aAnna D. Holmes, PhD; aKimberly A. Waite, BS; aMichael C. Chen, PhD; aKiruthi Palaniswamy, PharmD; aThomas H. Wiser, PharmD; bZoe D. Draelos, MD; cElyse S. Rafal, MD; dW. Philip Werschler, MD; aAlison E. Harvey, PhD aGalderma Laboratories, LP, Fort Worth, Texas; bDermatology Consulting Services, High Point, North Carolina; cDermResearchCenter of New York, Inc., Stony Brook, New York; dUniversity of Washington School of Medicine, Seattle, Washington
Disclosure: Drs. Holmes, Chen, Wiser, Palaniswamy, and Harvey and Ms. Waite are employees of Galderma. Dr. Werschler reports no relevant conflicts on interest. Dr. Draelos was paid by Galderma to conduct research on brimonidine gel 0.33%. Dr. Rafal received a remuneration to conduct the study. Preparation of this manuscript was supported by Galderma Laboratories, LP.
Abstract
Background: The topical ?2 adrenergic receptor agonist brimonidine gel 0.33% is an effective and safe pharmacological treatment for the facial erythema of rosacea. However, adverse events of worsened redness have occasionally been reported with its use. Objective: A detailed analysis of adverse events is needed to accurately define worsening erythema and the adverse-events profile associated with brimonidine gel treatment. Methods and measurements: A retrospective review of related dermatological adverse events occurring in subjects enrolled in the two pivotal four-week Phase 3 studies and the 52-week long-term safety study for brimonidine gel was conducted. Measurements included total adverse-event incidences; number of subjects experiencing adverse events; study discontinuation due to adverse events, severity, onset, episodic duration period; and correlation of adverse events to subject disposition, and rosacea profile. Results: Flushing and erythema were the most commonly reported adverse events, occurring in a total of 5.4 percent of subjects in the Phase 3 studies and in 15.4 percent in the long-term study. Most adverse events were mild or moderate in severity, transient, and intermittent. Adverse events occurred early in treatment, and duration was short-lived in the majority of cases. Adverse-event patterns were not remarkably altered with regard to subject disposition in the long-term study. Conclusion: Adverse events of worsening redness are not frequent, are transient in nature, and occur early in the course of treatment with brimonidine gel. (J Clin Aesthet Dermatol. 2015;8(8):29–35.)
Rosacea is a chronic, inflammatory skin disease with a hallmark of centralized persistent erythema of the face.[1] The underlying mechanisms involve neurogenic, vascular, and inflammatory components, which can be activated by a variety of endogenous and environmental triggers.[2]
Erythema resulting from prolonged dilation of the superficial blood vessels has historically been difficult to address pharmacologically. Brimonidine topical gel 0.33% (Mirvaso® Gel, Galderma Laboratories, LP, Fort Worth, Texas), a selective ?2 adrenergic agonist, is approved for the topical treatment of persistent, nontransient facial erythema of rosacea and works through vasoconstriction of the superficial facial vasculature.[3],[4] When applied once daily in a thin layer to the face, brimonidine can provide clinically meaningful relief of the erythema of rosacea in more than 70 percent of patients for up to 12 hours.[5]
Rebound reactions have previously been reported with alpha adrenergic receptor agonists administered nasally and ophthalmically.[6],[7] Rebound is medically defined as a reversed response occurring upon withdrawal of a stimulus.[8] Therefore, the Phase 2b and Phase 3 clinical studies for brimonidine gel were designed to assess the possibility of rebound, defined as any aggravation effect on facial erythema that occurred after the treatment period concluded, compared to baseline clinician erythema assessments and patient self-assessments on Day 1.
No noteworthy rebound effect was observed 24 hours or seven days after cessation of treatment in the Phase 2b studies, or two or four weeks after cessation of treatment in both Phase 2b and Phase 3 studies.[5] Furthermore, a similar incidence was observed in both the treatment and vehicle groups, suggesting traditionally defined rebound reactions were not a common side effect with brimonidine gel treatment.
In clinical studies with brimonidine, any form of worsening redness that occurred during active treatment rather than after cessation of treatment was recorded as an adverse event (AE). Recently, two case reports were published describing four rosacea patients experiencing worsening “rebound” erythema 3 to 12 hours following application of topical brimonidine gel to the whole face,[9] as indicated, or to part of the face.[10] These worsening events seemingly coincide with similar AEs recorded during active treatment with brimonidine in clinical studies, rather than those defined as rebound following cessation of treatment. The objective of this paper is to provide a rigorous and detailed analysis of dermatological AEs occurring in clinical study subjects under active treatment in order to accurately define worsening erythema reactions as well as the comprehensive AE profile associated with topical brimonidine gel.
