Epiduo

Pregnancy

Risk Summary

Available pharmacovigilance data with Adapalene and Benzoyl Peroxide Topical Gel, 0.3%/2.5% use in pregnant women are insufficient to establish a drug-associated risk of major birth defects, miscarriage or other adverse maternal or fetal outcomes. Animal reproduction studies have not been conducted with the combination gel.

Adapalene gel, 0.3%

Available data from clinical trials with adapalene gel 0.3% use in pregnant women are insufficient to establish a drug-associated risk of major birth defects, miscarriage or other adverse maternal or fetal outcomes. In animal reproduction studies, oral administration of adapalene to pregnant rats and rabbits during organogenesis at dose exposures 41 and 81 times, respectively, the human exposure at the maximum recommended human dose (MRHD) of 2 g resulted in fetal skeletal and visceral malformations (see Data).

Benzoyl peroxide gel, 2.5%

The systemic exposure of benzoyl peroxide is unknown. Based on published literature, benzoyl peroxide is rapidly metabolized to benzoic acid (an endogenous substance), which is eliminated in the urine. Hence, maternal use is not expected to result in fetal exposure of the drug.

The 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 risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.

Data

Animal Data

No malformations were observed in rats treated with oral adapalene doses of 0.15 to 5.0 mg/kg/day, up to 8 times the MRHD of 2 grams of Adapalene and Benzoyl Peroxide Topical Gel, 0.3%/2.5% based on a mg/m2 comparison. However, malformations were observed in rats and rabbits when treated with oral doses of ≥ 25 mg/kg/day adapalene (41 and 81 times the MRHD, respectively, based on a mg/m2 comparison). Findings included cleft palate, microphthalmia, encephalocele, and skeletal abnormalities in rats and umbilical hernia, exophthalmos, and kidney and skeletal abnormalities in rabbits.

Dermal adapalene embryofetal development studies in rats and rabbits at doses up to 6.0 mg/kg/day (9.7 and 19.5 times the MRHD, respectively, based on a mg/m2 comparison) exhibited no fetotoxicity and only minimal increases in skeletal variations (supernumerary ribs in both species and delayed ossification in rabbits).

Lactation

Risk Summary

Adapalene gel, 0.3%

There are no data on the presence of adapalene topical gel or its metabolite in human milk, the effects on the breastfed infant, or the effects on milk production. In animal studies, adapalene is present in rat milk with oral administration of the drug. When a drug is present in animal milk, it is likely that the drug will be present in human milk. It is possible that topical administration of large amounts of adapalene could result in sufficient systemic absorption to produce detectable quantities in human milk (see Clinical Considerations).

Benzoyl peroxide gel, 2.5%

The systemic exposure of benzoyl peroxide is unknown. Based on the published literature, benzoyl peroxide is rapidly metabolized to benzoic acid (an endogenous substance), which is eliminated in the urine. Any amount of benzoyl peroxide excreted into human milk by a nursing mother would be expected to be rapidly metabolized by tissue and stomach esterases. There are no data on the presence of benzoyl peroxide in human milk, its effects on the breastfed infant or its effects on milk production.

The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for Adapalene and Benzoyl Peroxide Topical Gel, 0.3%/2.5% and any potential adverse effects on the breastfed child from Adapalene and Benzoyl Peroxide Topical Gel, 0.3%/2.5% or from the underlying maternal condition.

Clinical Considerations

To minimize potential exposure to the breastfed infant via breastmilk, use Adapalene and Benzoyl Peroxide Topical Gel, 0.3%/2.5% on the smallest area of skin and for the shortest duration possible while breastfeeding. Advise breastfeeding women not to apply Adapalene and Benzoyl Peroxide Topical Gel, 0.3%/2.5% directly to the nipple and areola to avoid direct infant exposure.

Pediatric Use

Safety and effectiveness of Adapalene and Benzoyl Peroxide Topical Gel, 0.3%/2.5% in pediatric patients under the age of 12 have not been established.

Geriatric Use

Clinical studies of adapalene and benzoyl peroxide topical gel, 0.3%/2.5% did not include sufficient numbers of subjects aged 65 years and over to determine whether they respond differently from younger subjects.

Hypersensitivity

Hypersensitivity reactions, including anaphylaxis, angioedema, and urticaria, have been reported with the use of benzoyl peroxide products. If a serious hypersensitivity reaction occurs, discontinue Adapalene and Benzoyl Peroxide Topical Gel, 0.3%/2.5% immediately and initiate appropriate therapy.

Photosensitivity

Avoid exposure to sunlight, including sunlamps, during the use of Adapalene and Benzoyl Peroxide Topical Gel, 0.3%/2.5%. Patients with high levels of sun exposure and those with inherent sensitivity to sun should exercise particular caution. Use of broad spectrum 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 Adapalene and Benzoyl Peroxide Topical Gel, 0.3%/2.5%.

