Epiduo Gel

Warnings
Precautions

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

Ultraviolet Light and Environmental Exposure

Exposure to sunlight, including sunlamps, should be minimized during the use of EPIDUO gel. Patients with high levels of sun exposure and those with inherent sensitivity to sun should exercise particular caution. Use of sunscreen products and protective apparel, (e.g., hat) are recommended when exposure cannot be avoided. Weather extremes, such as wind or cold, may be irritating to patients under treatment with EPIDUO gel.

Local Cutaneous Reactions

Erythema, scaling, dryness, and stinging/burning may be experienced with use of EPIDUO gel. These are most likely to occur during the first four weeks of treatment, are mostly mild to moderate in intensity, and usually lessen with continued use of the medication. Irritant and allergic contact dermatitis may occur. Depending upon the severity of these adverse reactions, patients should be instructed to use a moisturizer, reduce the frequency of the application of EPIDUO gel, or discontinue use. The product should not be applied to cuts, abrasions, eczematous or sunburned skin. As with other retinoids, use of “waxing” as a depilatory method should be avoided on skin treated with EPIDUO gel. Avoid concomitant use of other potentially irritating topical products (medicated or abrasive soaps and cleansers, soaps and cosmetics that have strong skin-drying effect and products with high concentrations of alcohol, astringents, spices, or limes).

Patient Counseling Information

[See FDA Approved Patient Labeling (PATIENT INFORMATION)]

Information for Patients

Advise patients to cleanse the area to be treated with a mild or soapless cleanser; pat dry. Apply EPIDUO gel as a thin layer, avoiding the eyes, lips and mucous membranes.

Advise patients not to use more than the recommended amount and not to apply more than once daily as this will not produce faster results, but may increase irritation.

EPIDUO gel may cause irritation such as erythema, scaling, dryness, stinging or burning.

Advise patients to minimize exposure to sunlight, including sunlamps. Recommend the use of sunscreen products and protective apparel, (e.g., hat) when exposure cannot be avoided.

EPIDUO gel may bleach hair and colored fabric.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment of Fertility

No carcinogenicity, photocarcinogenicity, genotoxicity, or fertility studies were conducted with EPIDUO gel. Carcinogenicity studies with adapalene have been conducted in mice at topical doses of 0.4, 1.3, and 4.0 mg/kg/day (1.2, 3.9, and 12 mg/m²/day), and in rats at oral doses of 0.15, 0.5, and 1.5 mg/kg/day (0.9, 3.0, and 9.0 mg/m²/day). In terms of body surface area, the highest dose levels are 9.8 (mice) and 7.4 times (rats) the MRHD of 2 grams of EPIDUO gel. In the rat study, an increased incidence of benign and malignant pheochromcytomas in the adrenal medulla of male rats was observed.

No significant increase in tumor formation was observed in rodents topically treated with 15-25% benzoyl peroxide carbopol gel (6-10 times the concentration of benzoyl peroxide in EPIDUO gel) for two years. Rats received maximum daily applications of 138 (males) and 205 (females) mg benzoyl peroxide/kg. In terms of body surface area, these levels are 27-40 times the MRHD. Similar results were obtained in mice topically treated with 25% benzoyl peroxide carbopol gel for 56 weeks followed by intermittent treatment with 15% benzoyl peroxide carbopol gel for rest of the 2 years study period, and in mice topically treated with 5% benzoyl peroxide carbopol gel for two years. The role of benzoyl peroxide as a tumor promoter has been well established in several animal species. However, the significance of this finding in humans is unknown.

In a photocarcinogenicity study conducted with 5% benzoyl peroxide carbopol gel, no increase in UV-induced tumor formation was observed in hairless mice topically treated for 40 weeks.

No photocarcinogenicity studies were conducted with adapalene. However, animal studies have shown an increased tumorigenic risk with the use of pharmacologically similar drugs (e.g., retinoids) when exposed to UV irradiation in the laboratory or sunlight. Although the significance of these findings to humans is not clear, patients should be advised to avoid or minimize exposure to either sunlight or artificial irradiation sources.

Adapalene did not exhibit mutagenic or genotoxic effects in vitro (Ames test, Chinese hamster ovary cell assay, mouse lymphoma TK assay) or in vivo (mouse micronucleus test).

Bacterial mutagenicity assays (Ames test) with benzoyl peroxide has provided mixed results, mutagenic potential was observed in a few but not in a majority of investigations. Benzoyl peroxide has been shown to produce single-strand DNA breaks in human bronchial epithelial and mouse epidermal cells, it has caused DNA-protein cross-links in the human cells, and has also induced a dose-dependent increase in sister chromatid exchanges in Chinese hamster ovary cells.

In rat oral studies, 20 mg adapalene/kg/day (120 mg/m²/day; 98 times the MRHD based on mg/m²/day comparison) did not affect the reproductive performance and fertility of F0 males and females, or growth, development and reproductive function of F1 offspring.

No fertility studies were conducted with benzoyl peroxide.

Use In Specific Populations

Pregnancy

Pregnancy Category C

There are no well-controlled trials in pregnant women treated with EPIDUO gel. Animal reproduction studies have not been conducted with the combination gel or benzoyl peroxide. Furthermore, such studies are not always predictive of human response; therefore, EPIDUO gel should be used during pregnancy only if the potential benefit justifies the risk to the fetus. No teratogenic effects were observed in rats treated with oral doses of 0.15 to 5.0 mg adapalene/kg/day, up to 25 times (mg/m²/day) the maximum recommended human dose (MRHD) of 2 grams of EPIDUO gel. However, teratogenic changes were observed in rats and rabbits when treated with oral doses of . 25 mg adapalene/kg/day representing 123 and 246 times MRHD, respectively. Findings included cleft palate, microphthalmia, encephalocele and skeletal abnormalities in rats; and umbilical hernia, exophthalmos and kidney and skeletal abnormalities in rabbits. Dermal teratology studies conducted in rats and rabbits at doses of 0.6-6.0 mg adapalene/kg/day [25-59 times (mg/m²) the MRHD] exhibited no fetotoxicity and only minimal increases in supernumerary ribs in both species and delayed ossification in rabbits.

Nursing Mothers

It is not known whether adapalene or benzoyl peroxide is excreted in human milk following use of EPIDUO gel. Because many drugs are excreted in human milk, caution should be exercised when EPIDUO gel is administered to a nursing woman.

Pediatric Use

Safety and effectiveness of EPIDUO gel in pediatric patients under the age of 9 have not been established.

Geriatric Use

Clinical studies of EPIDUO gel did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.

Last reviewed on RxList: 2/26/2013
This monograph has been modified to include the generic and brand name in many instances.

Warnings
Precautions
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