Materials and Methods
Patients and treatments. Two Phase 3 studies and one long-term safety study were conducted to evaluate the safety and efficacy of brimonidine gel. The multicenter, randomized, double-blind, parallel-group, vehicle-controlled, Phase 3 studies were identically designed and conducted simultaneously, with subjects randomized 1:1 to brimonidine gel (n=277) or vehicle (n=276) treatment arms for four weeks.[5] Subjects in the multicenter, open-label, long-term safety study (n=449) were treated with brimonidine gel for up to 52 weeks.[11] All subjects were ?18 years of age with moderate-to-severe facial erythema associated with rosacea. Subjects were instructed to apply one small pea-sized amount of brimonidine gel once daily to each of the five regions of the face (right cheek, left cheek, forehead, nose, and chin). Subjects with concomitant inflammatory lesions of rosacea were included in the long-term study, but limited to two lesions or less in the Phase 3 studies. Subjects with other concomitant facial dermatoses were excluded. Additional exclusion criteria in the Phase 3 studies included use of topical or oral rosacea or acne medications, antibiotics, corticosteroids, topical abrasives/astringents, or facial procedures during a specified time period leading up to study commencement; use of these concomitant medications was permitted and documented throughout the long-term study.
Analyses. A retrospective review of related dermatological AEs occurring on the treated area of the face in ?1% of the total safety population in the Phase 3 and long-term studies was conducted. Data reports were programmed and generated with SAS 9.3 software. The results of the two Phase 3 studies were combined for the purposes of this analysis.
Due to clinical resemblance, AEs captured by study investigators as irritation or dermatitis (all subforms) are combined and referred to as “irritation.” AEs captured as skin burning, skin discomfort, and skin pain are referred to cumulatively as “skin discomfort.”
Analyses include total AE incidence, subjects experiencing AEs, severity, onset, and study discontinuation due to AEs. AEs from the long-term study were further evaluated to determine episodic duration period, which was measured from initial onset of an AE or series of AEs to terminal resolution of the AE, with no further symptoms reported. Episodic duration period is inclusive of the entire period of time during which all individual episodes or reports occurred, including periods when no AE symptoms were present. AEs that were present at the time the study concluded were captured as “ongoing” and are reported separately. Standardized narrative reports of individual AE episodes were also evaluated to determine AE kinetics, including time of onset post-application, duration of isolated episodes, and possible triggers encountered.
Analyses of subject disposition (gender, age, Fitzpatrick skin type, blood pressure) and subject rosacea profile (disease duration, erythema severity at baseline, inflammatory lesion count at baseline) were also conducted for overall AE incidence and for specific AEs occurring in at least 10 subjects in the long-term study. Evaluation parameters are listed in the results section. AE incidence in each subpopulation was compared to AE incidence in the total population (including the subpopulation itself) and reported as a fold-change. A fold-change of ± 0.25 (25%) for total AE incidence and ± 0.50 (50%) for individual AE incidence in a subpopulation compared to the total population was considered to be a possible association signal.
Results
Study population. Study population demographics are shown in Table 1.[5],[11]
Adverse event incidence, severity, and subject discontinuation. In the four-week Phase 3 studies, 26 (9.4%) subjects using brimonidine gel and 11 (4%) subjects using vehicle gel reported related dermatological AEs that occurred in at least one percent of the safety population (Table 2 Part 1). Erythema was the most commonly occurring AE with brimonidine treatment, reported in 10 (3.6%) subjects; irritation was most common with vehicle gel, reported in five (1.8%) subjects. Adverse events were mild to moderate in severity in the brimonidine treatment arm and mild in the vehicle arm (Table 2 Part 1, Table 2 Part 2). Two subjects (0.8%) receiving active treatment discontinued due to AEs (Table 2 Part 1, Table 2 Part 2, Figure 1).
In the long-term, 52-week safety study, 130 (29%) subjects reported related dermatological AEs occurring in at least one percent of the safety population (Table 2 Part 1, Table 2 Part 2). Flushing, irritation, and erythema AEs were reported most frequently. The majority of AEs (87.4%) were mild or moderate in severity, and the discontinuation rate due to the reported AEs was 14.9% (Table 2 Part 1, Table 2 Part 2). Discontinuations over time were steady and were not related to the incidence rate of AEs in subjects (Figure 1). Irritation and flushing resulted in highest subject discontinuation rates, with 5.4 percent and 3.8 percent of total subjects opting to discontinue treatment, respectively (Table 2 Part 1, Table 2 Part 2). Three subjects (0.7%) were confirmed for allergy to brimonidine or its excipients by patch testing (Table 2 Part 1, Table 2 Part 2).
