The Effect of Upneeq (Oxymetazoline Hydrochloride 0.1%) on Palpebral Fissure Height, Eye Redness, and Patient-reported Eye Appearance
Phase: PHASE4
Conditions: Ptosis, Eyelid, Conjunctiva Inflamed, Eye Manifestations
Sponsor: University of Miami

 
Title: The effect of Upneeq (oxymetazoline hydrochloride 0.1%) on palpebral fissure height, 
eye redness, and patient-reported eye appearance. 
 
UMH Protocol Number: 20210199 
 
      NCT04831047 
 
 
 
3/29/23 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Protocol Title 
 
The effect of UpneeqTM (oxymetazoline hydrochloride 0.1%) on palpebral fissure height, eye 
redness, and patient-reported eye appearance. 
 
Objectives 
 
Aim 1:  
To determine the effect of UpneeqTM (oxymetazoline hydrochloride 0.1%) on palpebral fissure 
height. 
 
Aim 2: 
To determine the effect of UpneeqTM (oxymetazoline hydrochloride 0.1%) on eye redness. 
 
Aim 3: To evaluate the effect of UpneeqTM (oxymetazoline hydrochloride 0.1%) on patient-
reported eye appearance. 
 
Hypothesis: We hypothesize application of UpneeqTM (oxymetazoline hydrochloride 0.1%) will 
cause an increase in subjects’ palpebral fissure height, decrease in eye redness, and improvement 
in patient-reported eye appearance.  
 
Background 
 
Abnormal eyelid position often may be attributed to malfunctioning levator palpebrae 
superior muscle or Müller’s muscle. Müller’s muscle, a smooth muscle with a predominance of 
alpha-2 adrenergic receptors, contracts in response to sympathetic stimulation or topical 
adrenergic agonists.1,2 Therefore, topical ocular administration of compounds that agonize 
adrenergic receptors causes an increase in interpalpebral fissure height via contraction of 
Müller’s muscle, which helps mitigate ptosis effects as well as lending the cosmetically 
beneficial effect of an eye that is more open.3 Compounds such as apraclonidine, a medication 
with mixed alpha-2 and weak alpha-1 agonist properties, have been shown to reverse ptosis 
caused by Horner’s syndrome and botulinum injections and to help assess blepharoptosis 
preoperatively.4,5 Although the primary mechanism of apraclonidine is alpha-2 agonism, which 
inhibits norepinephrine release from sympathetic nerve terminals, it is also a weak alpha-1 
agonist, and allows for direct stimulation of smooth muscle. Multiple studies have observed the 
ability of topical apraclonidine to increase palpebral fissure height by elevating the upper lid.6–8 
Similarly, brimonidine, an alpha-2 adrenergic agonist with a much weaker affinity for the alpha-
1 receptor,9 has been used to decrease intraocular pressure by intensifying uveoscleral outflow 
and reducing aqueous humor inflow (brimonidine 0.2%)10, reduce ocular redness through 
vasoconstriction with low dose medication, and dilate the pupil to camouflage anisocoria 
associated with Horner’s syndrome.9,11,12 In addition, brimonidine has been observed to elevate 
patients’ eyelids via its alpha-1 and alpha-2 activation of Müller’s muscle in prior literature 
assessing glaucoma patients.13  
Similar to apraclonidine and brimonidine, oxymetazoline acts upon the alpha receptors as 
both an alpha-1 and alpha-2 receptor agonist.14,15 Oxymetazoline has been used as nasal spray to 
promote decongestion through nasal vasoconstriction,16–18 topical oxymetazoline has been used for 

