Dermatological Adverse Events Associated with Topical Brimonidine Gel 0.33% in Subjects with Erythema of Rosacea: A Retrospective Review of Clinical Studies
Holmes, Anna D; Waite, Kimberly A; Chen, Michael C; Palaniswamy, Kiruthi; Wiser, Thomas H; Draelos, Zoe D; Rafal, Elyse S; Werschler, W Philip; Harvey, Alison E
BACKGROUND:The topical Î±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/METHODS: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/CONCLUSIONS:Adverse events of worsening redness are not frequent, are transient in nature, and occur early in the course of treatment with brimonidine gel.
A fixed-dose combination of adapalene 0.1%-BPO 2.5% allows an early and sustained improvement in quality of life and patient treatment satisfaction in severe acne
Brodell, Robert T; Schlosser, Bethanee J; Rafal, Elyse; Toth, Darryl; Tyring, Stephen; Wertheimer, Albert; Kerrouche, Nabil; Bucher, Delphine
INTRODUCTION/BACKGROUND:Acne has a significant negative impact on quality of life (QoL): lack of self-confidence, depressive symptoms and suicidal thoughts. The objective was to assess the impact of an initial and continued therapy in severe acne patients through patient-related outcomes (PRO). METHODS:In two sequential double-blind randomized studies, patients received either adapalene 0.1% and benzoyl peroxide 2.5% (A-BPO) or vehicle, associated with doxycycline 100 mg for 12 weeks. Patients having obtained at least a good improvement according to investigator global assessment were re-randomized for a 24-week therapy with A-BPO or vehicle. PROs were assessed using the Acne-QoL and a patient treatment satisfaction questionnaire. RESULTS:QoL was improved at week 12 in all domains with a significant difference for the Acne-symptoms domain (p < 0.001) in favor of the A-BPO regimen. Additional 24-week A-BPO treatment showed a sustained improvement, significant (p < 0.001) for all domains except for Acne-symptoms. In the vehicle arm, QoL significantly worsened for all domains (p < 0.03). At weeks 12 and 36, a significantly higher proportion of patients receiving A-BPO vs. vehicle reported high satisfaction for five out of six treatment satisfaction items. CONCLUSIONS:The early and sustained improvement of these PROs is correlated to the fast onset of action of A-BPO, the treatment effectiveness and a good safety profile.
Tretinoin gel microsphere pump 0.04% plus 5% benzoyl peroxide wash for treatment of acne vulgaris: morning/morning regimen is as effective and safe as morning/evening regimen
Pariser, David; Bucko, Alicia; Fried, Richard; Jarratt, Michael T; Kempers, Steven; Kircik, Leon; Lucky, Anne W; Rafal, Elyse; Rendon, Marta; Weiss, Jonathan; Wilson, David C; Rossi, Ana Beatris; Ramaswamy, Ratna; Nighland, Marge
Topical tretinoin and benzoyl peroxide (BPO) are often prescribed in combination for the treatment of acne vulgaris; however, these products have not traditionally been administered simultaneously because of the potential for tretinoin degradation by BPO as well as the instability of tretinoin in daylight. The primary objective of this randomized, investigator-blinded, 12-week, phase 4 trial was to determine non-inferiority of a once-daily morning combination regimen of 5% BPO wash + tretinoin gel microsphere (TGM) 0.04% pump versus a sequential regimen (BPO in the morning/TGM in the evening) in patients > or = 12 years old with moderate facial acne vulgaris. The primary efficacy endpoint was the change from baseline in total acne lesions; the primary safety endpoint was the change in cutaneous irritation scores. The 247 participants (mean age: 18.5 years) were randomized to either the morning/morning regimen (n = 123) or the morning/evening regimen (n = 124). The morning/morning regimen was determined to be non-inferior to the morning/evening regimen in reduction of total acne lesions. The tolerability of both regimens was comparable. The morning/morning regimen is a safe and effective treatment option for patients with moderate acne vulgaris.
