie, a way to lean on readers less for intermediate and near work during the day, to complement a monovision or multifocal contact-lens plan, or to serve someone who just dislikes progressives. I would be more cautious in higher uncorrected hyperopes and advanced presbyopes, who will likely still need correction for fine print; in patients with meaningful dry eye or surface disease, where instillation discomfort and redness matter more.

Rather than expecting one universally superior product, I see these drops as potentially complementary options. Phentolamine's mechanism may make it particularly attractive for patients who want a non-miotic, non-accommodative approach.

The VEGA program also explored phentolamine in combination with low-dose pilocarpine, which raises an interesting possibility of tailoring the pharmacologic effect, although any combination should be guided by the eventual FDA labeling and clinical evidence rather than assuming that combination therapy is appropriate for routine practice.

The combination data actually came from the earlier VEGA-1 Ocuphire Pharma trial, where adding 0.4% pilocarpine to 0.75% phentolamine raised three-line responders to 60.5% from 45.2% but roughly doubled the adverse events, to 34.1% from 19.4%, a clear illustration of the efficacy-versus-tolerability trade-off that any combination approach has to weigh.