Onset and duration of adverse events. AE onset occurred early in treatment across the Phase 3 and long-term studies. Of 35 brimonidine-associated AEs reported in the Phase 3 studies, 15 (42.9%) occurred within the first week of treatment, 11 (31.4%) in the second week, and nine (25.7%) in the final two weeks of the study (Figure 1).
In the long-term study, 85 (41.1%) AEs occurred within the first month and 124 (60%) within the first three months of brimonidine treatment (Figure 1). Analysis of individual AEs showed 51 percent of combined flushing and erythema AEs occurring in the first month and 78 percent in the first quarter. Four of the five most commonly reported AEs exhibited median onset between three and five weeks (Figure 2). Conversely, median onset for irritation was approximately six months, with irritation accounting for almost half (46.4%) of all AEs occurring after the first quarter of the study. The range for onset of most AEs, however, extended through the treatment period (Figure 2).
In the long-term study, the duration period during which all individual AE episodes were reported (including periods when no AE symptoms were present) is shown in Figure 2. Erythema and flushing AEs were reported over a median period of approximately 3.5 weeks and five weeks, respectively, after which no additional episodes were reported. Flushing and erythema AEs exhibited a noticeable duration separation pattern over 52 weeks, where 44 percent of episodic AEs resolved permanently within a month of the initial AE report, while 48 percent continued to occur episodically over a greater than 90-day period or were ongoing at time of study completion. Subjects reported the irritation AE to occur episodically over a median period of two weeks. Median duration periods of other AEs are shown in Figure 2, with duration range from a single day to ongoing throughout the study. Subject discontinuation did not discernably influence duration patterns.
Narrative reports of individual AE episodes consistently demonstrated AEs to be intermittent in nature, transient, and not influenced by trigger encounter in the majority of cases. Erythema and flushing AEs exhibited similar kinetics, with many subjects reporting an exaggerated recurrence of erythema as the effects of brimonidine were wearing off (typically 8–12 hours post-application) and a second subset reporting acute paradoxical erythema within six hours of brimonidine application. Duration of individual AE episodes was typically between 30 minutes and three hours although a minority reported longer duration periods. Irritation AE kinetics were more variable, with onset most commonly reported 2 to 8 hours post-application and duration from a few hours to the following day. Other AEs were typically reported shortly after brimonidine application with resolution within hours.
Influence of subject disposition and rosacea profile on adverse events. In the long-term study, total AE incidence in subpopulations defined by subject disposition and rosacea profile are presented in Table 3
Males had a reduced overall AE incidence compared to the total subject population. Other subject-specific variables did not alter overall AE incidence.
Specific AEs occurring at a heightened (1.5-fold [+50%]) or reduced (0.50-fold [-50%]) incidence in subpopulations are listed in Table 3
Discussion
AEs captured as flushing and erythema in the Phase 3 and long-term safety studies with brimonidine gel are primarily reflective of the perceived “rebound” effect reported in clinical case studies[9],[10] and by patients during real-world use. Although pathologically distinct, reporting of erythema, flushing, and rosacea AEs by investigators in these studies may overlap somewhat due to similar clinical presentation.
In the Phase 3 studies, flushing and erythema were reported at a higher incidence in the brimonidine treatment arm compared to the vehicle arm, while other AEs were reported in both groups (Table 2 Part 1, Table 2 Part 2). These data may suggest that erythema and flushing are specific for the brimonidine compound, while other common AEs may be indicative of generally heightened skin sensitivity in rosacea patients.[12]
AE incidence, onset, and duration patterns are useful predictors for patient tolerability to brimonidine following initiation of treatment. Overall, AE incidence associated with brimonidine use was fairly low and of mild-to-moderate severity in the majority of cases across studies. Excluding irritation and rash, AEs occurred early in treatment, with more than half initiating in the first month of brimonidine treatment in the long-term study (Figure 1, Figure 2). Intermittent, transient AE episodes occurred over a period of 17 days in the median subject (Figure 2).
Because the majority of AEs occurred early in treatment and permanently resolved without sequelae during continued treatment, it is interesting to consider if the skin and superficial vasculature can become acclimated to tolerate the presence of an ?2 adrenergic receptor agonist over time in subjects with tolerability issues, similar to the “retinization” effect that occurs with prolonged retinoid use.[13]
Although many of the AEs reported here exhibited predictable kinetics, it is also important to note that the range among subjects for both onset day and episodic duration period of AEs encompassed the length of the study, and half of flushing or erythema AEs in the long-term study recurred over protracted periods.