Fluorouracil cream 0.5% for actinic keratoses on multiple body sites: an 18-month open-label study
Stough, Dow; Bucko, Alicia D; Vamvakias, George; Rafal, Elyse S; Davis, Steven A
This prospective 18-month, open-label, multicenter study assessed the long-term safety and efficacy of fluorouracil cream 0.5% in 277 participants with multiple actinic keratoses (AKs) on the face/anterior scalp and other body sites. Two treatment/observation cycles were separated by 12 months. During treatment cycle 1 (TC1), all participants were treated with fluorouracil cream 0.5% for 4 weeks with 4-week follow-up. Twelve months later, all participants were assessed for treatment cycle 2 (TC2); participants with face/anterior scalp AKs (N = 98) were re-treated with fluorouracil cream 0.5% for 4 weeks with 4-week follow-up. Only 4 participants (7.4%) experienced a treatment-related adverse event (AE) that was not an application site reaction or eye irritation. No unexpected AEs were reported; most were mild or moderate. After TC1 (week 8), the number of AK lesions was significantly reduced on the face/anterior scalp and all other treated body sites (P < .0001). Clearance rates were 30.5% (hands), 39.8% (face/anterior scalp), and 79.1% (lips). After TC2 (week 60), face/anterior scalp AKs were significantly reduced (P < .0001) and the clearance rate was 33.3%. This study indicates that fluorouracil cream 0.5% with a patented microsponge delivery system was well-tolerated and effective in treating and preventing recurrence of AK lesions up to 18 months after initial treatment.
Fluorouracil cream 0.5% for the treatment of actinic keratoses on the face and anterior scalp: interim results of an 18-month open-label study
Stough, Dow; Bucko, Alicia D; Vamvakias, George; Rafal, Elyse S; Davis, Steven A
OBJECTIVE:This study further assessed the long-term safety and efficacy of fluorouracil cream 0.5% in patients with multiple actinic keratosis (AK) on the face/anterior scalp and other body sites. DESIGN/SETTING/METHODS:This 18-month, prospective, open-label, multicenter study comprised two treatment cycles separated by 12 months. Cycle 1 included treatment of AK lesions on the face, anterior scalp, posterior scalp, ears, neck, lips, arms, and/or hands. Once-daily fluorouracil cream 0.5% was applied for four weeks as tolerated, followed by four weeks of follow-up in each treatment cycle. PARTICIPANTS/METHODS:Adults (N=277) with five or more visible and/or palpable AK lesions on the face/anterior scalp and five or more lesions on the posterior scalp, ears, neck, lips, arms, and/or hands were enrolled. MEASUREMENTS/METHODS:Main outcome measures included adverse events (AEs) and reduction/clearance of AK lesions on the face/anterior scalp after four weeks of treatment. RESULTS:RESULTS for treatment of AK lesions on the face/anterior scalp for Cycle 1 are reported. All 277 patients were treated during Cycle 1. Besides anticipated application-site reactions (67.9% and 19.1% of patients experiencing mild-to-moderate and severe events, respectively) and eye irritation, overall incidence of treatment-emergent AEs was low. No individual AE appeared in greater than four percent of patients. At the end of Cycle 1, significant reductions were noted in lesion counts on the face/anterior scalp (84.8%; P<0.0001). Clearance rate for lesions on the face and anterior scalp was 39.8 percent at eight weeks. CONCLUSION/CONCLUSIONS:RESULTS indicate that fluorouracil cream 0.5% is safe and effective for patients with multiple AK lesions on the face/anterior scalp.
Subcutaneous efalizumab is not effective in the treatment of alopecia areata
Price, Vera H; Hordinsky, Maria K; Olsen, Elise A; Roberts, Janet L; Siegfried, Elaine C; Rafal, Elyse S; Korman, Neil J; Altrabulsi, Basel; Leung, Hoi M; Garovoy, Marvin R; Caro, Ivor; Whiting, David A
BACKGROUND:Alopecia areata (AA) is a T-cell-mediated autoimmune disease. Efalizumab is a T-cell-targeted therapy approved for the treatment of psoriasis. OBJECTIVE:To assess the efficacy and safety of efalizumab in the treatment of moderate-to-severe AA. METHODS:Sixty-two patients were enrolled into this phase II, placebo-controlled trial. The trial consisted of three 12-week periods-a double-blind treatment period, an open-label efalizumab treatment period, and a safety follow-up. RESULTS:There were no statistical differences between treatment groups in percent hair regrowth, quality-of-life measures, or changes in biologic markers of disease severity after 12 or 24 weeks. In both groups, there was an approximately 8% response rate for hair regrowth (at 12 weeks). Efalizumab was well tolerated. LIMITATIONS/CONCLUSIONS:Numbers were too small for certain analyses. CONCLUSION/CONCLUSIONS:A 3- to 6-month trial of efalizumab was not effective in promoting hair regrowth in this small cohort of patients with moderate-to-severe AA.