rosacea,19 and ophthalmic oxymetazoline has been used for non-infectious conjunctivitis to 
improve hyperemia.20–22 The combination of alpha-1 and alpha-2 agonist action of oxymetazoline 
may be more effective in acting upon Muller’s muscle to increase palpebral height compared to 
apraclonidine and brimonidine, which primarily target the alpha-2 receptors with partial alpha-1 
receptor activation. Two randomized Phase III trials have reported significant improvement in 
mean number of points visualized on peripheral field test and increase in marginal reflex 
distance,23 leading to the FDA approval of UpneeqTM (oxymetazoline hydrochloride 0.1%) for 
ptosis. Of note, these studies have primarily examined patients with a relatively large degree of 
ptosis (mean baseline MRD1 1.09 mm). It is possible that patients with mild or minimal eyelid 
malposition may also benefit from oxymetazoline; however, this has not yet been evaluated.  
While eyelid position has been shown as a recent indication for oxymetazoline ophthalmic 
use, oxymetazoline may result in ocular surface vessel vasoconstriction to improve eye redness, 
which may provide an alternative role for this medication beyond its effect on ptosis. Previous 
studies with the apraclonidine and brimonidine demonstrated improvement in eye redness 
through conjunctival blanching, likely through the alpha-2 agonist effect on the smooth muscle 
of ocular vessels to result in vasoconstriction.11,24 Therefore, it is possible that oxymetazoline, 
which similarly has both alpha-1 and alpha-2 activity, may have similar effects on improving eye 
redness. Prior studies have reported improvement in hyperemia and eye redness in patients with 
non-infectious conjunctivitis following oxymetazoline use20,21,25; however, no study has yet 
evaluated the effect of oxymetazoline on reducing redness in healthy eyes, which may improve 
cosmesis.  
 
Improvement in eyelid position and eye redness may lead to subjective patient-reported 
improvement in cosmesis, which may be important for improvement in self-confidence, 
psychological well-being, and increased comfort in social settings.26 Prior studies investigating 
the effect of surgical ptosis repair have reported improvement in perceived eye appearance. 
However, no study has yet evaluated the effect of medical management of eyelid position on 
subjective eye appearance.  The FACE-Q is a patient-reported outcome measurement developed 
to address the lack of instruments for facial aesthetic procedures.27–30  FACE-Q has been 
previously reported as one of only 3 patient-reported outcome measures that met international 
recommendations for how such tools should be developed and validated per Oxford review of 
cosmetic surgery patient-reported outcome measures.29 It has been used to evaluate patient-
reported outcomes associated with multiple facial surgical procedures including botulinum toxin 
injections, blepharoplasties, and other cosmetic eye treatments.29,31,32 Therefore, the FACE-Q may 
be a useful, well-validated method of measuring patient perception of eye appearance following 
administration of topical medications that may result in improved cosmesis.   
 
 
To the authors’ knowledge, there are currently no randomized control trials objectively 
observing the effects of oxymetazoline on eye redness. Additionally, further studies are needed 
to better evaluate the effect of oxymetazoline on palpebral fissure height and the potential 
variability of this effect in different individuals, including those with different eyelid positions. 
Lastly, no studies have evaluated patient-reported aesthetic appearance before and after 
oxymetazoline use. In this randomized controlled study, we aim to record changes in palpebral 
fissure height and eye redness before and after administration of 0.1% oxymetazoline ophthalmic 
solution, aiming to gain a deeper understanding of oxymetazoline’s therapeutic potential as well 
as evaluate patient-reported subjective changes in appearance. 

 
Inclusion and Exclusion Criteria* 
 
Inclusion Criteria 
• 
Adults age 18 and above able to provide informed consent to participate 
• 
Subject with stable ocular health, defined as no ocular conditions requiring ongoing topical 
therapy or recent surgical intervention 
 
Exclusion Criteria 
• Adults unable to consent 
• Individuals less than 18 years of age 
• Prisoners 
• Pregnant women. 
• Patients will be asked if they are pregnant by research staff before participation in the 
study.  
• Known contradictions or sensitivities to study medication (oxymetazoline) 
• Ocular surgery within the past 3 months or refractive surgery within the past six months 
• Grossly abnormal lid margins, anatomical abnormalities, previous eyelid or orbital 
surgery 
• Variable ptosis or eyelid position (e.g., myasthenia gravis, thyroid eye disease, or 
blepharospasm)  
• Significant pre-existing ptosis of any cause (defined as MRD1 < 1mm) 
• Any ocular or systemic condition that, in the opinion of the investigator, would confound 
study data, interfere with the subject’s study participation, or affected the subject’s safety 
or trial parameters 
• Presence of an active ocular infection  
• Prior (within 5 days of beginning study treatment) use of eye whiteners (eg, 
vasoconstrictors), decongestants, antihistamines (including over the counter and herbal 
topical ophthalmic medications), phenylephrine dilating drops, any other topical 
ophthalmic agents 
• Inability to sit comfortably for 15 – 30 minutes 
 
Subject Identification and Recruitment 
Potential subjects will be identified during their normal clinic visit at the Bascom Palmer Eye 
Institute, primarily within the Oculoplastics department. The attending physician will ask eligible 
patients if they are interested in hearing about the study. No phone calls for recruitment will be 
made prior to the regular clinic visit. Patients may additionally be referred from other providers 
within the Bascom Palmer Eye Institute during their regular visits or from the emergency room. 
Bascom Palmer employees and University of Miami Miller School of Medicine students would 
also be invited to participate if interested. 
 