Based on the AE profiles reported, the subject discontinuation rates due to AEs are not unexpected (Table 2 Part 1, Table 2 Part 1). Surprisingly, discontinuation rates remained low and steady over time and did not appear to correlate with early AE onset (Figure 1). These data may be explained, in part, by high discontinuation rates associated with the late-onset irritation AE and much lower rates in subjects with erythema or flushing. This suggests that for many patients, the advantage of brimonidine’s effect may outweigh the disadvantage of erythema-associated AEs. Subject discontinuation rates over time in clinical studies, however, may not be equivalent to those experienced in a real-world setting.[14]
Subject subpopulations evaluated to identify risk factors for development of AEs revealed that subject demographics and rosacea profile did not overtly influence the AE profile (Table 3
Because several of the analyses presented here represent a small number of subjects, the strength of these associations may not be representative of the real-world population. Furthermore, these analyses do not control for subject-specific variables, such as concomitant medications used or underlying medical conditions, which could confound the data. Taken together, these associations are not meant to dictate patient selection for brimonidine treatment, but rather to promote cognizance that AEs may be influenced by many factors, as we continue to learn about the effects of this drug. Dermatologist recommendations for optimizing the use of brimonidine gel are discussed elsewhere.[17]
Conclusion
The incidence of worsened erythema and other AEs with brimonidine use was reasonably low and occurred early in the clinical development program. Most subjects chose to continue treatment regardless of AEs experienced. Setting realistic expectations for possible AEs are important for provider and patient success with brimonidine.
References
1. Wilkin J, Dahl M, Detmar M, et al. Standard classification of rosacea: Report of the National Rosacea Society Expert Committee on the Classification and Staging of Rosacea. J Am Acad Dermatol. 2002;46:584–587.
2. Steinhoff M, Buddenkotte J, Aubert J, et al. Clinical, cellular, and molecular aspects in the pathophysiology of rosacea. J Invest Dermatol Symp Proc. 2011;15:2–11.
3. Piwnica D, Rosignoli C, de Menonville ST, et al. Vasoconstriction and anti-inflammatory properties of the selective alpha-adrenergic receptor agonist brimonidine. J Dermatolog Sci. 2014;75:49–54.
4. Mirvaso® [package insert]. Fort Worth, TX: Galderma Laboratories, LP; 2013.
5. Fowler J Jr, Jackson M, Moore A, et al. Efficacy and safety of once-daily topical brimonidine tartrate gel 0.5% for the treatment of moderate to severe facial erythema of rosacea: results of two randomized, double-blind, and vehicle-controlled pivotal studies. J Drugs Dermatol. 2013;12:650–656.
6. Ramey JT, Bailen E, Lockey RF. Rhinitis medicamentosa. J Invest Allerg Clin Immunol. 2006;16:148–155.
7. Brown SM, Khanani AM, McCartney DL. The effect of daily use of brimonidine tartrate on the dark-adapted pupil diameter. Am J Ophthalmol. 2004;138:149–151.
8. O’Toole MT. Encyclopedia and Dictionary of Medicine, Nursing, and Allied Health. 7th ed. W.B. Saunders Co.; 2003.
9. Ilkovitch D, Pomerantz RG. Brimonidine effective but may lead to significant rebound erythema. J Am Acad Dermatol. 2014;70:e109–e110.
10. Routt ET, Levitt JO. Rebound erythema and burning sensation from a new topical brimonidine tartrate gel 0.33%. J Am Acad Dermatol. 2014;70:e37–e38.
11. Moore A, Kempers S, Murakawa G, et al. Long-term safety and efficacy of once-daily topical brimonidine tartrate gel 0.5% for the treatment of moderate-to-severe facial erythema of rosacea: results of a 1-year open-label study. J Drugs Dermatol. 2014;13:56–61.
12. Lonne-Rahm SB, Fischer T, Berg M. Stinging and rosacea. Acta Derm Venereol. 1999;79:460–461.
13. Draelos ZD, Ertel KD, Berge CA. Facilitating facial retinization through barrier improvement. Cutis. 2006;78:275–281.
14. van Onzenoort HA, Menger FE, Neef C, et al. Participation in a clinical trial enhances adherence and persistence to treatment: a retrospective cohort study. Hypertension. 2011;58:573–578.
15. Tran C, Knowles SR, Liu BA, Shear NH. Gender differences in adverse drug reactions. J Clin Pharmacol. 1998;38:1003–1009.
16. Soldin OP, Chung SH, Mattison DR. Sex differences in drug disposition. J Biomed Biotech. 2011;2011:187103.
17. Tanghetti EA, Jackson JM, Belasco KT, et al. Optimizing the use of topical brimonidine in rosacea management: panel recommendations. J Drugs Dermatol. 2015;14: 33–40.