A double-blinded, randomized, vehicle-controlled, multicenter, parallel-group study to assess the safety and efficacy of tretinoin gel microsphere 0.04% in the treatment of acne vulgaris in adults
Berger, Richard; Barba, Alicia; Fleischer, Alan; Leyden, James J; Lucky, Anne; Pariser, David; Rafal, Elyse; Thiboutot, Diane; Wilson, David; Grossman, Rachel; Nighland, Marge
This double-blinded, randomized, vehicle-controlled, multicenter, parallel-group, 12-week, phase 4 study was conducted in adults with mild to moderate acne vulgaris. Of 178 subjects randomized to be treated, 88 subjects (49%) were treated with tretinoin gel microsphere 0.04% and 90 subjects (51%) were treated with vehicle. Inflammatory lesion counts were statistically significantly reduced at 2 weeks in tretinoin-treated subjects (P = .0110), and reductions in total lesion counts also were noted. The reduction in total lesion counts reached statistical significance at week 4 (P = .0305); at week 12, mean total, inflammatory, and noninflammatory lesion counts were statistically significantly lower in the tretinoin treatment group versus vehicle group (P < .05), and mean percentage reductions in lesion counts were significantly greater in the subjects with noninflammatory lesions treated with tretinoin compared with vehicle (P < .05). Mean percentage reductions in total, inflammatory, and noninflammatory lesion counts were 35.5%, 38.2%, and 33.6%, respectively, at week 12 for the tretinoin treatment group compared with 20.9%, 19.2%, and 20.4%, respectively, for the vehicle group (all P < .05). All adverse events were of mild or moderate intensity with the exception of severe skin irritation in one tretinoin-treated subject. At week 12, there were no statistically significant differences between treatment groups for any measured tolerability parameter.
Incidence of infection during efalizumab therapy for psoriasis: analysis of the clinical trial experience
Langley, Richard G B; Carey, Wayne P; Rafal, Elyse S; Tyring, Stephen K; Caro, Ivor; Wang, Xiaolin; Wetherill, Graham; Gordon, Kenneth B
BACKGROUND:Because many therapies for psoriasis disrupt the normal inflammatory cascade and could theoretically impair the body's ability to respond to external pathogens, a possible increase in the incidence of infection is a concern with any new psoriasis therapy that affects the immune system. Efalizumab is a biologic therapy targeted to inhibit T cells. Its efficacy has been shown in clinical trials encompassing >3500 patients with psoriasis. OBJECTIVES/OBJECTIVE:The aims of this article were to review the incidence of infection observed in efalizumab-treated patients during 12-week, Phase III clinical trials, compare the incidence rate with that in patients receiving placebo, and evaluate the incidence of infection observed in patients with extended (>12-week) efalizumab use. METHODS:Adverse events (AEs) of infection were tabulated from a pooled data set of 2335 patients enrolled to receive 12 weeks of subcutaneous (SC) efalizumab 1 or 2 mg/kg . wk or placebo in 4 randomized, double-blind, placebo-controlled, Phase III efalizumab clinical studies. The incidence of infection was further evaluated using pooled data from 1115 patients who received up to 24 weeks of efalizumab therapy during 5 clinical trials with treatment extension arms and from 170 patients who received up to 108 weeks (27 months) of continuous therapy in an open-label, Phase III efalizumab trial of 36 months' total duration. RESULTS:The incidence and severity of AEs of infection during 12 weeks of efalizumab therapy were comparable to those observed in patients receiving placebo (overall, 28.6% vs 26.3%). Infections did not appear to increase with extended therapy of up to 27 months. Serious infections requiring hospitalization occurred in 1.1% of efalizumab-treated patients. CONCLUSION/CONCLUSIONS:The present review of the available Phase III clinical trial suggests that efalizumab is not associated with an increased risk for infection in patients receiving initial or long-term (27-month) treatment for moderate to severe chronic plaque psoriasis.
