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Retinal Physician

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Vitreoretinal Adverse Effects Associated With Oxymetazoline Drops for Blepharoptosis

Alpha agonists may play a role in vitreoretinal traction.

By: Jessica L. Barest, MD, Alan R. Dayan, MD
Retinal Physician November 1, 2023 Vol 20, Issue November/December 2023 Page(s): 30-33

Vitreoretinal adverse effects are known to occur with muscarinic agonists and are believed to result from miosis.1 Alpha agonists also have miotic effects, and vitreoretinal side effects are explicitly listed in the FDA insert that to date have no pathophysiologic explanation.2 This article presents a case of a peripheral retinal tear with posterior vitreous detachment, vitreous hemorrhage, subclinical retinal detachment, and epiretinal membrane temporally associated with the use of oxymetazoline hydrochloride ophthalmic solution 0.1% (Upneeq; RVL Pharmaceuticals), a nonselective alpha agonist eye drop recently approved for the transient cosmetic treatment of blepharoptosis.3 We hypothesize that pharmacologically induced pupillary modulation itself is the common denominator to explain these vitreoretinal adverse effects. Further study is warranted to determine causality and inform safety profile for prescribers and patients.

CASE REPORT

A healthy 56-year-old female complained of new-onset of floaters centrally in her vision after using oxymetazoline 0.1% eye drops once daily for 2 consecutive days in the right eye only for the treatment of ptosis (a monocular trial was advised to assess efficacy). The patient reported that the ptotic eyelid noticeably elevated within minutes of drop instillation and subsided after several hours; the visual symptoms began within hours and persisted. The second application again transiently elevated the eyelid, but the continued visual symptoms prompted her to discontinue further use. The untreated left eye was asymptomatic.

Initial diagnosis was inferior retinal hemorrhage and floater in the right eye. Subsequent exams by retina specialists identified a peripheral horseshoe retinal tear temporally in the right eye that was treated with argon laser, and a prominent posterior vitreous detachment. Follow-up exams over the next few months revealed vitreomacular traction and epiretinal membrane, and horseshoe tear with subclinical retinal detachment well demarcated by laser with overlying vitreous hemorrhage (Figures 1 and 2).

Figure 1. Fundus and red-free images of right eye (A, B) showing temporal retinal horseshoe tear with subclinical detachment and overlying vitreous hemorrhage well demarcated by laser. The left eye is within normal limits (C, D).
Figure 1. Fundus and red-free images of right eye (A, B) showing temporal retinal horseshoe tear with subclinical detachment and overlying vitreous hemorrhage well demarcated by laser. The left eye is within normal limits (C, D).
Figure 2. Macular optical coherence tomography demonstrating epiretinal membrane in the right eye (A). The left eye is within normal limits (B).
Figure 2. Macular optical coherence tomography demonstrating epiretinal membrane in the right eye (A). The left eye is within normal limits (B).

The patient had no personal or family risk factors for retinal detachment and had undergone a routine ophthalmic exam 3 months prior to this emergency that documented clear vitreous and normal retinal exams bilaterally.

DISCUSSION

An association between eye drops and vitreoretinal traction is well established in the ophthalmic literature, specifically relating to miosis and muscarinic agonists.1,4-6 However, the selective alpha-2 agonist brimonidine, in its prescription (0.1%, 0.15%, 0.20%) and nonprescription (0.025%) strengths, also has miotic effect, and its FDA insert documents vitreoretinal side effects in 1% to 4% of patients.2,7-10 Although not listed in the FDA warnings, the nonselective alpha-1 and alpha-2 agonist apraclonidine also affects the pupil, and vitreoretinal adverse effects are reported in the FDA Adverse Event Reporting System (FAERS).11-14 While “ciliary spasm” is the accepted theory for the mechanism of vitreoretinal traction for muscarinic agents such as pilocarpine, to date there is no pathophysiologic explanation in the literature for the occurrence of vitreoretinal issues with alpha agonists.1 We propose that miosis itself is the common denominator, and that it is possible that the chemically similar alpha-1 and alpha-2 agonist oxymetazoline 0.1% could lead to similar, as yet unrecognized, complications.

Pilocarpine and its miotic effect has recently garnered significant attention with the FDA approval of pilocarpine hydrochloride 1.25% (Vuity; Allergan/AbbVie) as a safe treatment for presbyopia.15 The initial reports did not document any adverse retinal complications.16 However, recent case reports highlight a temporal relationship between pilocarpine 1.25% use and the onset of vitreoretinal symptoms, vitreomacular traction, and retinal detachment, predominantly occurring in patients between 40 and 60 years old.16-19 It is theorized that this population had asymptomatic, undetected vitreoretinal traction and that miosis along with forward movement of the lens/vitreous face led to these rare but serious visual consequences.16-19 Recommendations for retinal screening evaluations, including dilated ophthalmic exams and optical coherence tomography (OCT), and attention to symptom warnings, are now being advised prior to prescribing this pupil-modulating medication.16-19

Brimonidine and apraclonidine are mainstays of the medical treatment of glaucoma with well known miotic properties.7-10,13,14 In light of the aforementioned issues with pilocarpine 1.25%, the safety information related to pharmacologic manipulation of the pupil, regardless of mechanism, is an important topic for further clinical and scientific evaluation. Described as a partial alpha-1 agonist with 5-fold higher affinity for alpha-2 receptors, oxymetazoline 0.1% clinical studies report that the medication “selectively” targets the alpha receptors on Mueller’s muscle, resulting in an average 1 mm of eyelid elevation within minutes and lasting for at least 6 hours after instillation.20-24 Regarding the pupil, however, oxymetazoline studies only report “absence of clinically significant mean change in pupil diameter” and “no reports of mydriasis.”21 There is no mention of miosis.

