Pharmacokinetics of ingenol mebutate gel under maximum use conditions in large treatment areas.

PURPOSE: Actinic keratoses (AKs) exist on a continuum with squamous cell carcinoma and can occur as sub-clinical and clinically visible lesions in cancerized fields on sun-damaged skin. Ingenol mebutate effectively treats AKs on areas up to 25 cm2, but actinic keratosis can affect larger areas of skin. This trial evaluated systemic exposure and safety of ingenol mebutate gel on larger areas of skin under maximum use conditions. METHODS: Phase I, multicenter, open-label, uncontrolled, non-randomized trial. Patients received ingenol mebutate gel for three consecutive days on approximately 250 cm2 of sun-damaged skin on the full face (0.027%), the scalp (0.027%), or arm (0.06%). RESULTS: Of 61 patients, 10 (face =8; arm =2) had ingenol mebutate in whole blood at subnanomolar levels (0.235-0.462 nM). The assayed metabolites were below the lower limit of quantification. Local skin responses increased during Days 1-4 and declined thereafter, approaching baseline by Day 16. Most adverse events were pain/pruritus of mild or moderate intensity. CONCLUSIONS: Subnanomolar systemic exposure to ingenol mebutate was measured after application of the gel to approximately 250 cm2 on the full face, scalp, or arm under maximum use conditions. No clinically relevant systemic adverse reactions were observed, and local skin responses were manageable.

Efficacy and Safety of Once-Daily Dapsone Gel, 7.5% for Treatment of Adolescents and Adults With Acne Vulgaris: First of Two Identically Designed, Large, Multicenter, Randomized, Vehicle-controlled Trials.

BACKGROUND: Treatment of acne vulgaris (acne) with dapsone gel, 5% requires twice-daily dosing, and some patients may not adhere to this regimen.
OBJECTIVE: The objective of this study was to assess the efficacy and safety of a new, once-daily formulation of dapsone gel, 7.5%, with a 50% higher dapsone concentration, versus vehicle over 12 weeks in patients with acne.
METHODS: This 12-week, randomized, double-blind, vehicle-controlled, multicenter clinical trial enrolled patients with moderate acne aged 12 years and older with 20 to 50 inflammatory lesions and 30 to 100 noninflammatory lesions on the face, and an acne grade of 3 (moderate) on the Global Acne Assessment Score (GAAS). Patients were randomized to receive topical dapsone gel, 7.5% or vehicle once daily for 12 weeks. Investigators assessed GAAS success rate (proportion of patients with GAAS of 0 or 1) and percent change from baseline in inflammatory, noninflammatory, and total lesions.
RESULTS: The intent-to-treat population comprised 2102 patients, 1044 in the dapsone gel, 7.5% group and 1058 in the vehicle group. At week 12, 29.9% of patients in the dapsone gel, 7.5% group and 21.2% in the vehicle group (P<.001) had GAAS success. Mean inflammatory lesions decreased by 55.5% and 49.0%, noninflammatory lesions decreased by 44.4% and 38.4%, and total lesions decreased by 48.7% and 42.4% in the dapsone gel, 7.5% and vehicle groups (all P<.001), respectively, at week 12. The incidence of adverse events was similar in the dapsone gel, 7.5% (19.1%) and vehicle (20.6%) groups. Most events in both groups were mild or moderate in severity. Most patients receiving dapsone gel, 7.5% and vehicle had a severity rating of "none" for stinging/burning, dryness, scaling, and erythema scales at all time points.
CONCLUSIONS: Dapsone gel, 7.5% applied topically once daily is an effective, safe, and well-tolerated treatment for acne.

J Drugs Dermatol. 2016;15(5):553-561.

Efinaconazole solution in the treatment of toenail onychomycosis: a phase 2, multicenter, randomized, double-blind study.

BACKGROUND: Onychomycosis is a common nail infection that is difficult to treat successfully. The prevalence increases with age and is associated with diabetes. Oral treatments are limited by drug interactions and potential hepatotoxicity; topical treatments, by modest efficacy. OBJECTIVE: We investigated the efficacy and safety of a solution using a novel topical triazole antifungal, efinaconazole, in distal lateral subungual onychomycosis (DLSO). METHODS: Multicenter, randomized, double-blind, vehicle-controlled phase 2 study in mild to moderate toenail DLSO (n=135). Subjects randomized (2:2:2:1 ratio) to receive efinaconazole 10% solution (with or without semiocclusion), efinaconazole 5% solution, or vehicle, once daily for 36 weeks, with one 4-week posttreatment follow-up (week 40). Efficacy assessments included complete cure, mycologic cure, clinical efficacy, and other assessments of overall treatment effectiveness. No efficacy variables were designated as primary. RESULTS: At follow-up, complete cure was numerically higher in all active groups (16%-26%) compared with vehicle (9%). Mycologic cure rates with efinaconazole 10% semiocclusion, efinaconazole 10%, and efinaconazole 5% were 83%, 87%, and 87%, respectively. Efinaconazole 10% (with or without semiocclusion) demonstrated significantly greater clinical efficacy and treatment effectiveness when compared with vehicle (P=.0088 and .0064; .0056 and .0085, respectively, for both efinaconazole 10% groups). Adverse events were generally similar and mild. Local-site reactions were restricted to few subjects and did not differ meaningfully from those produced by vehicle. CONCLUSIONS: This study provided evidence that once-daily efinaconazole 10% solution (with or without semiocclusion) applied topically for 36 weeks was more effective than vehicle in treating DLSO and was well tolerated. Based on these results, efinaconazole 10% solution was chosen for the phase 3 development program.

