Xolegel

XOLEGEL- ketoconazole gel
Almirall, LLC

1 INDICATIONS AND USAGE

XOLEGEL is indicated for the topical treatment of seborrheic dermatitis in immunocompetent adults and children 12 years of age and older.

Safety and efficacy of XOLEGEL for treatment of fungal infections have not been established.

2 DOSAGE AND ADMINISTRATION

XOLEGEL is for topical use only, and not for oral, ophthalmic, or intravaginal use.

XOLEGEL should be applied once daily to the affected area for 2 weeks.

3 DOSAGE FORMS AND STRENGTHS

XOLEGEL is a translucent to clear amber colored gel containing 2% ketoconazole.

4 CONTRAINDICATIONS

None.

5 WARNINGS AND PRECAUTIONS

5.1 Flammable Contents

XOLEGEL is flammable. Avoid being near fire, flame, or smoking during and immediately following application of XOLEGEL.

5.2 Systemic Effects

Hepatitis and, at high doses, lowered testosterone and ACTH induced corticosteroid serum levels have been seen with orally administered ketoconazole; these effects have not been seen with topically administered ketoconazole.

5.3 Local Effects

XOLEGEL can cause local irritation at the application site. If irritation occurs or if the disease worsens, use of the medication should be discontinued and the health care provider should be contacted [see ADVERSE REACTIONS (6.1)].

6 ADVERSE REACTIONS

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

In the 3 safety and efficacy trials, 65 of 933 subjects (7%) experienced at least one treatment-related adverse event. The most common treatment-related adverse reaction was application site burning (4%). Treatment-related application site reactions that were reported in < 1% of subjects were: dermatitis, discharge, dryness, erythema, irritation, pain, pruritus, and pustules. Other treatment-related adverse reactions that were reported in < 1% of subjects were: eye irritation, eye swelling, keratoconjunctivitis sicca, impetigo, pyogenic granuloma, dizziness, headache, paresthesia, acne, nail discoloration, facial swelling.

7 DRUG INTERACTIONS

Formal drug interaction studies with XOLEGEL have not been performed. Coadministration of oral ketoconazole with CYP3A4 metabolized HMG-CoA reductase inhibitors such as simvastatin, lovastatin and atorvastatin, may increase the risk of skeletal muscle toxicity, including rhabdomyolysis. These effects have not been observed with topically administered ketoconazole.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary
There are no available data on XOLEGEL use in pregnant women to evaluate for a drug associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes.

In animal reproduction studies with pregnant rats, structural abnormalities (syndactylia and oligodactylia) were observed following oral doses of ketoconazole during organogenesis (see Data). The available data do not allow calculation of relevant comparisons between the systemic exposure of ketoconazole observed in animal studies to the systemic exposure observed in humans after topical use of XOLEGEL.

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2%-4% and 15%-20%, respectively.

Data
Animal Data
Oral administration of ketoconazole at 80 mg/kg/day to pregnant rats during organogenesis was associated with structural abnormalities (syndactylia and oligodactylia) . However, these effects may be related to maternal toxicity, which was also seen at this and higher dose levels.

In oral peri- and postnatal development studies in rats, maternal toxicity, prolonged gestation, embryolethality and fetotoxicity were observed at ketoconazole doses of 40 mg/kg/day and higher.

8.2 Lactation

Risk Summary
There are no data available on the presence of ketoconazole in human milk, its effects on the breastfed infant, or its effects on milk production. After topical application, ketoconazole concentrations in plasma are low and therefore concentrations in human breast milk are likely to be low [see Clinical Pharmacology (12.3)].

The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for XOLEGEL and any potential adverse effects on the breastfed infant from XOLEGEL or from the underlying maternal condition.

Clinical ConsiderationsAdvise breastfeeding women not to apply XOLEGEL directly to the nipple and areola to avoid direct infant exposure.

8.4 Pediatric Use

Safety and effectiveness in pediatric subjects below the age of 12 have not been established.

8.5 Geriatric Use

Of the 933 subjects in the three safety and efficacy trials, 193 (20.7%) were 65 and older, while 61 (6.5%) were 75 and older. No overall differences in safety or effectiveness were observed between these subjects and younger subjects but greater sensitivity of some older individuals cannot be ruled out.

11 DESCRIPTION

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

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 the molecular formula C26 H28 Cl2 N4 O4 and a molecular weight of 531.43.

Figure 1

Chemical Structure
(click image for full-size original)

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

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

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

The mechanism of action of ketoconazole in the treatment of seborrheic dermatitis is unknown.

12.2 Pharmacodynamics

Pharmacodynamic markers for seborrheic dermatitis have not been identified.

12.3 Pharmacokinetics

In a pharmacokinetic absorption trial, eighteen subjects, both males and females, with severe seborrheic dermatitis (range 1-14% of body surface area) applied XOLEGEL 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 Tmax was 8 hours on Day 7 and 7 hours on Day 14. Mean (± SD) AUC0-24 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.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

A 2-year dermal carcinogenicity study conducted in mice with topical administration of ketoconazole gel at doses up to 80 mg ketoconazole/kg/day exhibited no evidence of carcinogenic activity. A long-term feeding study in mice and in rats showed no evidence of carcinogenic activity.

Ketoconazole produced no evidence of mutagenicity in the dominant lethal mutation test in male and female mice at single oral doses up to 80 mg/kg. When tested in the Ames assay, ketoconazole was not mutagenic to Salmonella typhimurium in the presence or absence of metabolic activation. Ketoconazole, in combination with another drug, gave equivocal results in the mouse micronucleus test.

At oral doses of 75 mg/kg/day, ketoconazole impaired the reproductive performance in female (decreased pregnancy and implantation rates) and male (increased abnormal sperm and decreased sperm motility) rats.

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