Participants who qualify for the study and express an interest in participating will have the study 
explained to them by a research study member and can ask questions. They will receive 
information on risks and benefits to research participation. They will receive a copy of the 
consent form and if desired may be able to take the consent form home prior to signing for 

further consultation. Those who are interested in participation will be given a scheduled 
appointment to meet with research staff. 
 
UpneeqTM Drug Product 
 
UpneeqTM is an FDA approved drug for the treatment of ptosis. It is available in a drop 
formulation. This agent should be considered exempt from IND requirements as the study is 
using the drug in realm of FDA indications and meets the below IND criteria.  
 
• 
The research is not intended to be reported to the FDA as a well-controlled study in 
support of a new indication for use nor intended to be used to support any other significant 
change in the labeling for the drug. 
• 
The research is not intended to support a significant change in the advertising for the 
product. 
• 
The research does not involve a route of administration or dosage level or use in a patient 
population or other factor that significantly increases the risks (or decreases the acceptability of 
the risks) associated with the use of the drug product. 
• 
The research is conducted in compliance with the marketing limitations described in 21 
CFR §312.7. 
 
Drug insert is available and attached to the IRB protocol.  
 
Procedures Involved 
We anticipate that procedures listed below will take about 30 to 40 minutes per patient. Except 
as noted, the procedures below are not considered standard of care and are being conducted for 
the study alone.  
 
Part 1: Pre-treatment data collection 
• Patients will complete a pre-treatment survey to evaluate the perceived baseline eye 
appearance. 
• Patients will undergo pre-treatment baseline photography. Images will be taken in a room 
with the same conditions.  
• An Ipad (Apple Inc, Cupertino, California, U.S.A.) with the Upneeq software app will be 
used. This app directs subjects to a standardized position and distance from the Ipad to 
measure the MRD1 and MRD2 in each eye. The subjects will focus on the Ipad with their 
eyes in primary gaze. 
• All photographs will be taken with the dedicated Ipad camera, which will use 
standardized aperture, shutter speed, and exposure time.  
• Photographs will be recorded and saved as JPG files (1200 9 797 pixels, 24-bit, RGB) in 
a locked folder. When not in use, the Ipad and accompanying software will be secured in 
a locked drawer. 
Part 2: UpneeqTM application 

• Subjects will be randomized to receive either UpneeqTM or balanced saline placebo in both 
eyes. 
• Based on the randomization results, the examiner will apply UpneeqTM eye drops or saline 
to the subject’s eyes.  
Part 3: Post-treatment data collection 
• Subjects will wait 2 hours after they receive eye drops. 
• Subjects will be photographed at 2 hours after drop instillation according to the procedure 
described above. This will allow Upneeq to reach its average time for maximum effect.  
• Patients will complete a post-treatment survey to evaluate the perceived change in eye 
appearance following UpneeqTM administration.  
Part 4: Data analysis 
• Data will be recorded and stored in a secure Microsoft Office Excel (Microsoft 
Corporation, Redmond, WA, U.S.A.) spreadsheet. Data will be graphically analyzed and 
represented with Adobe Photoshop (Adobe, Inc., San Jose, CA, U.S.A). 
• Data assessed will involve assessing pre and post-treatment MRD1 and MRD2, 
investigator-assessed measurements of conjunctival color including the Validated Bulbar 
Redness Scale and patient-reported outcome measures such as those measured through 
the FACE-Q survey or other patient perceptions of the drop and changes in appearance 
before and after drop instillation. 
• User performing analysis will be blinded to which patients received study drug or control. 
 
No additional follow-up outside of the patient’s next routine clinic visit will be needed. Patients 
who do have symptoms concerning any post-procedural complications will be instructed to 
notify study staff immediately. A phone number will be provided. Clinical examination post-
procedure will be at Bascom Palmer Eye Institute.  
 
