Dermal sensitization, safety, tolerability, and patient preference of tazarotene 0.045% lotion from five clinical trials.

BACKGROUND: Topical retinoids are recommended for acne treatment, but their use may be limited by irritation or dermatitis. Herein is an overview of the dermal sensitization, safety, tolerability, and participant satisfaction data from phase-1, -2, and -3 studies of lower-dose tazarotene 0.045% polymeric emulsion lotion. METHODS: Two phase-1, single-blind, vehicle-controlled dermal safety studies were conducted in healthy participants aged ≥18 years. One phase-2 (NCT02938494) and two phase-3 studies (NCT03168334; NCT03168321) were double-blind, randomized, and vehicle-controlled over 12 weeks in participants aged ≥9 years (≥12 years, phase-2) with moderate-to-severe acne. RESULTS: A total of 2029 participants (tazarotene 0.045% lotion or vehicle) were included across the 5 studies (safety populations: n = 1982). In the phase-1 studies, tazarotene had a low potential for irritancy/contact dermatitis and did not induce sensitization. In all studies, tazarotene lotion was well tolerated and had a positive safety profile. In addition, tazarotene lotion reduced the severity of hyperpigmentation and erythema and participants preferred it more than previous acne treatments. CONCLUSIONS: The results from these five studies show that the tolerability, safety, and patient satisfaction of topical tazarotene 0.045% lotion, combined with its efficacy, make it an important option for the treatment of acne.

Three-year U.S. pharmacovigilance report of brodalumab.

Brodalumab, an interleukin-17 receptor A antagonist, is approved for treatment of moderate-to-severe plaque psoriasis in adults without response or with loss of response to other systemic therapies. In the United States, there is a boxed warning for brodalumab regarding suicidal ideation and behavior; however, no causal relationship between brodalumab and suicidality was established during pivotal trials. In the 2-year pharmacovigilance data, no completed suicides or suicide attempts were reported. The most frequent adverse event (AE) was arthralgia. The safety profile of brodalumab is now being updated after 3 years of pharmacovigilance data. Here, we outline pharmacovigilance data reported to Ortho Dermatologics by patients and healthcare professionals in the United States from August 15, 2017, to August 14, 2020. Brodalumab exposure estimates were obtained by calculating the time between first and last prescription-dispensing authorization dates. Data from 1854 patients were collected, and brodalumab exposure was estimated to be 2736 patient-years. The most frequent AE was arthralgia (111 events; 0.04 events per patient-year). One episode of suicide attempt was reported in a patient with a history of depression. No completed suicides were reported. There were 81 serious infections reported, none of which were fungal. Over the 3-year period, 30 malignancies occurred in 25 patients, none of which were determined to be related to brodalumab. Three-year pharmacovigilance data are consistent with the safety profile of brodalumab previously reported in long-term analyses of clinical trials and the 2-year pharmacovigilance data.

Two-Year US Pharmacovigilance Report on Brodalumab.

INTRODUCTION: Brodalumab is a human interleukin-17 receptor A antagonist indicated for the treatment of moderate-to-severe plaque psoriasis in adult patients who are candidates for systemic therapy or phototherapy and have failed to respond or have lost response to other systemic therapies. In the United States, brodalumab carries a boxed warning about suicidal ideation and behavior; however, no causal association was established between brodalumab and suicides reported during pivotal trials. We have previously reported results from an analysis of 1-year pharmacovigilance data in patients in the United States who took brodalumab, in which the most commonly reported adverse event was psoriasis flare. There were no completed suicides, suicide attempts, or serious fungal infections. Here, we provide a 2-year US pharmacovigilance report. METHODS: This analysis summarizes pharmacovigilance data reported to Ortho Dermatologics by US patients and healthcare providers from August 15, 2017, through August 14, 2019. The most common adverse events listed in the brodalumab package insert (incidence ≥ 1%; arthralgia, headache, fatigue, diarrhea, oropharyngeal pain, nausea, myalgia, injection-site reactions, influenza, neutropenia, and tinea infections) and adverse events of special interest are reported. RESULTS: Data were collected from 2677 patients in the United States who took brodalumab, with an estimated exposure of 1656 patient-years. Arthralgia was the most commonly reported adverse event (73 events; 0.04 events per patient-year). No suicide attempts or completed suicides were reported; there were 25 reports of depression. There were 46 serious infections and no serious fungal infections. One event of Crohn's disease was reported, which led to discontinuation. There were 13 malignancies, with none deemed related to brodalumab. CONCLUSIONS: This pharmacovigilance report supports the safety profile of brodalumab previously reported from long-term analyses of clinical trials and 1-year pharmacovigilance data.

Safety, Tolerability, and Pharmacokinetics of Therapeutic and Supratherapeutic Doses of Tramadol Hydrochloride in Healthy Adults: A Randomized, Double-Blind, Placebo-Controlled Multiple-Ascending-Dose Study.

