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DRUGS IN DERMATOLOGY
Topical Oxymetazoline (Rhofade)
in Rosacea
Nicole K. Nagrani, Adrianna M. Gonzalez, Patrick M. Zito,
Brad P. Glick, and Richard M. Rubenstein
ABSTRACT: By definition, a drug is a medicine or substance
that exerts a physiologic effect on an organism. In dermatol
ogy, various medications and substances are utilized on a
daily basis, ranging from topical treatments to anesthetics
in micrographic surgery. The purpose of this section is to fo
cus on some of the more common substances, specifically
how they work, how they are utilized, and routine alterna
tives (if available). The mechanism of action, usage, and
alternative options of the medication topical oxymetazoline
are discussed.
Key words: Demodex folliculorum, Erythematotelangiectatic,
Oxymetazoline, Rhofade, Rosacea
R
osacea is a common and chronic relapsing inflam
matory dermatosis primarily affecting the cheeks,
nose, chin, and forehead. The cutaneous manifes
tations are diverse but are characterized by persistent facial
erythema, telangiectasias, inflammatory papules and pus
tules, facial flushing, nonpitting facial edema, and sometimes
phymatous growth (Two et al., 2015) Depending on the
predominant feature, rosacea may be classified into one
Nicole K. Nagrani, BS, Department of Dermatology & Cutaneous
Surgery, Miller School of Medicine, University of Miami, Miami, FL.
Adrianna M. Gonzalez, BS, Department of Dermatology & Cutaneous
Surgery, Miller School of Medicine, University of Miami, Miami, FL.
Patrick M. Zito, DO, PharmD, RPh, FASCP, FRSPH, Department of
Dermatology & Cutaneous Surgery, Miller School of Medicine, Uni
versity of Miami, Miami, FL; College of Health Sciences, School of
Nursing, Walden University, Minneapolis, MN; and Larkin Com
munity Hospital - Palm Springs Campus, Hialeah, FL.
Brad P. Glick, DO, MPH, FAAD, Larkin Community Hospital - Palm
Springs Campus, Hialeah, FL.
Richard M. Rubenstein, MD, FAAD, Larkin Community Hospital -
Palm Springs Campus, Hialeah, FL.
The authors declare no conflict of interest.
Correspondence concerning this article should be addressed to
Patrick M. Zito, DO, PharmD, RPh, FASCP, FRSPH, College of Health
Sciences, School of Nursing, Walden University, 100 Washington Ave.,
S. Suite 900, Minneapolis, MN 55401. E-mail: Patrick.zito@waldenu.edu
Copyright (c) 2020 by the Dermatology Nurses' Association.
DOI: 10.1097/JDN.0000000000000564
of four different subtypes including erythematotelangiectatic,
papulopustular, phymatous, and ocular (Two et al., 2015).
The erythema of rosacea can be further subdivided into (a)
sole erythema, (b) erythema with telangiectasias, (c) erythema
with edema, and (d) erythema with inflammatory papules
and nodules (Wollina, 2014). Diffuse facial erythema must
be distinguished from the perilesional erythema associated
with inflammatory lesions to optimize treatment (Del Rosso,
2012; Wollina, 2014).
The most common form is the erythematotelangiectatic
type, which presents with persistent centrofacial erythema
and telangiectasia, without additional inflammatory lesions
(Del Rosso et al., 2013; Hoover & Erramouspe, 2018).
The redness is maintained in between flares, although it
may be exacerbated by certain triggers such as alcohol, spicy
foods, and increased sun exposure (Hoover & Erramouspe,
2018). Although the pathogenesis has yet to be fully eluci
dated, rosacea is thought to be related to overgrowth of skin
organisms, dysregulation of the innate immune system, and
aberrant signaling of the neurovascular system (Two et al.,
2015). Significantly higher levels of Demodex folliculorum,
a saprophytic mite that resides in the pilosebaceous unit,
have been reported in several studies done on patients
with rosacea. The facial erythema of rosacea correlates
with the increased density and diameter of the underlying
vasculature, which is modulated by the sympathetic ner
vous system (Del Rosso, 2017). In addition, cathelicidin
peptide (LL-37), an antimicrobial peptide, is elevated in
rosacea skin. Although topical antibiotics have a role in con
trolling the underlying bacterial infection associated with
the inflammation seen in rosacea, they are not as effective
in controlling the inflammatory factors that lead to vaso
dilation and redness in erythematotelangiectatic rosacea
(Del Rosso, 2013). These superficial blood vessels are
encased by a sheath of smooth muscles, which allow for
vasoconstriction after alpha-1-adrenergic receptor agonism.
Constriction of these blood vessels may significantly reduce
facial erythema, although it will not affect capillaries nor
telangiectasias as the adrenergic effect is limited to the
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DRUGS IN DERMATOLOGY
precapillary arterioles (Del Rosso, 2013, 2017; Fowler
et al., 2015; Shanler & Ondo, 2007).