Fluorouracil cream 0.5% for actinic keratoses on multiple body sites: an 18-month open-label study.

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.

Safety of a novel gel formulation of clindamycin phosphate 1.2%-tretinoin 0.025%: results from a 52-week open-label study.

Acne affects as many as 50 million individuals in the United States. Topical therapy combining a retinoid and an antibiotic is recommended as a first-line therapeutic option for mild to moderately severe acne. Although treatment for extended durations may be required, little long-term safety data on these combination therapies are available. This report summarizes the long-term safety and tolerability of a novel combination product for the treatment of acne vulgaris in participants 12 years and older. The combination treatment is a gel formulation containing a crystalline suspension of clindamycin phosphate 1.2%-tretinoin 0.025% (CLIN/RA). Two cohorts participated in a long-term (up to 52 weeks), multicenter, open-label, safety evaluation of CLIN/RA. Treatment duration was 6 months for the first cohort (N = 442) and 12 months for the second cohort (N = 213). Overall, the CLIN/RA gel was well-tolerated; 92%, 91%, and 94% of participants reported no itching, burning, or stinging, respectively. The most frequent adverse events were acne (29/442; 7% [usually a flare]), sunburn (12/442; 3%), hypersensitivity (7/442; 2%), contact dermatitis (5/442; 1%), and application-site desquamation (3/442; 1%). These results confirm the safety of CLIN/RA gel for mild to moderately severe acne. The CLIN/RA gel fixed-dose combination provided minimal adverse events and a favorable safety profile for 2 agents with established efficacy for the treatment of acne vulgaris.

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.

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: 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: 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: 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: RESULTS indicate that fluorouracil cream 0.5% is safe and effective for patients with multiple AK lesions on the face/anterior scalp.

Randomized, double-blind, multicenter comparison of oral cefditoren 200 or 400 mg BID with either cefuroxime 250 mg BID or cefadroxil 500 mg BID for the treatment of uncomplicated skin and skin-structure infections.

BACKGROUND: Uncomplicated skin and skin-structure infections are commonly observed in medical practice. Because these infections typically are confined to the superficial layers and seldom lead to the destruction of skin structures and resultant systemic dissemination, in general they can be treated with an oral antibiotic with potent microbiologic activity against gram-positive pathogens. OBJECTIVE: This paper compares the efficacy and tolerability of 3 beta-lactam antibiotics in patients with uncomplicated skin and skin-structure infections. METHODS: Two double-blind, multicenter, parallel-group studies were conducted, in which patients aged > or = 12 years with uncomplicated skin and skin-structure infections were randomized to receive cefditoren 200 or 400 mg, cefuroxime 250 mg, or cefadroxil 500 mg, each BID for 10 days. Study 1 compared cefditoren with cefuroxime; Study 2 compared cefditoren with cefadroxil. Clinical and microbiologic responses were assessed at a posttreatment visit (within 48 hours of treatment completion) and test-of-cure visit (7-14 days after treatment completion). Patients were monitored closely throughout the study with the use of physical examinations, clinical laboratory tests, and assessment of adverse events. RESULTS: A total of 1,685 patients (855 males, 830 females; mean age, 41.1 years [range, 12-95 years]) were enrolled. Within both studies, the 3 treatment groups were similar at baseline based on demographic characteristics and types of infection. Cellulitis (26%), wound infection (25%), and simple abscess (15%) were the most common infections. Clinical cure rates at the test-of-cure visit were 85% (443/523) for cefditoren 200 mg, 83% (427/516) for cefditoren 400 mg, 88% (234/265) for cefuroxime, and 85% (211/248) for cefadroxil. At the test-of-cure visit, cefditoren 200 mg had eradicated significantly fewer of the causative pathogens isolated before treatment in microbiologically evaluable patients than did cefuroxime in Study 1 (P = 0.043) but significantly more of the pathogens than did cefadroxil in Study 2 (P = 0.018). Eradication rates for the most commonly isolated pathogens were generally similar in the 3 treatment groups in both studies, with the only significant difference favoring cefditoren 200 and 400 mg over cefadroxil for Peptostreptococcus species in Study 2 (P = 0.016 and P = 0.003, respectively). A minority of patients (< or = 5% in any treatment group) discontinued study-drug treatment prematurely due to a treatment-related adverse event, with statistically higher rates for cefditoren 400 mg than for cefditoren 200 mg and the comparator cephalosporins (each P < 0.05). All 3 cephalosporins were generally well tolerated. Most adverse events (>93%) were categorized as mild to moderate, with the most common being diarrhea, nausea, and headache. CONCLUSION: In this population of patients with uncomplicated skin and skin-structure infections, including those due to Staphylococcus aureus or Streptococcus pyogenes, the clinical cure rate and tolerability of cefditoren were comparable to those of cefuroxime and cefadroxil.