This randomized, double-blind, parallel-group multiple-ascending-dose study evaluated the safety, tolerability, and pharmacokinetics of tramadol hydrochloride in healthy adults to inform dosage and design for a subsequent QT/QTc study. Healthy men and women, 18 to 45 years old (inclusive), were sequentially assigned to the tramadol 200, 400, or 600 mg/day treatment cohort and within each cohort, randomized (4:1) to either tramadol or placebo every 6 hours for 9 oral doses. Of the 24 participants randomized to tramadol (n = 8/cohort), 22 (91.7%) completed the study. The AUCtau,ss of tramadol increased approximately 2.2- and 3.6-fold for the (+) enantiomer and 2.0- and 3.5-fold for the (-) enantiomer with increasing dose from 200 to 400  and 600 mg/day, whereas the Cmax,ss increased 2.1- and 3.3-fold for the (+) enantiomer and 2.0- and 3.2-fold for the (-) enantiomer. Overall, 21 participants (87.5%) participants reported ≥1 treatment-emergent adverse event; most frequent were nausea (17 of 24, 70.8%) and vomiting (7 of 24, 29.2%). Vomiting (affected participants and events) increased with increasing dose from 200 to 600 mg/day but was mild (5 of 24) or moderate (2 of 24) in severity. All tested dosage regimens of tramadol showed acceptable safety and tolerability profile for further investigation in a thorough QT/QTc study.

A Phase 2, Multicenter, Double-Blind, Randomized, Vehicle Controlled Clinical Study to Assess the Safety and Efficacy of a Halobetasol/Tazarotene Fixed Combination in the Treatment of Plaque Psoriasis.

BACKGROUND: Psoriasis is a chronic, immune-mediated disease that varies widely in its clinical expression. Treatment options focus on relieving symptoms, reducing inflammation, induration, and scaling, and controlling the extent of the disease. Topical corticosteroids are the mainstay of treatment, however long-term safety remains a concern, particularly with the more potent formulations. Combination therapy with a corticosteroid and tazarotene may improve psoriasis signs at a lower corticosteroid concentration providing a superior safety profile. OBJECTIVE: To investigate the efficacy and safety of a once-daily application of a fixed combination halobetasol propionate 0.01% and tazarotene 0.045% (HP/TAZ) lotion in comparison with its monads and vehicle in subjects with moderate-to-severe plaque psoriasis. METHODS: Multicenter, randomized, double-blind, vehicle-controlled Phase 2 study in moderate or severe psoriasis (N=212). Subjects randomized (2:2:2:1 ratio) to receive HP/TAZ, individual monads, or vehicle, once-daily for 8 weeks. Efficacy assessments included treatment success (defined as at least a 2-grade improvement from baseline in the IGA score and a score of 'Clear' or 'Almost Clear'), and impact on individual signs of psoriasis (erythema, plaque elevation, and scaling) at the target lesion. Safety and treatment emergent adverse events (TEAEs) were evaluated throughout. RESULTS: HP/TAZ lotion demonstrated statistically significant superiority over vehicle as early as 2 weeks. At week 8, 52.5% of subjects had treatment success compared with 33.3%, 18.6%, and 9.7% in the HP (P=0.033), TAZ (P less than 0.001), and vehicle (P less than 0.001) groups, respectively. HP/TAZ lotion was superior to its monads and vehicle in reducing the psoriasis signs of erythema, plaque elevation, and scaling at the target lesion. At week 8, a 2-grade improvement in IGA was achieved by 54.2% of subjects for erythema, 67.8% for plaque elevation, and 64.4% for scaling. Most frequently reported TEAEs were application site reactions, and were more likely associated with the tazarotene component. Side effects such as skin atrophy were rare. CONCLUSIONS: HP/TAZ lotion was consistently more effective than its monads or vehicle in achieving treatment success and reducing psoriasis signs of erythema, plaque elevation, and scaling at the target lesion. Safety data were consistent with the known safety profile of halobetasol propionate and tazarotene, and did not reveal any new safety concerns with the combination product.

J Drugs Dermatol. 2017;16(3):197-204.

High prevalence of anxiety disorders among adolescent Tibetan refugees.

INTRODUCTION: Psychiatric disturbance has been shown to result from stress associated with events related to being a refugee. Children of refugees also experience significant stress but little is known about the prevalence of psychiatric disorders in this group. This survey explores the prevalence of psychiatric disorders in a Tibetan refugee enclave in rural North India. METHODS: A prevalence survey was conducted using the Beck Anxiety Inventory (BAI) to determine the prevalence of anxiety amongst the Tibetan community. Three hundred fifty forms were distributed amongst the students; 335 were completed of which 300 were considered suitable to be collated and analysed. RESULTS: The results revealed that 21% of the study population had significant levels of anxiety classed as moderate or severe using the BAI. Late adolescents had higher levels of significant moderate and severe anxiety than early and middle adolescents x(2) = 92.95 (P < 0.0001). Female participants had higher levels of moderate and severe anxiety but this was not statistically significant (x(2) = 1.286, P = 0.2568). CONCLUSION: There were high rates of anxiety in this study of Tibetan school aged children. School based anxiety prevention programmes and other interventions should be considered in such vulnerable populations especially amongst females and late adolescents who are disproportionately affected. These findings indicate a need for further evaluation of young Tibetan refugees for definitive diagnosis of anxiety disorders, specific phobias, social anxiety, post traumatic stress disorders and other anxiety disorders.