Nonclinical safety assessment of Efinaconazole Solution (10%) for onychomycosis treatment.

Efinaconazole is a triazole developed as a 10% solution for topical treatment of onychomycosis, a common fungal nail infection. Efinaconazole solution and topical formulation vehicle administered dermally to mice (13weeks), rats (6months) and minipigs (9months) produced transient erythema, minimal to modest hyperkeratosis, and mild microscopic skin inflammation. The liver was the target organ of systemic toxicity; reversible, minimal to moderate vacuolated changes were noted in the rat dermal study at 15 and 50mg/kg/day. No systemic toxicity was observed in mice and minipigs, at approximate high dermal doses of 930 and 170mg/kg/day, respectively. Daily subcutaneous injection of propylene glycol vehicle or efinaconazole to rats for 6months produced severe local inflammation and systemic spread, evidenced by peritoneal adhesions, spinal cord necrosis and urinary tract disease. Mortalities occurred in all groups but were increased at the high dose (30 or 40mg/kg/day), suggesting that vehicle effects were exacerbated by efinaconazole. Efinaconazole was not carcinogenic in a 2-year mouse dermal study and was not genotoxic. Exposure-based safety margins at the NOAEL were 70-698 relative to onychomycosis patients. In conclusion, efinaconazole demonstrated low/moderate toxicity, consistent with other azole antifungals, and high safety margins for topical onychomycosis therapy.

Efficacy and tolerability of a fixed combination of clindamycin phosphate (1.2%) and low concentration benzoyl peroxide (2.5%) aqueous gel in moderate or severe acne subpopulations.

BACKGROUND: Oral antibiotics are commonly prescribed for moderate or severe acne, but there may be limitations due to concerns about side effects associated with systemic treatments. OBJECTIVE: To evaluate the efficacy and safety of a fixed combination clindamycin phosphate 1.2% and benzoyl peroxide 2.5% (clindamycin-BP 2.5%) aqueous gel in the treatment of moderate or severe acne subpopulations. METHODS: Two multicenter, double-blind studies randomized 2,813 subjects with moderate or severe acne to clindamycin-BP 2.5% gel, each active ingredient, or vehicle gel, once daily for 12 weeks. Efficacy evaluations included inflammatory and non-inflammatory lesion counts and evaluator's global severity score at baseline and weeks 4, 8 and 12. Adverse events and subjects' evaluations of product tolerability were also monitored. Subpopulation efficacy and safety analyses by baseline acne severity were performed for the combined data from the two phase 3 studies. RESULTS: Clindamycin-BP 2.5% gel significantly reduced inflammatory, non-inflammatory and total lesions compared with each active ingredient and vehicle in subjects with moderate acne and compared with vehicle in severe acne subjects at week 12. Significant improvements in evaluator's global severity score were evident for subjects with moderate acne in the clindamycin-BP 2.5% group compared with each active ingredient and vehicle and compared with vehicle in subjects with severe acne at week 12. Rates of adverse events were low and similar between treatment groups and baseline acne severity. CONCLUSION: Clindamycin-BP 2.5% aqueous gel is an effective and safe once-daily treatment for moderate or severe acne.

An aqueous gel fixed combination of clindamycin phosphate 1.2% and benzoyl peroxide 2.5% for the once-daily treatment of moderate to severe acne vulgaris: assessment of efficacy and safety in 2813 patients.

OBJECTIVE: We sought to evaluate efficacy, safety, and tolerability of a combination of clindamycin phosphate 1.2% and benzoyl peroxide 2.5% (clindamycin-BPO 2.5%) aqueous gel in moderate to severe acne vulgaris. METHODS: A total of 2813 patients, aged 12 years or older, were randomized to receive clindamycin-BPO 2.5%, individual active ingredients, or vehicle in two identical, double-blind, controlled 12-week, 4-arm studies evaluating safety and efficacy (inflammatory and noninflammatory lesion counts) using Evaluator Global Severity Score and subject self-assessment. RESULTS: Clindamycin-BPO 2.5% demonstrated statistical superiority to individual active ingredients and vehicle in reducing both inflammatory and noninflammatory lesions and acne severity. Visibly greater improvement was observed by patients with clindamycin-BPO 2.5% as early as week 2. No substantive differences were seen in cutaneous tolerability among treatment groups and less than 1% of patients discontinued treatment because of adverse events. LIMITATIONS: Data from controlled studies may differ from clinical practice. CONCLUSIONS: Clindamycin-BPO 2.5% provides statistically significant greater efficacy than individual active ingredients and vehicle with a highly favorable safety and tolerability profile.