Outcomes Measured 
Primary outcome: 
Outcome Measure Title: Change in palpebral fissure height 
Outcome Measure Description: Palpebral fissure height will be calculated from the sum of 
marginal reflex distance 1 and 2 measured from the photograph by Ipad software and recorded 
by investigators. 
Outcome Measure Timeframe: Baseline prior to drop administration, Day 1 
 
Secondary outcomes: 
Outcome Measure Title: Change in eye redness 
Outcome Measure Description: Scoring of ocular redness from clinical photographs will be 
performed by investigators on a 0 - 100 unit scale as compared to standardized reference 
photographs (0 = no redness, 100 = very red).  Images may also be analyzed quantitatively using 
software to calculate changes in redness between photographs. 
Outcome Measure Timeframe: Baseline prior to drop administration, Day 1 
 
Outcome Measure Title: Change in Patient-reported eye appearance 
Outcome Measure Description: Patient-reported eye appearance will be assessed by patient 
completion of the FACE-Q Eye Module Survey.  These surveys have a total raw score of 7 
(worst) to 28 (best). Higher scores indicate greater satisfaction. These survey scores will be 

assessed individually. Additionally patients will be queried regarding their perception of the drop 
including changes in eye appearance before or after drop instillation. 
Outcome Measure Timeframe: Baseline prior to drop administration, Day 1 
 
Adverse Events and Serious Adverse Events 
Treatment-emergent adverse events, defined as any event not present prior to the initiation of the 
drug treatment or any event already present that worsens in either intensity or frequency 
following exposure to the drug treatment, will be monitored and reported throughout the study. 
Treatment emergent adverse scale will be graded as the following:  
- Mild: Transient or mild discomfort (<48 hours) to the subject; no medical 
intervention/therapy required. 
- Moderate: Mild to moderate limitation in activity of the subject; no or minimal medical 
intervention/therapy required. 
- Severe: Marked limitation in activity of the subject, some assistance usually required; 
medical intervention/therapy required including possible hospitalization.  
 
Serious adverse events are defined as those which result in death, hospitalization, persistent 
or significant incapacity or substantial disruption of the ability to conduct normal life functions 
(aka disability), or congenital anomaly / birth defect.  
 
Previously reported treatment-emergent adverse effects are described further in the risks section 
below. 
 
Withdrawal of Subjects 
Patients may withdraw at any time at their discretion. Subject withdrawn from and/or terminated 
from research with or without their consent are those who are found to not meet 
inclusion/exclusion criteria, and/or are not able to complete the research protocol in its entirety, 
as well as those who suffer a treatment-emergent adverse effect requiring medication 
discontinuation. For any subjects who withdraw from research, including partial withdrawal 
from procedures, study data of the withdrawn subject will not be included in statistical analysis 
and will be shredded.  
 
Data and Specimen Banking* 
Not applicable. 
 
Data Management* 
 
Steps to Secure Data 
The study coordinator will assign each patient a specific ID number and place this information 
on a separate spreadsheet. The study coordinator will collect the sex, patient’s age, and dates of 
service, but no other identifiable information. No names will be used in the forms. Presentations 
and publications will not identify individual patients. Data from the subjects’ medical records 
will be encrypted and stored securely as detailed below. Identifiable data will not be stored for 
future use beyond the timeframe of this study.  The release of data will be only to study members 
and no other outside organization.  
 

Data will be kept under lock and key in Dr. Wendy Lee’s office at the Bascom Palmer Eye 
Institute Oculoplastics Research Laboratory on the 4th floor (900 NW 17th Street, Miami, FL 
33136), data encoded in the computer will be password-protected and will be available only to 
study personnel, and protected health information will not be re-used or disclosed for other 
purposes. Study members will be trained on how to log in and log out of the computers. The 
study coordinator will assign each patient a specific ID number and the sex, patient’s age and 
date of on a separate spreadsheet. The study coordinator will record the study results with the 
specific sample ID on another spreadsheet. 
 
Statistical Analysis Plan 
Statistical analysis will be performed by the researchers. A paired t-test will be used to analyze 
the difference in palpebral fissure height, eye redness, and patient-reported eye appearance as 
measured through the FACE-Q survey. 114 subjects will be required to perform perimetric 
statistics. Chi-squared testing will be used to assess categorical variables. P <0.05 will be 
considered significant.  
 
Risks to Subjects* 
 
The primary risks to the subjects are adverse reactions to the medication. These risks are 
explained to patients prior to their arrival to the Oculoplastics Clinic.  Previously described 
potential adverse reactions to include instillation site discomfort, punctate keratitis, and blurry 
vision although in general is well-tolerated.21–23,33 Potential psychosocial risks to subjects include 
time taken from their day to undergo tests, potentially missing work, and anxiety or discomfort 
from the eye drop instillation process. This study is not collecting sensitive information, thus no 
potential risk to reputation or legal risks should occur.  
 