Emergence of Oxymetazoline in Facial Erythema
Treatment of rosacea often incorporates multiple modalities,
ranging from topical drugs to oral drugs and combination
therapy (Staedtler et al., 2017). To modulate vasculature ac
tivity, topical alpha-adrenergic receptor agonists were devel
oped and have been found to be effective in decreasing facial
erythema. The alpha-1-adrenergic agonist, oxymetazoline,
has been historically used for nasal congestion, as it con
stricts the vessels of the nasal mucosa when applied intrana
sally. The vasoconstrictive properties of this medication are
now being applied for the management of cutaneous dis
eases such as rosacea. In January 2017, the Food and Drug
Administration approved oxymetazoline hydrochloride 1%
cream (Rhofade, Allergan Pharmaceuticals, Irvine, CA) for
the treatment of rosacea. Data were taken from two random
ized controlled trials where the safety and efficacy of topical
oxymetazoline hydrochloride 1% cream were evaluated for
the treatment of persistent facial erythema of rosacea. Eight
hundred eighty-five patients with moderate-to-severe facial er
ythema related to rosacea were enrolled, with 79% of patients
being female and 90% being White. Patients were random
ized into two groups, with 489 receiving oxymetazoline and
483 given vehicle. They were instructed to apply the creams
topically to the face once daily for 29 days. On the 29th
day, facial erythema was analyzed at 3, 6, 9, and 12 hours
postdose. Facial erythema was evaluated on both patient-
and clinician-reported 5-point scales, and the combination
of this value was used to determine the number of patients
experiencing a 2-point improvement from baseline. Results
showed a significant decrease in facial erythema using
oxymetazoline (12%-18%) at each time point compared
with vehicle (5%-9%). In the long-term open-label study
lasting 52 weeks, oxymetazoline continued to show simi
lar results in which oxymetazoline was found to be supe
rior to vehicle, therefore establishing efficacy of the drug.
Furthermore, the clinical trials were designed to evaluate
for rebound erythema after discontinuation of the topical
medication. There was no indication either on the package
inserts or in the  clinical  trial data to indicate posttreatment
rebound, intermittent flushing, or worsening of facial ery
thema after discontinuation of the oxymetazoline (Del
Rosso, 2017; Hoover & Erramouspe, 2018).
Adverse Effects
In the clinical trials, topical treatment with oxymetazoline
was well tolerated with adverse effects being mild to moderate
in severity. Side effects in patients applying oxymetazoline
every day for 29 days included application site dermatitis
(2%), worsening inflammatory lesions of rosacea (1%),
pruritus at application site (1%), erythema (1%), and pain
(1%; Katzung et al., 2017). The long-term clinical trial had
244
similar adverse effects, with similar rates: worsening inflam
matory lesions of rosacea (3%), application site dermatitis
(3%), pruritus (2%), pain (2%), and erythema (2%; Lexi-
Comp, 2020; Litt & Shear, 2017). In both studies, the
worsening of facial erythema was minimal during active
treatment and after discontinuation of therapy with topical
oxymetazoline, suggesting this is an uncommon side effect
(Del Rosso, 2017).
Alternatives
The first topical medication approved for persistent facial
erythema of rosacea was brimonidine 0.33% (brimonidine
tartrate 0.5%) gel in August 2014. Brimonidine differs from
oxymetazoline by its selective action on alpha-2 adrenergic
receptors where it also acts as a vasoconstrictor of the
superficial vasculature ("Mirvaso," 2016). Brimonidine
onset of action is approximately 30 minutes and lasts up
to 6 hours. Adverse effects of topical brimonidine include flush
ing (10%), erythema (8%), rosacea (5%), nasopharyngitis
(5%), skin burning sensation (4%), increased intraocular
pressure (4%), and headache (4%). Moreover, data from
the brimonidine clinical trials describe that some subjects
experienced rebound erythema that was worse in severity
when compared with baseline, an adverse effect that was
not seen with topical oxymetazoline ("Mirvaso," 2016).
Currently, there are no studies comparing the safety
and efficacy of oxymetazoline with that of brimonidine.
Using the results from the existing clinical trials to make a
comparison is difficult because of the different measurement
scales used in each study. The Clinical Erythema Assessment
scale and Patient Self-Assessment scale were utilized in the
brimonidine studies, whereas the Clinical Erythema Assess
ment and Subject Self-Assessment scales were utilized in
the oxymetazoline studies (Hoover & Erramouspe, 2018;
Fowler et al., 2015). Although both assessments are based
on 5-point scales, there are different definitions for each
point, and therefore no correlation can be drawn between
the two studies (Hoover & Erramouspe, 2018). Further
research to determine the therapeutic differences between
these two medications is still needed.