However, given its chemical similarities to brimonidine and apraclonidine, it seems unlikely that oxymetazoline would have no effect on the pupil. Shemesh et al report that brimonidine 0.1% results in “clinically significant reduction in pupil diameter under dark luminance conditions” and “the reduction is achieved within 30 minutes of instillation and remained stable for at least 6 hours.”7 Also, although apraclonidine’s eyelid elevating ability and mydriatic effect to diagnose Horner syndrome are well known, miosis is also proven to occur with both apraclonidine 0.5% and 1% in healthy individuals.13,14 Cambron et al noted that in healthy patients, apraclonidine’s “more pronounced alpha-2 receptor agonist effect” results in miosis when “the noradrenalin-mediated contraction of the dilatator muscles by alpha-1 receptors is suddenly reduced,” and that the degree of miosis is most pronounced 30 to 60 minutes after instillation and can persist until 5 hours after instillation.13 These descriptions of rapid onset and duration of effect closely approximate that of oxymetazoline 0.1%, and thus assessment and comparison of both eyelid and pupillary effects among the alpha agonists would be very informative.

The methods of pupillary measurement in the oxymetazoline studies compared to brimonidine and apraclonidine studies are germane to this discussion. Oxymetazoline studies evaluated the effect on the pupil using digital photographs and handheld caliper and millimeter ruler, and were done under ambient lighting conditions with no mention of eye color, examiner consistency, or focal point at which the pupillary measurements were made.21,22,24 By contrast, studies on brimonidine (0.15%, 0.20%, and nonprescription strength 0.025%) as well as apraclonidine (0.5% and 1%) that demonstrated significant miotic effect on healthy subjects took these parameters into account, and used pupillometers, luminance meters, and infrared videos to ensure measurement accuracy.7-10,13,14 Until further studies are done with equal precision, it is reasonable to believe that oxymetazoline may have similar pupillary effects that were not identified because of inadequate pupil evaluation.

Oxymetazoline 0.1% is chemically similar to brimonidine and apraclonidine. Therefore, it would follow that it could have the same side effect profile attributable to these medications. As stated by Wirta et al, “the molecular targets of oxymetazoline, alpha-adrenergic receptors, are widely expressed in smooth muscle and blood vessels of the eye, including the conjunctiva, iris ciliary structures and aqueous outflow tract” and this may explain the occurrence of ocular treatment-emergent adverse effects (TEAE).21 Of note, pilocarpine 1.25%, brimonidine, apraclonidine, and oxymetazoline 0.1% all report “vision blur” as a TEAE — and the oxymetazoline authors concede that the mechanism behind this finding warrants further investigation.2,3,11,15,21 Michalak et al speculate that for pilocarpine 1.25%, “‘vision blur’ listed in the adverse events/side effects column could potentially be attributed to a number of mild vitreoretinal interface changes.”16 This theory could be extrapolated to oxymetazoline and other alpha agonists, and thus more detailed studies to better understand pharmacologic effects at the iris/ciliary body are necessary to determine long-term safety and risk-benefit profiles.

CONCLUSION

A temporal association of miosis-inducing eye drops and the onset of vitreoretinal complications in patients with and without risk factors for retinal detachment has been established. Although a causal relationship needs further investigation and the incidence of retinal detachment is rare, all prescribers and patients who are prescribing or being prescribed eye drops with possible pupillary modulating effects, including oxymetazoline 0.1%, should be informed and warned of the potential for adverse effects, including retinal detachment. At this point it is clear that the rapid and abrupt onset of action of oxymetazoline 0.1% indicates a powerful effect on the eyelid, and like similar alpha agonist eye drops, undoubtedly has effects on other delicate ocular tissues, specifically the pupil, that have yet to be clarified. A possible connection between pharmacologic manipulation of the pupil as it relates to vitreoretinal dynamics is thus an area in need of further study. It is of significance that the population interested in oxymetazoline 0.1% for treatment of blepharoptosis is the same population interested in pilocarpine 1.25% for treatment of presbyopia — that is, those who are 40 to 60 years old and in a “pre-PVD” state and most susceptible to possible adverse effects from pupil modulation.16,17 Oxymetazoline 0.1% is FDA approved for temporary cosmetic relief of droopy eyelids. Although it represents a viable alternative to cosmetic surgery for some patients, much is still unknown. The ophthalmic, dermatologic, and cosmetic surgical communities who prescribe this medication, as well as the community at large, should be made aware of possible risks to healthy eyes in exchange for a transient cosmetic effect. RP

Jessica L. Barest, MD, is a comprehensive ophthalmologist and associate attending physician at New York Eye and Ear Infirmary of Mount Sinai in New York, New York. Alan R. Dayan, MD, is a vitreoretinal specialist with New York Retina Consultants in New York, New York and an assistant professor of ophthalmology at New York Eye and Ear Infirmary of Mount Sinai. The authors report no financial disclosures. Reach Dr. Barest at jlbarest@gmail.com. Editor’s note: Hear discussion of this article on the Retina Podcast at www.retinapodcast.com.

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