Safety and efficacy of desonide hydrogel 0.05% in pediatric subjects with atopic dermatitis.

Low to mid potency corticosteroids remain a cornerstone of therapy for atopic dermatitis (AD). Since AD is most prevalent in the younger pediatric population and is chronic in nature, safety is of particular concern especially for children under 2 years of age. A novel desonide (0.05%) formulation was developed in a nonirritating and moisturizing aqueous gel (hydrogel) that is free of alcohol and surfactants. The safety and efficacy of this new class VI low potency topical steroid was substantiated in 2 phase III clinical trials in mild to moderate AD subjects aged 3 months to 18 years (mean age 6.7 years and 30% under 3 years). A total of 425 subjects were treated with desonide hydrogel and 157 subjects with the hydrogel vehicle. Desonide hydrogel 0.05% was extremely well-tolerated and provided statistically significant improvements in all primary (P < .001) and secondary (P < .006) efficacy endpoints in both studies. This novel desonide formulation represents an advancement in the treatment of AD.

A look at the safety of metronidazole 1% gel: cumulative irritation, contact sensitization, phototoxicity, and photoallergy potential.

Rosacea is a common, recurrent, inflammatory dermatologic disorder characterized by the presence of facial erythema, visible blood vessels, papules, and pustules. The condition may cause serious psychologic morbidity and may significantly affect quality of life. The first topical rosacea therapy approved by the US Food and Drug Administration was metronidazole for the treatment of inflammatory lesions and erythema. Previously, metronidazole was available as a 0.75% gel. Improved solubility was achieved in a new, stable, aqueous gel that permitted the formulation of metronidazole 1.0%. This new formulation is highly spreadable, easy to use, cosmetically friendly, mild to the skin, nondrying, and moisturizing. The safety of metronidazole 1% gel was determined by the evaluation of its cumulative irritation, contact sensitization, phototoxicity, and photoallergy potential in healthy male and female patients. In this formulation, metronidazole was not irritating under occlusive application. Additionally, metronidazole 1% gel had a low potential for causing sensitization reactions, and no evidence suggested phototoxic or photoallergic reactions.

Effect of desonide hydrogel 0.05% on the hypothalamic-pituitary-adrenal axis in pediatric subjects with moderate to severe atopic dermatitis.

Desonide, a low potency corticosteroid, has been used widely as a topical treatment for inflammatory dermatoses for over 30 years. A recent formulation advance has enabled the development of desonide 0.05% into a novel moisturizing aqueous gel (hydrogel) that is free of alcohol and surfactants. This multicenter, open-label study evaluated the hypothalamic-pituitary-adrenal axis suppression potential, tolerability, and efficacy of this new Class VI topical steroid formulation in pediatric subjects with moderate-to-severe atopic dermatitis (mean body surface area = 51%). Forty children, aged 6 months to 6 years were enrolled and treated twice daily for 4 weeks. Desonide hydrogel 0.05% was well tolerated and no treatment-related adverse events were reported. No suppression of adrenal function was observed in subjects who completed the study without protocol violations related to cosyntropin administration or cortisol testing (n=34). Of the subjects who completed the study with complications in cortisol testing (n=3), there was one subject (1/37=3%) who had a low poststimulation cortisol level at week 4. Efficacy was demonstrated by marked improvement in overall disease state and in the signs and symptoms of atopic dermatitis. This study validates the systemic safety of a novel desonide hydrogel formulation in young pediatric patients and confirms the longstanding tolerability and efficacy profile of desonide.