Subjects will be instructed to call immediately for an appointment if they notice a change in their 
vision, eye redness, or the development of pain in either eye. Care will be taken by all study 
members to prevent the occurrence of any adverse events.  
 
There are no well-controlled studies of oxymetazoline in pregnant women, and the risks to the 
fetus or embryo are unknown/unforeseen. One prior publication reported possible renal 
collecting system abnormalities after using inhaled oxymetazoline34; however, another larger 
prospective study found no increased risk of malformations associate with nasal inhalant use 
including oxymetazoline,35 and no alterations in maternal or fetal circulation were found to be 
associated with oxymetazoline use.36 No studies have been performed evaluating topical 
oxymetazoline ophthalmic solution. Oxymetazoline is classified as US FDA pregnancy category 
C.  
 
• 
US FDA pregnancy category C: Animal reproduction studies have shown an adverse effect 
on the fetus and there are no adequate and well-controlled studies in humans, but 
potential benefits may warrant use of the drug in pregnant women despite potential risks. 
 
Participants will be informed of the above information and reserve the right to decline 
participation in the study. We will not be following pregnancy outcomes.  
 

Unanticipated problems or complications will be reported to the IRB according to posted 
guidelines.  
 
Risks of the study are listed above and will be minimized by the following:  
• Study will be discontinued if subjects experience any negative effect from the 
medication 
• Patients with a known sensitivity or history of adverse reaction to oxymetazoline 
or similar medications will be excluded from the study 
 
As with any study, there is a risk of confidentiality breach. The research members will assign 
each patient a specific ID number and place this information on a separate spreadsheet. No 
names will be used in the forms. Presentations and publications will not identify individual 
patients. 
 
 
Potential Benefits to Subjects* 
 
There will be no direct benefit to patients participating in the study. Their involvement may 
provide satisfaction for aiding in future research, particularly if they would be interested in 
personally using the agent to increase their own palpebral fissure height or eye redness in the 
future. 
 
Vulnerable Populations* 
 
Bascom Palmer employees and Miller School of Medicine students are considered vulnerable 
populations as they would be invited to participate in the study if they were interested.  
 
Setting 
 
Study location will be at the Bascom Palmer Eye Institute. 
 
Resources Available 
 
Principal investigator will be in charge of the studies and has been involved in multiple human 
clinical trials at the University of Miami. 
 
Resident physicians have extensive experience in clinical research, slit lamp examination, and 
obtaining clinical photographs, and data collection and analysis. 
 
Research fellow at the Bascom Palmer Eye Institute has experience with data collection and 
analysis.  
 
 
Prior Approvals 
 
None. 

 
Recruitment Methods 
 
Wendy Lee, MD, the principle investigator of this study, will assess patients for study eligibility 
by reviewing the medical record. These patients will be coming in during their normal visit at the 
Bascom Palmer Eye Institute Oculoplastics Clinic. Dr. Lee will ask eligible patients if they are 
interested in hearing about the study. No phone calls for recruitment will be made prior to the 
regular clinic visit. Other subjects may additionally be referred from other providers within the 
Bascom Palmer Eye Institute during their regular visits. Bascom Palmer employees and 
University of Miami Miller School of Medicine students would also be invited to participate if 
interested. No payment will be provided to patients for their participation.  
 
Subjects who qualify for the study and express an interest in participating will have the study 
explained to them by a research study member and have the opportunity to ask questions. They 
will receive information on risks and benefits to research participation. They will receive a copy 
of the consent form and if desired may be able to take the consent form home prior to signing for 
further consultation. Those who are interested in participation will be given a scheduled 
appointment to meet with research staff. 
 
 
Local Number of Subjects 
 
The goal of this pilot study is to assess the ability of UpneeqTM in patients as an agent to increase 
eyelid height as well as possibly improve eye redness and patient-reported eye appearance. The 
time and resource constraints of our current pilot study allow for only approximately 114 
participants.  
 
 
Confidentiality 
 
Check all that apply:  
  Data obtained or created for this research will be stored on an encrypted 
electronic device or system owned by the University of Miami or on a cloud 
storage system that has been approved by the University of Miami for storage or 
research data.  
 
 The Investigator (or research staff) will record (e.g. write down, abstract) data 
collected in a manner that does not include any indirect or direct identifiers and 
the recorded data will not be linked to the individual’s’ identity.   
 
