Oxymetazoline for Ptosis

Invited Commentary

Invited Commentary

Oxymetazoline for Ptosis Elizabeth A. Bradley, MD, MHS; David J. Bradley, MD, PhD, ScM

Oxymetazoline (Afrin) nasal spray was approved by the US Food and Drug Administration (FDA) more than 50 years ago for the treatment of nasal congestion. In July 2020, the FDA approved a new formulation in which a higher concentration of oxymetazoline has been incorporated into Related article eyedrops. These eyedrops allow oxymetazoline to elevate the eyelid by activating α-adrenergic receptors in the Muller muscle. In this issue of JAMA Ophthalmology, Slonim et al1 report the results of 2 industry-sponsored randomized placebo-controlled masked trials that assess the efficacy of oxymetazoline, 0.1%, eyedrops for ptosis. Repurposing an old drug has its appeal. An old drug comes with a known adverse effect profile and an established manufacturing base. However, proving that an old drug can safely and effectively take on a new role may not be easy. Consider the experience with hydroxychloroquine. Long a mainstay in the treatment of malaria, lupus erythematosus, and rheumatoid arthritis, hydroxychloroquine has been associated in observational data with improved survival among patients with coronavirus disease 2019.2 However, despite some initial promising findings, the drug has faced considerable controversy, and the FDA revoked its emergency use authorization. Randomized clinical trials have not necessarily shown benefit.3 Finding a new purpose for an old drug may be even more daunting if the drug is perceived as a potential threat to established surgical practice. Such a drug could conceivably help patients delay or even avoid the potential discomfort, cost, and morbidity of surgery. However, in addition to appropriate scientific skepticism, use of the drug may be met with resistance from surgeons whose livelihood may be harmed financially by the drug. In their studies of oxymetazoline hydrogen chloride (HCl), 0.1%, Slonim et al1 randomized a total of 304 patients with acquired ptosis to topical oxymetazoline HCl, 0.1%, vs vehicle in 2 trials. These are industry-sponsored trials for which the authors report that RevitaLid Inc played a role in the conduct, analysis, and reporting of the studies. All but 1 participant was an adult, and all participants had clinically relevant involutional ptosis defined by superior visual field loss and reduced eyelid height. Response to therapy was evaluated at 1 day and 14 days of treatment, and safety was evaluated over 42 days of follow-up. Using Leicester Humphrey Visual Field (HVF) static perimetry as the primary outcome, the authors showed a change in the oxymetazoline treatment arm of 4 to 5 points of superior visual field more than the change in the vehicle arm. The secondary outcome, change in upper eyelid height, increased by less than 0.5 mm in the treatment arm compared with the vehicle arm on day 1 and by 0.67 mm compared with vehicle on day 14. Oxymetazoline HCl, 0.1%, was generally well tolerated, with no change in visual acuity or injamaophthalmology.com

traocular pressure but with somewhat higher rates of punctate keratitis, conjunctival hyperemia, and subjectively blurred vision in the study group. As acknowledged by the authors,1 the study has limitations that may be associated with the clinical applicability of their findings. Although static perimetry is commonly used in the evaluation of ptosis, little has been published about the performance of the Leicester HVF program that is the study’s primary outcome. It is unclear whether a gain of 4 to 5 points of superior visual field, or roughly half a line of points on the Leicester HVF, represents meaningful clinical change. The corresponding less than 1 mm of eyelid elevation produced by oxymetazoline compared with vehicle may also be of marginal clinical benefit. While it is possible that this degree of eyelid elevation yields substantial improvements in visual function and patient self-image, an assessment of health-related quality of life was not included in the study. Additionally, the short study duration did not allow for a full assessment of adverse effects, including known α-adrenergic agonist adverse effects of follicular conjunctivitis and dry eye. The short study duration also leaves unanswered the question of possible loss of drug effect over time. Tachyphylaxis is a known response to treatment with α-adrenergic agonists4 but can take many weeks or longer to develop, a timeline that exceeds the 14 days used to assess treatment efficacy in this study. The studies by Slonim et al1 were not designed to compare oxymetazoline with surgery. Compared with historical case series, the visual field and eyelid height improvement observed in the Slonim et al1 studies with oxymetazoline are less than is usually seen with surgical repair of ptosis, where patients often gain more than 20 points of static perimetry visual field5 and eyelid elevation greater than 2.5 mm.6 But as the authors note, surgery is not without possible unwanted effects, including dry eye, lagophthalmos, and overcorrection or undercorrection. The most obvious clinical application for oxymetazoline HCl, 0.1%, is in patients with a small amount of cosmetically objectionable ptosis for whom a perfect result with a single surgery cannot be guaranteed. If such a patient could use a daily eyedrop to alleviate ptosis and avoid surgery, both patient and surgeon would likely embrace the therapy. The fact that the drug can be used for both cosmetic and functional indications raises the possibility that payers will require prior authorization for its use in the form of visual field testing and clinical photographs. Such authorization is required by commercial and government payers for nearly all ptosis surgery in adults. Obtaining prior authorization on behalf of patients adds to the administrative complexity and cost of clinical practice. When required, prior authorization submission is the most costly item of postencounter costs, exceeding coding and billing.7 Requiring prior authorization to prescribe oxymetazoline HCl, 0.1%, would likely dampen physician enthusiasm for the drug. (Reprinted) JAMA Ophthalmology Published online October 1, 2020

