EPIDUO (Page 2 of 4)

6.2 Postmarketing Experience

The following adverse reactions have been identified during postapproval use of EPIDUO gel: eyelid edema, sunburn, blister, pain of skin, pruritus, swelling face, conjunctivitis, skin discoloration, rash, eczema, throat tightness and allergic contact dermatitis. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

7 DRUG INTERACTIONS

Concomitant topical acne therapy should be used with caution because a possible cumulative irritancy effect may occur, especially with the use of peeling, desquamating, or abrasive agents.

No formal drug-drug interaction studies were conducted with EPIDUO gel.

8 USE IN SPECIFIC POPULATIONS

8.1 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.

8.3 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.

8.4 Pediatric Use

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

8.5 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.

11 DESCRIPTION

EPIDUO (adapalene and benzoyl peroxide) gel, 0.1%/2.5% is a white to very pale yellow, opaque gel for topical use containing adapalene 0.1% and benzoyl peroxide 2.5%.

Active: Adapalene, a synthetic retinoid, is a naphthoic acid derivative with retinoid-like properties. The chemical name for adapalene is (6-[3-(1-adamantyl)-4-methoxyphenyl]-2- naphthoic acid). It has the following structural formula:

Adapalene:

adapalene structure

Molecular formula: C28 H28 O3 Molecular weight: 412.5

Benzoyl Peroxide is a highly lipophilic oxidizing agent that localizes in both bacterial and keratinocyte cell membranes. The chemical name for benzoyl peroxide is dibenzoyl peroxide. It has the following structural formula:

Benzoyl Peroxide:

bp structure

Molecular formula: C14 H10 O4 Molecular weight: 242.23

EPIDUO gel contains the following inactive ingredients: acrylamide/sodium acryloyldimethyltaurate copolymer, docusate sodium, edetate disodium, glycerin, isohexadecane, poloxamer 124, polysorbate 80, propylene glycol, purified water, and sorbitan oleate.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Adapalene

Adapalene binds to specific retinoic acid nuclear receptors but does not bind to cytosolic receptor protein. Biochemical and pharmacological profile studies have demonstrated that adapalene is a modulator of cellular differentiation, keratinization and inflammatory processes. However, the significance of these findings with regard to the mechanism of action of adapalene for the treatment of acne is unknown.

Benzoyl peroxide

Benzoyl peroxide is an oxidizing agent with bactericidal and keratolytic effects.

12.2 Pharmacodynamics

Pharmacodynamics of EPIDUO gel is unknown.

12.3 Pharmacokinetics

A pharmacokinetic study was conducted in 10 adult subjects with acne vulgaris who were treated once daily for 30 days with 2 grams/day of EPIDUO gel applied to 1000 cm2 of acne involved skin, (face, chest, and upper back).

Two subjects (20%) had quantifiable adapalene plasma concentrations above the limit of quantification (LOQ = 0.1ng/mL). The highest adapalene Cmax and AUC0-24h was 0.21 ng/mL and 1.99 ng•h/mL, respectively. Excretion of adapalene appears to be primarily by the biliary route. Pharmacokinetics of EPIDUO gel in pediatric subjects have not been evaluated.

Benzoyl peroxide is absorbed by the skin where it is converted to benzoic acid and eliminated in the urine.

13 NONCLINICAL TOXICOLOGY

13.1 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.

14 CLINICAL STUDIES

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.

Table 3: Clinical Efficacy of EPIDUO Gel at Week 12
Study 1
EPIDUO gel(N=149) Adapalene 0.1% in Vehicle gel(N=148) Benzoyl Peroxide 2.5% in Vehicle gel(N=149) Vehicle gel(N=71)
IGA: Two Grade Improvement and Clear Almost Clear 32(21.5%) 18(12.2%) 18(12.1%) 4(5.6%)
Inflammatory Lesions: Mean Absolute (Percent) Change 16.0(52.4%) 11.4(39.9%) 10.5(35.8%) 9.5(31.8%)
Non-inflammatory Lesions: Mean Absolute (Percent) Change 23.4(45.9%) 15.2(29.6%) 13.7(32.2%) 13.2(27.8%)
Study 2
EPIDUO gel(N=415) Adapalene 0.1% in Vehicle gel(N=420) Benzoyl Peroxide 2.5% in Vehicle gel(N=415) Vehicle gel(N=418)
IGA: Two Grade Improvement and Clear or Almost Clear 125(30.1%) 83(19.8%) 92(22.2%) 47(11.3%)
Inflammatory Lesions: Mean Absolute (Percent) Change 15.4(53.4%) 12.3(41.7%) 13.7(47.6%) 8.7(30.2%)
Non-inflammatory Lesions: Mean Absolute (Percent) Change 24.6(48.1%) 21.0(40.8%) 19.2(37.2%) 11.3(23.2%)

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.

Study 3
EPIDUO GelN=142 Vehicle GelN=143
IGA: Two Grade Improvement and Clear or Almost Clear 67 (47.2%) 22 (15.4%)
Inflammatory Lesions: Mean Absolute (Percent) Change 7.4 (36.0%) 0.7 (-13.2%)*
Non-inflammatory Lesions: Mean Absolute (Percent) Change 20.2 (54.7%) 2.9 (2.3%)

* -That is, a mean percent increase of 13.2%

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