 The investigator (or research staff) will record (e.g. write down, abstract) the data 
collected in a manner that does not include any direct identifiers of the subject. 
The investigator will assign a code to each subject and link the code to the 
subject’s identity.  The research team will maintain the link to the subject’s 
identity on a document separate from the research data.  Both documents will be 
stored in separate files on a University of Miami encrypted device or on a 

University of Miami approved cloud storage system. The research team will 
destroy the identifiers at the earliest opportunity. 
 
 The research team will maintain the research data for at least three years.  
 
  Bio-Specimens obtained for this research will be stored without any direct or 
indirect identifiers.   
 
  Bio-Specimens obtained for this research will be stored in a de-identified coded 
manner.   
 
  When required to transport data or bio-specimens for this research, the research 
team will transport the data and bio-specimens in a de-identified (or anonymous) 
manner with a link to the individual subject’s identity maintain separately from 
the data and/or bio-specimen. 
 
Authorization for Use and Disclosure of Protected Health Information (HIPAA)  
 
 If the research team will access patient medical records or other identifiable health 
information for this research, you must obtain a waiver of the requirement for written 
authorization from the patients to access their medical records.   
 
Type of Request: 
 Waiver of Authorization for access to medical record for subject identification/recruitment. 
 Waiver of Authorization for access to medical record to obtain data for the research. 
 
Confirm that you will destroy or de-identify the information you collect at the earliest 
opportunity.  
I confirm 
 
Confirm that the information you collect will not be reused or disclosed to any other person 
or entity, except as required by law, for authorized oversight of the research study or for 
other research for which the use or disclosure of PHI is permissible.           I confirm          
 
Provisions to Protect the Privacy Interests of Subjects 
 
An adequate plan to protect identifiers from improper use and disclosure is included in our study. 
Patient data will be collected under patient initials only.  Data will be kept under lock and key in 
Dr. Wendy Lee’s office at the Bascom Palmer Eye Institute Oculoplastics Research Laboratory 
on the 4th floor (900 NW 17th Street, Miami, FL 33136), data encoded in the computer will be 
password-protected and will be available only to study personnel, and protected health 
information will not be re-used or disclosed for other purposes. Separation of identifiers and data 
during storage, use and transmission will be implemented. Additionally, paper shredding and 
erasure of electronic data will be done at the earliest opportunity. 
 

Consent Process 
 
After identifying eligible study subjects, those who are interested in participating will be given a 
scheduled appointment to meet with research staff to review the consent form. The consent 
process will take place at Bascom Palmer Eye Institute.  Adequate time will be devoted to the 
consent discussion; the patients will be given ample time to review the consent form and ask 
questions. If patients have a different language than English, such as Spanish, as their native 
language, a translator will be used to explain the research process.  A separate consent translated 
in that appropriate language will be created prior to signing the consent. A witness will be used if 
the patient has vision impairment and is unable to read the consent.  
 
Process to Document Consent in Writing 
 
Consent of the subject will be documented in writing. 
 
 
Bibliography/References Cited 
1.  
Esmaeli-Gutstein B, Hewlett BR, Pashby RC, Oestreicher J, Harvey JT. Distribution of 
adrenergic receptor subtypes in the retractor muscles of the upper eyelid. Ophthal Plast 
Reconstr Surg. 1999;15(2):92-99. doi:10.1097/00002341-199903000-00005 
2.  
Skibell BC, Harvey JH, Oestreicher JH, et al. Adrenergic receptors in the ptotic human 
eyelid: correlation with phenylephrine testing and surgical success in ptosis repair. Ophthal 
Plast Reconstr Surg. 2007;23(5):367-371. doi:10.1097/IOP.0b013e3181462a2e 
3.  
Munden PM, Kardon RH, Denison CE, Carter KD. Palpebral fissure responses to topical 
adrenergic drugs. Am J Ophthalmol. 1991;111(6):706-710. doi:10.1016/s0002-
9394(14)76775-3 
4.  
Park SJ, Jang SY, Baek JS, Chin S, Jang JW. Distribution of Adrenergic Receptor Subtypes 
and Responses to Topical 0.5% Apraclonidine in Patients With Blepharoptosis. Ophthal 
Plast Reconstr Surg. 2018;34(6):547-551. doi:10.1097/IOP.0000000000001095 
5.  
Wijemanne S, Vijayakumar D, Jankovic J. Apraclonidine in the treatment of ptosis. J 
Neurol Sci. 2017;376:129-132. doi:10.1016/j.jns.2017.03.025 
6.  
Kirkpatrick CA, Shriver EM, Clark TJE, Kardon RH. Upper Eyelid Response to Topical 
0.5% Apraclonidine. Ophthal Plast Reconstr Surg. 2018;34(1):13-19. 
doi:10.1097/IOP.0000000000000843 
7.  
Yazici B, Beden U. Use of 0.5% apraclonidine solution in evaluation of blepharoptosis. 
Ophthal Plast Reconstr Surg. 2008;24(4):299-301. doi:10.1097/IOP.0b013e31817f526a 
8.  
Koc F, Kavuncu S, Kansu T, Acaroglu G, Firat E. The sensitivity and specificity of 0.5% 
apraclonidine in the diagnosis of oculosympathetic paresis. Br J Ophthalmol. 
2005;89(11):1442-1444. doi:10.1136/bjo.2005.074492 

