Xolegel (Ketoconazole Topical) - Description and Clinical Pharmacology

DESCRIPTION

XOLEGEL Gel contains the antifungal agent ketoconazole USP at 2% in a topical anhydrous gel vehicle.

Chemically ketoconazole is (±)- cis -1-Acetyl-4-[p-[[2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]piperazine, with a molecular weight of 531.43.

Each gram contains: 20 mg ketoconazole USP, 34% dehydrated alcohol USP, ascorbic acid USP, butylated hydroxytoluene NF, citric acid monohydrate USP, glycerin USP, hydroxypropyl cellulose NF, polyethylene glycol 400 NF, PPG-15 stearyl ether, propylene glycol USP, FD&C yellow No. 6, D&C yellow No. 10

XOLEGEL Gel is a smooth, translucent to clear, amber gel.

CLINICAL PHARMACOLOGY

The contribution to efficacy of individual components of the vehicle has not been established.

Pharmacokinetics:

In a pharmacokinetic absorption study, eighteen subjects, both males and females, with severe seborrheic dermatitis (range 1-14% of body surface area) applied XOLEGEL Gel once daily for 2 weeks. The median total amount of gel applied was 4.6 g (range 1.65–46.3 g). Daily doses ranged from 0.05 to 3.47 g. Mean (± standard deviation [SD]) peak plasma levels were 1.35 (± 3.18) ng/mL on Day 7 (range from <0.1 ng/mL to 13.9 ng/mL), and 0.80 (± 1.22) ng/mL on Day 14 (range from <0.1 ng/mL to 5.4 ng/mL). Median T_max was 8 hours on Day 7 and 7 hours on Day 14. Mean (± SD) AUC_0-24 values were 20.8 (± 44.7) ng•h/mL and 15.6 (± 26.4) ng•h/mL on Day 7 and 14, respectively.

The plasma levels from an oral dose of 200 mg ketoconazole taken with a meal are approximately 250 times higher than the resulting plasma levels of ketoconazole following topical application of XOLEGEL Gel.

Microbiology: Ketoconazole is an antifungal agent which, in vitro, inhibits the synthesis of ergosterol, a key sterol in the cell membrane of Malassezia furfur (also known as Pityrosporum ovale), which leads to the death of the organism.

Mode of Action: It is postulated that the therapeutic effect of ketoconazole in seborrheic dermatitis is due to the reduction of Malassezia furfur (also known as Pityrosporum ovale), but this has not been proven.

CLINICAL STUDIES

Study 1 was a multicenter, double-blind, randomized, vehicle-controlled trial which enrolled 459 patients 12 years of age and older with moderate to severe seborrheic dermatitis. A total of 229 patients were treated with XOLEGEL Gel, and 230 patients were treated with vehicle. All patients were treated once daily for 14 days, and efficacy was assessed at Day 28 (i.e., 2 weeks after end of treatment). Effective Treatment was defined as:

• an Investigator’s Global Assessment score of ≤ 1 (completely clear or almost clear) and
• erythema and scaling scores of 0 (none) if the baseline score was 2, or 1 (mild) if the baseline score was 3.

The proportion of patients effectively treated is shown in the following table.

Table 1

	XOLEGEL Gel N=229	Vehicle Gel N=230
Proportion of patients effectively treated	58 (25.3%)	32 (13.9%)

Two additional double-blind, randomized, vehicle-controlled, parallel, and multi-center studies that included a total of 316 patients treated with XOLEGEL Gel provided supportive evidence of the efficacy of XOLEGEL Gel for treatment of seborrheic dermatitis. Patients applied either XOLEGEL Gel or vehicle study treatment to the affected area(s) once daily for 14 days and were followed through Day 28. Efficacy was assessed by the proportion of patients who were completely clear at Day 28.