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Invited Commentary

Oxymetazoline for Ptosis

In summary, the report by Slonim et al1 introduces a potential novel avenue of treatment for a common problem using an updated formulation of an old drug. Defining the appropriate role for oxymetazoline HCl, 0.1%, in clinical practice requires future studies that demonstrate improved healthrelated quality of life, reasonable drug cost, low administrative burden, durable treatment effect, and minimal adverse ef-

fects with long-term use. Even with such future studies, the modest improvements in visual field and eyelid height reported in this study suggest that the drug may be most useful for managing mild ptosis or for more substantial ptosis in which surgical correction is not advised because of ocular or medical comorbidities. For that group of patients, the “new trick” offered by this “old dog” could be very appealing.

ARTICLE INFORMATION

REFERENCES

Author Affiliations: Mayo Clinic Department of Ophthalmology, Mayo Foundation, Rochester, Minnesota (E. A. Bradley); Mayo Clinic Department of Cardiovascular Medicine, Mayo Foundation, Rochester, Minnesota (D. J. Bradley).

1. Slonim CB, Foster S, Jaros M, et al. Association of oxymetazoline hydrochloride, 0.1%, solution administration with visual field in acquired ptosis: a pooled analysis of 2 randomized clinical trials. JAMA Ophthalmol. Published online October 1, 2020. doi:10.1001/jamaophthalmol.2020.3812

Corresponding Author: Elizabeth Bradley, MD, MHS, Mayo Clinic Department of Ophthalmology, 200 First Street SW, Rochester, MN 55905 ([email protected]). Published Online: October 1, 2020. doi:10.1001/jamaophthalmol.2020.3833 Conflict of Interest Disclosures: None reported. Additional Contributions: We thank Andrea Tooley, MD, for assistance with this commentary.

concepts and clinical implications. N Engl J Med. 1996;334(9):580-585. doi:10.1056/ NEJM199602293340907 5. Patipa M. Visual field loss in primary gaze and reading gaze due to acquired blepharoptosis and visual field improvement following ptosis surgery. Arch Ophthalmol. 1992;110(1):63-67. doi:10.1001/ archopht.1992.01080130065027

2. Arshad S, Kilgore P, Chaudhry ZS, et al; Henry Ford COVID-19 Task Force. Treatment with hydroxychloroquine, azithromycin, and combination in patients hospitalized with COVID-19. Int J Infect Dis. 2020;97:396-403. doi:10. 1016/j.ijid.2020.06.099

6. Fuller ML, Briceño CA, Nelson CC, Bradley EA. Tangent screen perimetry in the evaluation of visual field defects associated with ptosis and dermatochalasis. PLoS One. 2017;12(3):e0174607. doi:10.1371/journal.pone.0174607

3. Cavalcanti AB, Zampieri FG, Rosa RG, et al; Coalition Covid-19 Brazil I Investigators. Hydroxychloroquine with or without azithromycin in mild-to-moderate Covid-19. N Engl J Med. 2020. doi:10.1056/NEJMoa2019014

7. Tseng P, Kaplan RS, Richman BD, Shah MA, Schulman KA. Administrative costs associated with physician billing and insurance-related activities at an academic health care system. JAMA. 2018;319 (7):691-697. doi:10.1001/jama.2017.19148

4. Insel PA. Seminars in medicine of the Beth Israel Hospital, Boston: adrenergic receptors: evolving

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JAMA Ophthalmology Published online October 1, 2020 (Reprinted)

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Oxymetazoline for Ptosis Invited Commentary Invited Commentary Oxymetazoline for Ptosis Elizabeth A. Bradley, MD, MHS; David J. Bradley, MD, PhD, S...
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