Presbyopia is an ocular condition ripe for treatment disruption. It afflicts nearly every member of the population by the time they reach their mid forties — an estimated 128 million adults in the US — and most patients dream of an easier solution than multifocal contact lenses, glasses, or a surgical procedure. Enter 1.25% pilocarpine ophthalmic solution (Vuity; Allergan/Abbvie), a dilute form of pilocarpine that is the first FDA-approved eye drop for the treatment of presbyopia. Since Vuity’s approval last year, it has become a near daily occurrence for patients in our clinics to request a prescription or report it as a new ocular medication, and while the medication may be safe for use in most individuals, it may not be appropriate or safe for everyone. This review aims to educate retina specialists about patients who may potentially be at risk prior to using this medication and to propose guidelines to help identify them.

TRIAL RESULTS OF GEMINI 1 AND GEMINI 2

Vuity was approved by the FDA in October 2021 following the positive results of 2 phase 3 randomized control trials, GEMINI 1 and GEMINI 2. The trials followed a total of 750 patients who used Vuity daily for 30 days.^1,2 In the trials, 29% of patients experienced a 3 or more line increase in distance-corrected near visual acuity at day 30, hour 3 vs 10% in controls. The effects lasted approximately 6 hours. Reported adverse events (AE) were all mild and included headaches (14.1%), visual impairment (4.3%), conjunctival hyperemia (2.5%), vision blur (2.5%), eye irritation (2.5%), eye pain (2.5%), increased lacrimation (2.5%), nausea (2.5%), and punctate keratitis (0.6%).³

HISTORIC ADVERSE EVENTS WITH MIOTIC THERAPY

Although the trials for Vuity reported no cases of retinal tears, retinal detachment, macular holes, or vitreomacular traction, full-strength pilocarpine (2% to 4%) has fallen out of use in routine glaucoma management over the past few decades due to its adverse side-effect profile, which includes an increased risk of vitreoretinal interface disorders.^4-6 The proposed mechanism is that it causes the ciliary body to contract, anteriorly displacing the vitreous and causing sudden-onset traction where the vitreous is strongly adherent to the retina.

TRIAL LIMITATIONS

Despite the large number of patients eligible for treatment with Vuity, in total, the 2 trials included only 750 patients, which was underpowered to detect vitreoretinal interface diseases, and the patients were only followed for 30 days. In addition, although retinal detachments and macular holes may have been readily detected during the trial due to significantly decreased vision, the GEMINI trials did not include any optical coherence tomography (OCT), retinal imaging, or dilated fundus exams as part of the study protocol. Dilated fundus exams were conducted at the screening visit and at the day 30/exit visit for all study participants. This means that minimally symptomatic retinal holes/tears or vitreomacular traction may have easily been missed during the study. For example, “visual impairment” or “vision blur” listed in the adverse events/side effects column could potentially be attributed to a number of mild vitreoretinal interface changes.

MARKETING EFFORTS

Abbvie has been marketing Vuity directly to consumers, with commercial spots airing beginning in early March. In the nearly 1-minute ad spot, various individuals stop the narrator to check that they really can stop wearing glasses or contact lenses to read up close with Vuity. According to real-time television ad tracking service iSpot.tv , Abbvie has spent an estimated $19.4 million on over 9,600 airings of the commercial thus far (data compiled from March 7, 2022 to April 24, 2022).⁷

Of note, at the conclusion of the ad, there is only a mention to “contact your doctor immediately if you have sudden vision loss” without expounding on any of the potential risks. This is in contrast to the packaging insert from the FDA, which states: “Risk of retinal detachment. Rare cases of retinal detachment have been reported with other miotics when used in susceptible individuals and those with pre-existing retinal disease. Patients should be advised to seek immediate medical care with sudden onset of vision loss.”⁸

EARLY REPORTS OF ADVERSE EVENTS FOLLOWING VUITY ADMINISTRATION

In the few months that Vuity has been on the market, retina specialists are beginning to encounter cases of retinal tears, detachments, and symptomatic scotomas attributable to vitreomacular traction immediately following use of Vuity. Most of these cases are being referred by optometric colleagues, which should not be surprising given that optometrists provide 85% of comprehensive eye care visits in this country, and are likely to be the initial prescribers of the drops. As of the writing of this article (Monday, May 2, 2022), there have been 129 total cases, including 29 labeled as serious cases, attributed to Vuity on the FDA’s Adverse Events Reporting System (FAERS) Public Dashboard.