Skin Irritation/Contact Dermatitis

Erythema, scaling, dryness, and stinging/burning may be experienced with use of Adapalene and Benzoyl Peroxide Topical Gel, 0.3%/2.5%. 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 Adapalene and Benzoyl Peroxide Topical Gel, 0.3%/2.5%, 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 Adapalene and Benzoyl Peroxide Topical Gel, 0.3%/2.5%. 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).

Clinical Trials Experience

The following adverse reactions are discussed in greater detail elsewhere in the labeling:

•

Hypersensitivity [see Warnings and Precautions ]

•

Skin Irritation/Contact Dermatitis [see Warnings and Precautions ]

Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice. During the randomized, double-blind, vehicle- and active-controlled clinical trial, 217 subjects were exposed to adapalene and benzoyl peroxide topical gel, 0.3%/2.5%. A total of 197 subjects with acne vulgaris, 12 years and older, were treated once daily for 12 weeks. Adverse reactions reported within 12 weeks of treatment in at least 1% of subjects treated with adapalene and benzoyl peroxide topical gel, 0.3%/2.5% and for which the rate with adapalene and benzoyl peroxide topical gel, 0.3%/2.5% exceeded the rate for the vehicle are presented in Table 1:

Table 1. Adverse Reactions Occurring in ≥1% of Subjects with Acne Vulgaris in a 12-week Clinical Trial

Local tolerability evaluations, presented in Table 2, were conducted at each trial visit in the clinical trial by assessment of erythema, scaling, dryness, and stinging/burning, which peaked at Week 1 of therapy and decreased thereafter.

Table 2. Incidence of Local Cutaneous Irritation in 12-week Clinical Trial in Subjects with Acne Vulgaris

Postmarketing Experience

The following adverse reactions have been identified during postapproval use of adapalene and benzoyl peroxide topical gel, 0.3%/2.5%. 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.

Skin and subcutaneous tissue disorders: sunburn, blister (including vesicles and bullae), pruritus, hyperpigmentation and hypopigmentation.

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.

Pharmacodynamics

Pharmacodynamics of Adapalene and Benzoyl Peroxide Topical Gel, 0.3%/2.5% is unknown.

Pharmacokinetics

A pharmacokinetic trial was conducted in 26 adult and adolescent subjects (12 to 33 years of age) with severe acne vulgaris who were treated with once-daily applications during a 4-week period with, on average, 2.3 grams/day (range 1.6 - 3.1 grams/day) of adapalene and benzoyl peroxide topical gel, 0.3%/2.5% applied as a thin layer to the face, shoulders, upper chest, and upper back. After a 4-week treatment, 16 subjects (62%) had quantifiable adapalene plasma concentrations above the limit of quantification of 0.1 ng/mL, with a mean Cmax of 0.16 ± 0.08 ng/mL and a mean AUC0-24hr of 2.49 ± 1.21 ng.h/mL. The most exposed subject had adapalene Cmax and AUC0-24hr of 0.35 ng/mL and 6.41 ng.h/mL, respectively. Excretion of adapalene appears to be primarily by the biliary route. Benzoyl peroxide is absorbed by the skin where it is converted to benzoic acid and eliminated in the urine.

Drug Interactions

No formal drug-drug interaction studies were conducted with Adapalene and Benzoyl Peroxide Topical Gel, 0.3%/2.5%.

Carcinogenesis, Mutagenesis, Impairment of Fertility

No carcinogenicity, genotoxicity, or fertility studies were conducted with adapalene and benzoyl peroxide topical gel, 0.3%/2.5%.

Carcinogenicity studies with adapalene were conducted in mice at topical doses of 0.4, 1.3, and 4.0 mg/kg/day (1.2, 3.9, 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). The highest dose levels are 3.2 (mice) and 2.4 (rats) times the MRHD of adapalene and benzoyl peroxide topical gel, 0.3%/2.5% based on a mg/m2 comparison. In the rat study, an increased incidence of benign and malignant pheochromocytomas reported 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 adapalene and benzoyl peroxide topical gel, 0.3%/2.5%) for two years. Rats received maximum daily applications of 138 (males) and 205 (females) mg/kg benzoyl peroxide (27-40 times the MRHD based on a mg/m2 comparison). 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 year study period, and in mice topically treated with 5% benzoyl peroxide carbopol gel for two years. Benzoyl peroxide is a tumor promoter in several animal species. The significance of this finding in humans is unknown.

Adapalene was not mutagenic or genotoxic in vitro (Ames test, Chinese hamster ovary cell assay, or mouse lymphoma TK assay) or in vivo (mouse micronucleus test). Benzoyl peroxide caused DNA strand breaks and DNA-protein cross-links in mammalian cells, increased sister chromatid exchanges in Chinese hamster ovary cells, and was mutagenic in a few, but not all, in vitro bacterial mutagenicity assays (Ames tests) conducted.

In rat oral studies, 20 mg/kg/day adapalene (32 times the MRHD based on a mg/m2 comparison) did not affect the reproductive performance and fertility of F0 males and females or the growth, development or reproductive function of F1 offspring. No fertility studies were conducted with benzoyl peroxide.