Oxymetazoline

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Article initiated by:

Gabriella Schmuter, M.D.

All contributors:

Ruby O Garcia, Ann Q Tran, Nagham Al-Zubidi, MD, Michael T Yen, MD, Gabriella Schmuter, M.D.

Assigned editor:

Ayman Okla Suleiman, MD

Review:

Assigned status Update Pending

 by Ayman Okla Suleiman, MD on January 10, 2024.

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Contributing Editors:	add

Overview

Upneeq (oxymetazoline hydrochloride, RVL Pharmaceuticals) ophthalmic solution 0.1% was initially approved in the United States in 2020 as the first FDA-approved medication for acquired blepharoptosis.

Background

Ptosis is a condition whereby the upper eyelid progressively descends over time due to factors such as aging, trauma, or muscular dysfunction. Within adult populations, the incidence of ptosis increases with age and has a prevalence rate between 4.7 and 13.5% in adult populations. This condition can significantly impact both a patient’s visual field and aesthetic appearance, which leads many individuals to seek treatment. Traditionally, surgical intervention has been the mainstay of treatment for acquired ptosis. However, Upneeq has provided a non-surgical option for temporary relief of ptosis. The cost of a 30-day supply of Upneeq is approximately $229 and is packaged in single use, individual vials.

Disease Entity

Acquired ptosis can result from a variety of factors including age-related changes with muscular dysfunction involving the one or both upper eyelid elevator muscles which include the levator palpebrae superioris and Muller muscles. Weakness, stretching, or dysfunction in these muscles compromise the upper eyelid's ability to adequately lift upwards, which ultimately leads to a characteristic drooping appearance. Obtaining a comprehensive history -- including the onset, associated symptoms, duration, any relevant medical history, physical exam (including a thorough neurologic exam), assessment of eyelid position, symmetry, and extraocular muscle movements -- is necessary to rule out potentially vision-threatening etiologies of ptosis.

Mechanism of Action

Oxymetazoline is an alpha-adrenergic receptor agonist believed to selectively target Muller’s muscle to elevate the upper eyelid. This mechanism provides a temporary and reversible improvement in ptosis. The duration of action of oxymetazoline is approximately 8 hours following the recommended application of one drop of oxymetazoline daily.

Dosing, Administration, and Preparation

Oxymetazoline is formulated as an ophthalmic solution with each milliliter containing 0.1% of oxymetazoline hydrochloride. Inactive ingredients include calcium chloride, hydrochloric acid, hypromellose, magnesium chloride, potassium chloride, sodium acetate, sodium chloride, sodium citrate and water. Current prescribing guidelines recommend administration of one drop of oxymetazoline ophthalmic solution in the affected eye one time daily. To ensure optimal efficacy and to minimize the risk of irritation, contact lenses should be removed prior to administering oxymetazoline ophthalmic solution and should wait at least 15 minutes before reinserting them. Additionally, when using other ophthalmic medications concomitantly, a 15 minute interval between administrations is recommended to avoid potential interactions.

Clinical Trials

Oxymetazoline was assessed in two six-week long, randomized, double-masked, vehicle-controlled, parallel-group studies to evaluate the efficacy of 0.1% oxymetazoline ophthalmic solution in a total of 304 patients in the treatment of acquired blepharoptosis. Both studies employed a 2:1 randomization ratio of active to vehicle. Efficacy was measured using the Leicester Peripheral Field Test (LPFT) and marginal reflex distance 1 (MRD1). The efficacy of oxymetazoline was measured based on the mean increase from baseline in LPFT at 6 hours on day 1 and 2 hours on day 14.

Both trials demonstrated statistically significant increases in the superior visual field of the oxymetazoline treated group compared to the vehicle group at both 2 hour and 6 hour time points (Table 1). MRD1 measurements indicated a positive effect of oxymetazoline post-dose at day 1 at 6 hours and on day 14 at 2 hours post-dose (Table 1).