9.  
Torkildsen GL, Sanfilippo CM, DeCory HH, Gomes PJ. Evaluation of Efficacy and Safety 
of Brimonidine Tartrate Ophthalmic Solution, 0.025% for Treatment of Ocular Redness. 
Curr Eye Res. 2018;43(1):43-51. doi:10.1080/02713683.2017.1381269 
10.  Toris CB, Gleason ML, Camras CB, Yablonski ME. Effects of brimonidine on aqueous 
humor dynamics in human eyes. Arch Ophthalmol Chic Ill 1960. 1995;113(12):1514-1517. 
doi:10.1001/archopht.1995.01100120044006 
11.  McLaurin E, Cavet ME, Gomes PJ, Ciolino JB. Brimonidine Ophthalmic Solution 0.025% 
for Reduction of Ocular Redness: A Randomized Clinical Trial. Optom Vis Sci. 
2018;95(3):264-271. doi:10.1097/OPX.0000000000001182 
12.  deSousa J-L, Malhotra R. Brimonidine for anisocoria. Ophthalmology. 2007;114(7):1419. 
doi:10.1016/j.ophtha.2006.08.021 
13.  Burroughs JR, Anderson RL, Patrinely JR, Weinberg DA, McCann JD, McMullan TFW. 
Preoperative assessment of the eye and periocular region. Semin Plast Surg. 2007;21(1):5-
17. doi:10.1055/s-2007-967742 
14.  Hsia E, Tian M, Gil D. Reduction in ultraviolet B light-induced erythema by oxymetazoline 
and brimonidine is mediated by different α-adrenoceptors. Exp Dermatol. 2018;27(7):763-
768. doi:10.1111/exd.13557 
15.  Haenisch B, Walstab J, Herberhold S, et al. Alpha-adrenoceptor agonistic activity of 
oxymetazoline and xylometazoline. Fundam Clin Pharmacol. 2010;24(6):729-739. 
doi:https://doi.org/10.1111/j.1472-8206.2009.00805.x 
16.  Graf P, Hallén H. Effect on the Nasal Mucosa of Long-Term Treatment With 
Oxymetazoline, Benzalkonium Chloride, and Placebo Nasal Sprays. The Laryngoscope. 
1996;106(5):605-609. doi:https://doi.org/10.1097/00005537-199605000-00016 
17.  Graf P, Juto J-E. Decongestion Effect and Rebound Swelling of the Nasal Mucosa during 4-
Week Use of Oxymetazoline. ORL. 1994;56(3):157-160. doi:10.1159/000276633 
18.  Baroody FM, Brown D, Gavanescu L, DeTineo M, Naclerio RM. Oxymetazoline adds to 
the effectiveness of fluticasone furoate in the treatment of perennial allergic rhinitis. J 
Allergy Clin Immunol. 2011;127(4):927-934. doi:10.1016/j.jaci.2011.01.037 
19.  Draelos ZD, Gold MH, Weiss RA, et al. Efficacy and safety of oxymetazoline cream 1.0% 
for treatment of persistent facial erythema associated with rosacea: Findings from the 52-
week open label REVEAL trial. J Am Acad Dermatol. 2018;78(6):1156-1163. 
doi:10.1016/j.jaad.2018.01.027 
20.  Breakey AS, Cinotti AA, Hirshman M, Skowron RA, Samson CR, Danzig MR. A double-
blind, multi-centre controlled trial of 0.25% oxymetazoline ophthalmic solution in patients 
with allergic and non-infectious conjunctivitis. Pharmatherapeutica. 1980;2(6):353-356. 