CONCLUSIONS
Rosacea is a common facial dermatosis, and the appearance
associated with this disease has been found to negatively im
pact the quality of life by creating stigmatizing feelings and
anxiety in these patients (Duman et al., 2014). Although
many therapies are available for the treatment of rosacea,
the optimal therapy for the management of facial erythema
has yet to be established. On the basis of current research,
topical alpha-adrenergic agonist therapies have proven to
be safe and effective and are currently the only agents offered
to specifically target the facial erythema of rosacea. Topical
1% oxymetazoline should now be considered in the ar
mamentarium of medications used for facial erythema
Journal of the Dermatology Nurses' Association
Copyright (c) 2020 Dermatology Nurses' Association. Unauthorized reproduction of this article is prohibited.

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DRUGS IN DERMATOLOGY
in rosacea, as data suggest that it is an efficacious alterna
tive with minimal side effects compared with previously
approved topical medications.
REFERENCES
Del Rosso, J. Q. (2012). Advances in understanding and managing rosacea:
Part 2: The central role, evaluation, and medical management of diffuse
and persistent facial erythema of rosacea. Journal of Clinical Aesthetic
Dermatology, 5(3), 26-36. https://www.ncbi.nlm.nih.gov/pubmed/
22468177
Del Rosso, J. Q. (2013). Management of facial erythema of rosacea: What is
the  role of topical  -adrenergic receptor agonist therapy? Journal of the
Amercian Academy of Dermatology, 69(6, Suppl. 1), S44-S56. 10.1016/
j.jaad.2013.06.009
Del Rosso, J. Q. (2017). Topical -agonist therapy for persistent facial erythema
of rosacea and the addition of oxmetazoline to the treatment armamentar
ium: Where are we now? Journal of Clinical Aesthetic Dermatology,
10(7), 28-32. https://www.ncbi.nlm.nih.gov/pubmed/29104721
Del Rosso, J. Q., Thiboutot, D., Gallo, R., Webster, G., Tanghetti, E., Eichenfield,
L., Stein-Gold, L., Berson, D., & Zaenglein, A. (2013). Consensus recommen
dations from the American Acne & Rosacea Society on the management
of rosacea, part 1: A status report on the disease state, general measures,
and adjunctive skin care. Cutis, 92(5), 234-240. https://www.ncbi.nlm.
nih.gov/pubmed/24343208
Duman, N., Ersoy Evans, S., & Atakan, N. (2014). Rosacea and cardiovascu
lar risk factors: A case control study. Journal of the European Academy of
Dermatology and Venereology, 28(9), 1165-1169. 10.1111/jdv.12234
Fowler, J.,  Tan,  J., Jackson, J. M.,  Meadows,  K., Jones, T.,  Jarratt,  M., Leoni, M.
Brimonidine Phase III Study Group (2015). Treatment of facial erythema in
patients with rosacea with topical brimonidine tartrate: Correlation of
patient satisfaction with standard clinical endpoints of improvement
of facial erythema. J Eur Acad Dermatol Venereol, 29(3), 474-481.
10.1111/jdv.12587
Hoover, R. M., & Erramouspe, J. (2018). Role of topical oxymetazoline for
management of erythematotelangiectatic rosacea. Annals of Pharmacother,
52(3), 263-267. 10.1177/1060028017740139
Katzung, B. G., Trevor, A. J., & Access Medicine. (2017). Basic and clinical
pharmacology (14th ed.). McGraw-Hill Education.
Lexi-Comp. (2020). LexiDrugs oxymetazoline. http://www.lexi.com
Litt, J. Z., & Shear, N. H. (2017). Litt's drug eruption and reaction manual
(23rd ed.). Taylor & Francis.
Mirvaso (brimonidine) [product information]. (2016). Galderma Laborato
ries, LP.
Rhofade (oxymetazoline) [product information]. (2017). Allergan, PLC.
Shanler, S. D., & Ondo, A. L. (2007). Successful treatment of the erythema and
flushing of rosacea using a topically applied selective alpha1-adrenergic recep
tor agonist, oxymetazoline. Archives of Dermatology, 143(11), 1369-1371.
10.1001/archderm.143.11.1369
Staedtler, G., Shakery, K., Endrikat, J., Nkulikiyinka, R., & Gerlinger, C.
(2017). An empirically generated responder definition for rosacea treatment.
Clinical Cosmetic Investigative Dermatology, 10, 347-352. 10.2147/CCID.
S139352
Two, A. M., Wu, W., Gallo, R. L., & Hata, T. R. (2015). Rosacea: Part I. in
troduction, categorization, histology, pathogenesis, and risk factors. Jour
nal of the American Academy of Dermatology, 72(5), 749-758. 10.1016/
j.jaad.2014.08.028
Wollina, U. (2014). Recent advances in the understanding and management of
rosacea. F1000Research, 6, 50. 10.12703/P6-50
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Copyright (c) 2020 Dermatology Nurses' Association. Unauthorized reproduction of this article is prohibited.