Table 1. Clinical trial efficacy of 0.1% oxymetazoline ophthalmic solution at day 1 and day 14. Observed and change from baseline in mean points for the superior visual field on Leicester Peripheral Field Test (LPFT). [^a p-value and 95% CI based on ANCOVA model adjusted for baseline LFPT].

Trial 1				Trial 2
	Points Seen (SD) in Superior Visual Field		Mean Difference, [95% CL]a   p-valuea	Points Seen (SD) in Superior Visual Field		Mean Difference, [95% CL]a   p-valuea
	Upneeq N= 94	Vehicle N=46	Upneeq vs Vehicle	Upneeq N=109	Vehicle N=55	Upneeq vs Vehicle
Baseline	17.0 (4.4)	16.9 (5.2)		17.6 (4.3)	17.6 (5.5)
Day 1, Hour 6 Observed mean	22.2 (6.2)	18.4 (6.0)		23.9 (6.7)	19.7 (6.2)
Mean change from baseline	5.2 (6.0)	1.5 (3.9)	3.7 [1.8, 5.6] p<0.01	6.3 (6.7)	2.1 (4.3)	4.2 [2.4, 6.1] p<0.01
Day 14, Hour 2, Observed mean	23.4 (5.6)	19.1 (6.1)		25.3 (6.4)	20.0 (5.8)
Mean change from baseline	6.4 (5.0)	2.2 (5.8)	4.2 [2.0, 6.0] p<0.01	7.7 (6.4)	2.4 (5.3)	5.3 [3.7, 7.1] p<0.01

Contraindications

Oxymetazoline ophthalmic solution is indicated for the treatment of acquired blepharoptosis. Before starting oxymetazoline, patients are recommended to undergo a thorough evaluation for alternative etiologies of ptosis that may be vision or life threatening. It is important to note that oxymetazoline is specifically approved for involutional ptosis.

There are no absolute contraindications to the use of oxymetazoline. Caution should be exercised in patients with cardiovascular disease or those using monoamine oxidase inhibitors. Oxymetazoline is an alpha-adrenergic agonist which may affect blood pressure; therefore, careful consideration should be taken regarding the use of oxymetazoline in patients with a history of cardiovascular disease, orthostatic or poorly controlled hypotension, or poorly controlled hypertension. Immediate medical care is advised if patient’s condition worsens while taking oxymetazoline. The use of oxymetazoline for acquired ptosis has not been studied in pregnant, breastfeeding, or pediatric populations.

The safety and efficacy of oxymetazoline has not been established in pregnant women, breastfeeding women, or the pediatric population under the age of 13. Risks of congenital birth defect and spontaneous abortion in pregnant women are unknown. Clinical data is not available to evaluate the effects of oxymetazoline on breastmilk production or the presence of oxymetazoline in human breastmilk. However, in animal studies, oxymetazoline was noted in the milk of lactating rats. No significant differences in safety or effectiveness were observed in clinical trials between geriatric participants 65 years of age and older and younger adults. Oxymetazoline may be associated with an increased risk of angle closure glaucoma in patients with untreated narrow angle glaucoma. Patients experiencing acute angle closure symptoms such as eye pain, redness, blurred vision or photophobia are recommended to proceed for immediate medical care.

Adverse Effects

The most common adverse events observed with oxymetazoline ophthalmic solution during a phase 3 clinical trial included punctate keratitis, conjunctival hyperemia, dry eye, blurred vision, eye irritation, instillation site pain, and headache. Prolonged use of oxymetazoline ophthalmic solution may lead to rebound redness secondary to prolonged use of a vasoconstrictor. It is crucial to use the medication as prescribed and not to exceed the recommended dose of one drop once daily in the affected eye to mitigate the risk of adverse effects.

Conclusions

Upneeq (oxymetazoline hydrochloride) ophthalmic solution 0.1% is the only FDA-approved treatment for acquired blepharoptosis in adults. Care should be taken when using this medical treatment option to assure that vision and life-threatening ptosis is not overlooked.