21.  Rybiczka R, Mauracher E. Oxymetazoline ophthalmic solution versus naphazoline solution 
in non-infectious conjunctivitis. Pharmatherapeutica. 1983;3(6):376-381. 
22.  Fox SL, Samson CR, Danzig MR. Oxymetazoline in the Treatment of Allergic and Non-
Infectious Conjunctivitis. J Int Med Res. 1979;7(6):528-530. 
doi:10.1177/030006057900700609 
23.  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 
24.  Ackerman SL, Torkildsen GL, McLaurin E, Vittitow JL. Low-dose brimonidine for relief 
of ocular redness: integrated analysis of four clinical trials. Clin Exp Optom. 
2019;102(2):131-139. doi:https://doi.org/10.1111/cxo.12846 
25.  Nayak BK, Kishore K, Gupta SK. Evaluation of oxymetazoline and naphazoline in benign 
red eyes : A double blind comparative clinical trial. Indian J Ophthalmol. 1987;35(4):190. 
26.  Maisel A, Waldman A, Furlan K, et al. Self-reported Patient Motivations for Seeking 
Cosmetic Procedures. JAMA Dermatol. 2018;154(10):1167-1174. 
doi:10.1001/jamadermatol.2018.2357 
27.  Pusic AL, Klassen AF, Scott AM, Cano SJ. Development and Psychometric Evaluation of 
the FACE-Q Satisfaction with Appearance Scale: A New Patient-Reported Outcome 
Instrument for Facial Aesthetics Patients. Clin Plast Surg. 2013;40(2):249-260. 
doi:10.1016/j.cps.2012.12.001 
28.  Klassen A, Cano S, Scott A, Snell L, Pusic A. Measuring Patient-Reported Outcomes in 
Facial Aesthetic Patients: Development of the FACE-Q. Facial Plast Surg. 
2010;26(04):303-309. doi:10.1055/s-0030-1262313 
29.  Klassen AF, Cano SJ, Grotting JC, et al. FACE-Q Eye Module for Measuring Patient-
Reported Outcomes Following Cosmetic Eye Treatments. JAMA Facial Plast Surg. 
Published online January 19, 2017. doi:10.1001/jamafacial.2016.1018 
30.  Klassen AF, Cano SJ, Schwitzer JA, Scott AM, Pusic AL. FACE-Q scales for health-
related quality of life, early life impact, satisfaction with outcomes, and decision to have 
treatment: development and validation. Plast Reconstr Surg. 2015;135(2):375-386. 
doi:10.1097/PRS.0000000000000895 
31.  Chang BL, Wilson AJ, Taglienti AJ, Chang CS, Folsom N, Percec I. Patient Perceived 
Benefit in Facial Aesthetic Procedures: FACE-Q as a Tool to Study Botulinum Toxin 
Injection Outcomes. Aesthet Surg J. 2016;36(7):810-820. doi:10.1093/asj/sjv244 
32.  Chen B, Song H. Measuring satisfaction with appearance: Validation of the FACE-Q scales 
for double-eyelid blepharoplasty with minor incision in young Asians- retrospective study 

of 200 cases. J Plast Reconstr Aesthet Surg. 2017;70(8):1129-1135. 
doi:10.1016/j.bjps.2017.05.028 
33.  Samson CR, Danzig MR, Sasovetz D, Thompson HS. Safety and toleration of 
oxymetazoline ophthalmic solution. Pharmatherapeutica. 1980;2(6):347-352. 
34.  Menezes GA, Araujo Júnior E, Lopes J, Belmonte S, Tonni G, Werner H. Prenatal 
diagnosis and physical model reconstruction of agnathia-otocephaly with limb deformities 
(absent ulna, fibula and digits) following maternal exposure to oxymetazoline in the first 
trimester. J Obstet Gynaecol Res. 2016;42(8):1016-1020. doi:10.1111/jog.13014 
35.  Schatz M, Zeiger RS, Harden K, Hoffman CC, Chilingar L, Petitti D. The safety of asthma 
and allergy medications during pregnancy. J Allergy Clin Immunol. 1997;100(3):301-306. 
doi:10.1016/S0091-6749(97)70241-0 
36.  Rayburn WF, Anderson JC, Smith CV, Appel LL, Davis SA. Uterine and fetal Doppler 
flow changes from a single dose of a long-acting intranasal decongestant. Obstet Gynecol. 
1990;76(2):180-182.