Effect of a single course of isotretinoin therapy on bone mineral density in adolescent patients with severe, recalcitrant, nodular acne
DiGiovanna, John J; Langman, Craig B; Tschen, Eduardo H; Jones, Terry; Menter, Alan; Lowe, Nicholas J; Eichenfield, Lawrence; Hebert, Adelaide A; Pariser, David; Savin, Ronald P; Smith, Stacy R; Jarratt, Michael; Rodriguez, David; Chalker, Dan K; Kempers, Steven; Ling, Mark; Rafal, Elyse S; Sullivan, Sabra; Kang, Sewon; Shah, Leena P; Wu, Emily; Newhouse, Julie; Pak, Jonathan; Eberhardt, Douglas R; Bryce, Graeme F; McLane, John A; Ondovik, Michael; Chin, Catherine; Khoo, Ko-Chin; Rich, Phoebe
BACKGROUND:Adverse changes in bone have been reported for patients undergoing high-dose, long-term (several years) isotretinoin therapy for disorders of cornification. The effect of short-term (4-5 months) therapy at the lower dose recommended for acne on bone development in younger, growing adolescent (12-17 years) patients has not been well studied. OBJECTIVE:The purpose of the study was to evaluate the effect of a standard, single course of isotretinoin (Accutane) therapy on bone mineral density (BMD) of the lumbar spine and hip in adolescents ages 12 to 17 years with severe, recalcitrant, nodular acne. METHODS:In this open-label, multicenter study, 217 adolescents (81 girls) with severe, recalcitrant, nodular acne were enrolled and treated with isotretinoin twice daily with food at the recommended total dose of approximately 1 mg/kg for 16 to 20 weeks. BMD in the lumbar spine and hip was measured at baseline and at the end of therapy by dual energy radiograph absorptiometry. RESULTS:There was no clinically significant mean change in BMD measured at the lumbar spine (+1.4%, range: -4.9% to +12.3%) or total hip (-0.26%, range: -11.3% to +15.0%). Hyperostosis was not observed in any patient. Typical efficacy expected in the treatment of acne was observed. CONCLUSIONS:A 16- to 20-week course of isotretinoin treatment at the recommended dose for severe acne has no clinically significant effect on lumbar spine and total hip BMD in the adolescent (12-17 years) population.
Compared efficacy and safety of tretinoin 0.1% microsphere gel alone and in combination with benzoyl peroxide 6% cleanser for the treatment of acne vulgaris
Shalita, Alan R; Rafal, Elyse S; Anderson, Dina N; Yavel, Regina; Landow, Shoshana; Lee, Wei-Li S
Our purpose was to evaluate the efficacy and safety of a combination of benzoyl peroxide 6% cleanser and tretinoin 0.1% microsphere gel versus monotherapy with tretinoin 0.1% microsphere gel. Eighty-seven healthy males and nonpregnant nonlactating females between the ages of 12 and 30 years with moderate inflammatory acne vulgaris were enrolled in this randomized controlled, investigator-blind, parallel group clinical trial. Subjects were evaluated over 12 weeks for a total of 4 visits. The investigators and subjects completed questionnaires about the test medications. Data from the 56 subjects completing the protocol were considered in the analyses of efficacy and tolerability. The reduction in inflammatory lesions from baseline was significant for both treatment groups at the end of the study. However, there was a significantly greater reduction in the group receiving the combination regimen. Both treatment groups had significant reductions from baseline in noninflammatory lesions at week 12, but no differences were observed between treatment groups. With the exception of skin tightness, which was significantly greater at week 12 in the subjects who received the monotherapy, there were no significant differences between the 2 treatment groups with respect to localized irritation. Adverse events were rare in all subjects. Not only did the combination regimen result in a greater reduction of inflammatory acne lesions than use of the monotherapy but also it did not result in an increase in local irritation.