ology of this disease is far from clear at this time.2 However,
it is known that facial redness due to vascular changes can be
transient or persistent.5 Papulopustular lesions often have associated
redness (lesional or perilesional) which is different from
generalized vascular erythema.5, 10, 14 Finally, specific events of
flushing may occur via a different mechanism than generalized
erythema of rosacea and should clearly be differentiated from
physiologic blushing, which occurs involuntarily in response to
emotional and other stressors (eg, embarrassment).
Brimonidine is an alpha-2 adrenergic agonist that, when applied
topically, causes peripheral vasoconstriction via a direct
effect on smooth muscle-receptors.15-17 It is thought that the
vasoconstrictive action of topical brimonidine gel counteracts
abnormal dilation of facial blood vessels in patients with rosacea.
The safety and efficacy of brimonidine gel in rosacea were
evaluated in two large-scale, controlled phase III studies and
a long-term safety study.16, 17 Together, these studies enrolled
992 subjects, 726 of whom were treated with brimonidine
gel.16, 17 The phase III studies showed that brimonidine gel was
significantly more efficacious than its vehicle throughout the
study duration; in addition, it had a good safety profile.17 The
long-term study also showed that brimonidine gel works well
in the management of facial erythema of rosacea and demonstrated
that brimonidine can be used safely at least for
a period of 12 months.16 As the first drug approved for the
treatment of facial erythema of rosacea throughout the world,
brimonidine gel can have an essential role in the overall management
of rosacea. Since its introduction, there have been
reports in the literature and in informal communications on
a “rebound†or worsening of redness that can occur during
brimonidine gel therapy.18, 19 This article, written by a group of
dermatologists with more than 1 year of hands-on experience
with brimonidine (including as clinical trial investigators), is
designed to help guide clinicians in the use of brimonidine gel
as part of a rosacea treatment plan.
Because we believe that brimonidine gel is an important therapeutic
option addressing a key unmet need in rosacea, we have
listed here detailed steps that may be used to optimize efficacy
and minimize the potential for adverse events including the
phenomena often called “rebound†worsening of erythema.
We also propose more specific terms to clarify the onset and
type of erythema that has occurred.
A Closer Look at Brimonidine-Associated “Rebound†Phenomena
“Rebound†phenomena or treatment-related erythematous events
have been reported in brimonidine clinical trials, literature, postlaunch
spontaneous safety reporting (pharmacovigilance), and in
informal communications such as patient websites and physician
meetings.13, 17-19 This section discusses the events that have been
grouped together and categorized as “rebound†and provides recommendations for assessing redness associated with brimonidine
therapy based on available data and our clinical experience.
“Rebound†in the Brimonidine Clinical Development Program
Traditionally, “rebound†is defined as the emergence or reemergence
of symptoms that were absent or controlled during
treatment, but appear after discontinuation of treatment or
when the dosage is reduced. In the case of re-emergence, the
severity of the symptoms is often worse than pretreatment
levels.20 In the early stages of brimonidine clinical development
for rosacea, the US Food and Drug Administration (FDA)
provided guidance to the drug’s manufacturer that “reboundâ€
should be defined as worsening of subject’s rosacea after cessation
of brimonidine gel therapy. As shown in Figure 1, the
term “rebound†was not used for any worsening of redness
events during the active phase of the brimonidine gel studies
(any redness event during the active phase was recorded as
an adverse event); all assessments of “rebound†in the clinical
studies occurred after discontinuation of therapy.13
In their presentation of the phase III clinical study results, Fowler
et al reported that there was “no rebound or worsening of erythemaâ€
during the “4-week follow-up phase†after brimonidine
therapy had been discontinued.17 In accordance with the clinical
trial protocol, Fowler et al were utilizing the FDA definition of rebound
as an event occurring after cessation of therapy. During the
treatment phase of the study, the researchers reported worsening
of erythema and/or flushing as the most frequent treatment-related
adverse events; these were not recorded as “rebound.â€17
After receiving spontaneous reports of worsening erythema in
clinical practice after the drug became available in the US, data
from the clinical studies were re-analyzed to determine if signals
of rebound/worsening could be detected during the active
treatment period.13 A thorough discussion of this analysis is being
prepared as a separate publication by the study sponsor.
The reported adverse events that could have been suggestive
of a worsening phenomenon were: erythema/worsening of
