SINCE THE FDA’S APPROVAL OF Vuity (1.25% pilocarpine ophthalmic solution, AbbVie) in October 2021, it has become a near daily occurrence for patients in our clinics to solicit our professional opinion about it, request a prescription for it, or to report it as a new ocular therapy during their medication reconciliation. 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 prescribers about patients who may potentially be at risk prior to using this medication and to propose guidelines to help screen them out.

Trial Results: GEMINI, GEMINI 2, and VIRGO

Vuity achieved approval following the positive results of two phase 3, randomized, control trials: GEMINI 1 and GEMINI 2. The trials followed a total of 750 patients who used Vuity once 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 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

More recently, AbbVie published results from a separate phase 3 trial, VIRGO, evaluating twice daily dosing (6 hours apart) of Vuity compared to placebo in 230 additional patients, aged 40-55 years, over a 14-day evaluation period. As with the previous studies, the most common adverse events occurring at a frequency of >5% were headache and eye irritation.

Historical Adverse Events With Miotic Therapy

While the trials for Vuity reported no cases of retinal tears, retinal detachment, macular holes, or vitreomacular traction, full-strength pilocarpine (2-4%) 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.^4-8 The proposed mechanism is that pilocarpine activates muscarinic receptors on ciliary body smooth muscle cells, stimulating their contraction. This then releases tension on the zonules of the crystalline lens, resulting in forward displacement of this complex, which can cause anterior movement of the vitreous and induce sudden-onset traction, where the vitreous is strongly adherent to the retina.

Trial Criticisms

Despite the large number of patients eligible for treatment with Vuity, in total, the 2 pivotal trials leading to approval included only 750 patients, so they were underpowered to detect vitreoretinal interface diseases, and the patients were only followed for 30 days. In addition, while 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) or retinal imaging as part of the study protocol. Dilated fundus exams were conducted at the screening visit and at Day 30/exit visit for all study participants.

The lack of ancillary retinal diagnostic imaging could mean 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, and it was never fully elucidated in the studies.

Marketing Efforts

AbbVie has been marketing Vuity directly to consumers, with commercial spots airing beginning in early March. In a 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 $23.⁸ million on more than 13,400 airings of the commercial thus far (data compiled from March 7 to May 23, 2022).⁹

Notably, 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.”¹⁰

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.^11-13 Most of these cases are being referred by optometric colleagues, which should not be surprising given that optometrists provide 85% of comprehensive eyecare visits in this country and are likely to be the initial prescribers of the drops.

As of the most updated information on the FDA’s Adverse Events Reporting System (FAERS) Public Dashboard (June 30, 2022), there have been 425 total cases, including 71 labeled as serious cases, attributed to Vuity use. When specific adverse reactions were tabulated, they included the following: retinal detachment (19), retinal tear (6), vitreoretinal traction (2), and visual field defect (6).¹⁴

While it is early to conclude that there is 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. Thus, we will see many of the same adverse events with Vuity that we saw in the past when pilocarpine was routinely used.

There may be several potential explanations for the 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 that for whom pilocarpine was historically prescribed. 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 in the 40- to 55-year-old age group, and they are far less likely to have a PVD. Furthermore, the vitreous humor in this age group is likely in the pre-PVD stages of syneresis, adhesion, or even traction, and may be at the greatest risk for 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, a previous history of retinal detachment, retinal tears, retinal dialyses, pseudophakia, and aphakia.^4-6 Until the postmarket surveillance trials are completed, and we have more data on the true incidence of vitreoretinal adverse events, we 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) an 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). This committee serves as a peer-to-peer reporting system designed for monitoring postmarketing safety of medications and devices. You can access the reporting form at https://www.asrs.org/clinical/adverse-events-reporting . ■

References

1. Allergan. Efficacy Study of Pilocarpine HCL Ophthalmic Solution (AGN-190584) in Participants with Presbyopia (GEMINI 1). Clinicaltrials.gov website. https://clinicaltrials.gov/ct2/show/results/NCT03804268 . Revised December 28, 2021. Accessed April 23, 2022.
2. Allergan. Efficacy Study of Pilocarpine HCL Ophthalmic Solution (AGN-190584) in Participants with Presbyopia (GEMINI 2). Clinicaltrials.gov website. https://clinicaltrials.gov/ct2/show/results/NCT03857542 . Revised December 29, 2021. Accessed April 23, 2022.
3. Waring GO, Price F, Moshirfar M, Safyan E, Liu H, Robinson MR. Gemini I phase 3: safety and efficacy of Agn-190584 in participants with presbyopia. E-poster presented at: Annual meeting of the American Society of Cataract and Refractive Surgery; July 25, 2021; Las Vegas, NV.
4. Pape LG, Forbes M. Retinal detachment and miotic therapy. Am J Ophthalmol. 1978;85(4):558-566.
5. Walker JD, Alvarez MM. Vitreofoveal traction associated with the use of pilocarpine to reverse mydriasis. Eye (Lond). 2007;21(11):1430-1431.
6. Kraushar MF, Steinberg JA. Miotics and retinal detachment: Upgrading the community standard. Surv Ophthalmol. 1991;35(4):311-316.
7. Benedict WL, Shami M. Impending macular hole associated with topical pilocarpine. Am J Ophthalmol. 1992;114(6):765-766.
8. Garlikov RS, Chenoweth RG. Macular hole following topical pilocarpine. Ann Ophthalmol. 1975;7(10):1313-1316.
9. iSpot.tv. Vuity TV Spot, ‘Wait, What?’ Available at iSpot.tv. https://www.ispot.tv/brands/68j/vuity . Accessed August 14, 2022.
10. Allergan, an AbbVie Company. Package Insert for VUITY: NDA 214028. https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/214028s000lbl.pdf . Accessed April 23, 2022.
11. Amarikwa L, Michalak SM, Caul S, Mruthyunjaya P, Rahimy E. Vitreofoveal traction associated with pilocarpine for presbyopia. Ophthalmic Surg Lasers Imaging Retina. 2022;(7):410-411.
12. Al-Khersan H, Flynn HW Jr, Townsend JH. Retinal detachments associated with topical pilocarpine use for presbyopia. Am J Ophthalmol. 2022;242:52-55.
13. Eton EA, Zhao PY, Johnson MW, Rao RC, Huvard MJ. Rhegmatogenous retinal detachment following initiation of pilocarpine hydrochloride ophthalmic solution 1.25% for treatment of presbyopia. Retin Cases Brief Rep. 2022 Aug 12. [Online ahead of print]
14. FDA Adverse Events Reporting System (FAERS) Public Dashboard. https://fis.fda.gov/sense/app/95239e26-e0be-42d9-a960-9a5f7f1c25ee/sheet/45beeb74-30ab-46be-8267-5756582633b4/state/analysis . Accessed May 2, 2022.

Dr. Michalak is a vitreoretinal fellow at Byers Eye Institute, Stanford University, Palo Alto, CA.

Dr. Rahimy is a vitreoretinal specialist at the Palo Alto Medical Foundation, as well as adjunct clinical assistant professor in the Stanford Department of Ophthalmology.