While it is early to draw a direct causal relationship, it is likely that Vuity (1.25% pilocarpine) and full-strength pilocarpine prescribed for glaucoma (2% pilocarpine) have a similar impact on the ciliary body — contraction leading to rapid anterior displacement of the vitreous — and thus retina specialists will see many of the same adverse events with Vuity that they saw in the past when pilocarpine was routinely used.

There may be several potential explanations behind an increase in the incidence of such events, even with a lower strength dosage of pilocarpine. First, with presbyopia as an approved indication, the potential total market significantly expands the usage to a much larger population of individuals than pilocarpine was historically prescribed to. Should Vuity become widely used, by virtue of sheer volume of prescriptions and exposed individuals, we would expect to see more instances of vitreoretinal interface disorders. Second, when used as a glaucoma medication, pilocarpine was more likely to have been prescribed to older age groups, who were at risk for glaucoma progression and were more likely to have already had a posterior vitreous detachment (PVD). However, patients with presbyopia being prescribed Vuity are 40 to 55 years old and therefore are far less likely to have a PVD. Furthermore, the vitreous humor in that age group is likely in the pre-PVD stages of syneresis, adhesion, or even traction, and may be at highest risk of sudden anterior vitreous displacement, spurring acute development of one of the aforementioned adverse events.

PRELIMINARY RECOMMENDATIONS REGARDING PATIENT SELECTION

In the literature, patients at highest risk for miotic-induced vitreoretinal disorders were those with myopia, lattice degeneration, previous history of retinal detachment, retinal tears, retinal dialyses, pseudophakia, and aphakia.^4-6 Until postmarket surveillance trials are completed, and there are more data on the true incidence of vitreoretinal adverse events, we the authors recommend avoiding prescription of pilocarpine for patients with the above risk factors or those with vitreomacular adhesion or traction on OCT. We also recommend (1) OCT and dilated exam in every patient prior to initiating a prescription for Vuity, (2) patient counseling emphasizing strict retinal tear and retinal detachment return precautions, and (3) a low threshold for obtaining OCT imaging and a dilated exam in any patient reporting vague visual complaints following use of Vuity.

ADVERSE EVENT REPORTING

We encourage colleagues to report any cases of adverse vitreoretinal events following Vuity use to the ASRS ReST Committee (American Society of Retina Specialists Research and Safety in Therapeutics Committee). The ReST committee serves as a peer-to-peer reporting system designed for monitoring post-market safety of medications and devices. You can access the reporting form at: https://www.asrs.org/clinical/adverse-events-reporting . RP

REFERENCES

1. Allergan. Efficacy study of pilocarpine HCL ophthalmic solution (AGN-190584) in participants with presbyopia (GEMINI 1). Clinicaltrials.gov identifier: NCT03804268. Updated December 28, 2021. Accessed April 23, 2022. https://clinicaltrials.gov/ct2/show/results/NCT03804268
2. Allergan. Efficacy study of pilocarpine HCL ophthalmic solution (AGN-190584) in participants with presbyopia (GEMINI 2). Clinicaltrials.gov identifier: NCT03857542. Updated December 29, 2021. Accessed April 23, 2022. https://clinicaltrials.gov/ct2/show/results/NCT03857542
3. Waring GO 4th, Price FW Jr, Wirta D, et al. Safety and efficacy of AGN-190584 in individuals with presbyopia: the GEMINI 1 phase 3 randomized clinical trial. JAMA Ophthalmol. 2022;140(4):363-371. doi:10.1001/jamaophthalmol.2022.0059
4. Pape LG, Forbes M. Retinal detachment and miotic therapy. Am J Ophthalmol. 1978;85(4):558-566. doi:10.1016/s0002-9394(14)75255-9
5. Walker JD, Alvarez MM. Vitreofoveal traction associated with the use of pilocarpine to reverse mydriasis. Eye (Lond). 2007;21(11):1430-1431. doi:10.1038/sj.eye.6703023
6. Kraushar MF, Steinberg JA. Miotics and retinal detachment: upgrading the community standard. Surv Ophthalmol. 1991;35(4):311-316. doi:10.1016/0039-6257(91)90053-i
7. iSpot.tv. Vuity TV spot, “Wait, what?” https://www.ispot.tv/brands/68j/vuity . Accessed June 6, 2022.
8. Allergan, an AbbVie Company. Package Insert for VUITY: NDA 214028. Accessed June 6, 2022. https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/214028s000lbl.pdf
9. FDA Adverse Events Reporting System (FAERS) public dashboard. Accessed June 6, 2022. https://fis.fda.gov/sense/app/95239e26-e0be-42d9-a960-9a5f7f1c25ee/sheet/45beeb74-30ab-46be-8267-5756582633b4/state/analysis