Epiduo

Appropriate studies have not been performed on the relationship of age to the effects of Epiduo® in children younger than 9 years of age. Safety and efficacy have not been established.

Appropriate studies have not been performed on the relationship of age to the effects of Epiduo® Forte in children younger than 12 years of age. Safety and efficacy have not been established.

Epiduo is a prescription medicine used to treat acne in people 12 years of age and older. 

This medication may be prescribed for other uses. Ask your doctor or pharmacist for more information.

Medications can interact with certain foods. In some cases, this may be harmful and your doctor may advise you to avoid certain foods. In the case of Epiduo, there are no specific foods that you must exclude from your diet when receiving this medication. 

• If your symptoms or health problems do not get better or if they become worse, call your doctor.
• Do not share your drugs with others and do not take anyone else's drugs.
• Keep a list of all your drugs (prescription, natural products, vitamins, OTC) with you. Give this list to your doctor.
• Talk with the doctor before starting any new drug, including prescription or OTC, natural products, or vitamins.
• Some drugs may have another patient information leaflet. Check with your pharmacist. If you have any questions about Epiduo, please talk with your doctor, nurse, pharmacist, or other health care provider.
• If you think there has been an overdose, call your poison control center or get medical care right away. Be ready to tell or show what was taken, how much, and when it happened.

This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about Epiduo (adapalene and benzoyl peroxide). It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using Epiduo.

Review Date: October 4, 2017

Epiduo gel is indicated for the topical treatment of acne vulgaris in patients 9 years of age and older.

For topical use only; Epiduo gel is not for oral, ophthalmic, or intravaginal use.

Apply a thin film of Epiduo gel to affected areas of the face and/or trunk once daily after washing. Use a pea-sized amount for each area of the face (e.g., forehead, chin, each cheek). Avoid the eyes, lips and mucous membranes.

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).

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.

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 pheochromocytomas 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 the rest of the 2 year 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.

The safety and efficacy of Epiduo gel applied once daily for the treatment of acne vulgaris were assessed in two 12-week, multicenter, controlled clinical studies of similar design, comparing Epiduo gel to the gel vehicle in acne subjects.Treatment response was defined as the percent of subjects who had a two grade improvement and rated ‘Clear’ and ‘Almost Clear’ at Week 12 based on the Investigator's Global Assessment (IGA) and mean absolute change from baseline at Week 12 in both inflammatory and non-inflammatory lesion counts. An IGA score of 'Clear' corresponded to residual hyperpigmentation  and erythema may be present. An IGA score of ‘Almost Clear’ corresponded to a few scattered comedones and a few small papules.In Study 1, 517 subjects were randomized to Epiduo gel, adapalene 0.1% in vehicle gel, benzoyl peroxide 2.5% in vehicle gel, or vehicle gel. The median age of these 517 subjects was 15 years old and 60% were males. At baseline subjects had between 20 to 50 inflammatory lesions and 30 to 100 non-inflammatory lesions. The majority of subjects had a baseline IGA score of ‘Moderate’ which corresponded to more than half of the face is involved, many comedones, papules and pustules. The efficacy results at week 12 are presented in Table 3.In Study 2, 1668 subjects were randomized to Epiduo gel, adapalene 0.1% in vehicle gel, benzoyl peroxide 2.5% in vehicle gel, or vehicle gel. The median age of subjects was 16 years old and 49% were males. At baseline subjects had between 20 to 50 inflammatory lesions and 30 to 100 non-inflammatory lesions as well as an Investigator Global Assessment score of ‘Moderate’. The efficacy results at week 12 are presented in Table 3.In Study 3, 285 pediatric subjects 9 to 11 years of age were randomized to Epiduo gel or vehicle gel. The median age of subjects was 11 years and 24% were males. At baseline, subjects had a minimum of 20 but not more than 100 total lesions (inflammatory and/or non-inflammatory) with an Investigator Global Assessment score of 'Moderate'. The efficacy results at week 12 are presented in Table 3.

In both Studies 1 and 2 the treatment effect was smaller in subjects with a small number of baseline lesions than in subjects with a large number of baseline lesions.