HIGHLIGHTS OF PRESCRIBING INFORMATION
`
`These highlights do not include all the information
`needed to use EPIDUO Gel safely and effectively. See full
`
`prescribing information for EPIDUO Gel.
`
`
`EPIDUO™ (adapalene and benzoyl peroxide) Gel
`
`0.1%/2.5%
`For topical use only
`Initial U.S. Approval: 2008
`
`
`
`----------------------CONTRAINDICATIONS------------------
`None. (4)
`
`-----------------WARNINGS AND PRECAUTIONS----------
`Ultraviolet Light and Environmental Exposure: Avoid
`exposure to sunlight and sunlamps. Wear sunscreen when
`
`sun exposure cannot be avoided. (5.1)
`
`
`
`Erythema, scaling, dryness, and stinging/burning may occur
`with use of EPIDUO Gel. (5.2)
`
`----------------------ADVERSE REACTIONS-------------------
`
`Observed local adverse reactions in patients treated with
`-------------------INDICATIONS AND USAGE----------------
`EPIDUO Gel were erythema, scaling, dryness, stinging, and
`EPIDUO Gel is a combination of adapalene, a retinoid, and
`
`burning.
` Other most commonly reported adverse events
`
`
`benzoyl peroxide, and is indicated for the topical treatment of
`
`
`
`(≥ 1% in patients treated with EPIDUO Gel were dry skin,
`acne vulgaris in patients 12 years of age and older.(1)
`
`contact dermatitis, application site burning, application site
`
`irritation, skin irritation.(6)
`
`-----------------DOSAGE AND ADMINISTRATION---------
`
`
`Apply a thin film of EPIDUO Gel to affected areas of the
`face and/or trunk once daily after washing. Use a pea-sized
`To report SUSPECTED ADVERSE REACTIONS,
`amount for each area of the face (e.g. forehead, chin, each
`contact Galderma Laboratories L.P. at 1-866-735-4137 or
`
`cheek). Avoid the eyes, lips and mucous membranes. (2)
`
`
`FDA at 1-800-FDA-1088 or www.fda.gov/medwatch
`
`
`
`EPIDUO Gel is not for oral, ophthalmic, or intravaginal use.
`---------------------DRUG INTERACTIONS-------------------
`
`Exercise caution in using preparations containing sulfur,
`(2)
`resorcinol, or salicylic acid in combination with EPIDUO
`
`
`Gel. (7.1)
`-------------DOSAGE FORMS AND STRENGTHS----------
`
`Each gram of EPIDUO Gel contains 1 mg (0.1%) adapalene
`
`Concomitant use of topical products with a strong drying
`
`and 25 mg (2.5%) benzoyl peroxide in an aqueous based gel.
`effect can increase irritation. Use with caution. (7.1)
`(3)
`
`
`See 17 for PATIENT COUNSELING INFORMATION
`
`
`
`
`Revised: 12/2008
`
`________________________________________________________________________
`
`
`
`1
`
`AMN1012
`
`

`

`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`1 INDICATIONS AND USAGE
`2 DOSAGE AND ADMINISTRATION
`3 DOSAGE FORMS AND STRENGTHS
`4 CONTRAINDICATIONS
`5 WARNINGS AND PRECAUTIONS
`
`5.1 Ultraviolet Light and Environmental Exposure
`5.2 Local Cutaneous Reactions
`
`6 ADVERSE REACTIONS
`6.1 Clinical Studies Experience
`7 DRUG INTERACTIONS
`7.1 Concomitant Topical Medications
`
`8 USE IN SPECIFIC POPULATIONS
`8.1 Pregnancy
`8.3 Nursing Mothers
`8.4 Pediatric Use
`8.5 Geriatric Use
`10 OVERDOSAGE
`11 DESCRIPTION
`12 CLINICAL PHARMACOLOGY
`12.1 Mechanism of Action
`12.2 Pharmacodynamics
`12.3 Pharmacokinetics
`13 NONCLINICAL TOXICOLOGY
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`13.2 Animal Toxicology and/or pharmacology
`
`14 CLINICAL STUDIES
`16 HOW SUPPLIED/STORAGE AND HANDLING
`17 PATIENT COUNSELING INFORMATION
`*Sections or subsections omitted from the full prescribing information are not listed.
`
`
`
`2
`
`

`

`FULL PRESCRIBING INFORMATION
`
`
`1 INDICATIONS AND USAGE
`EPIDUO Gel is indicated for the topical treatment of acne vulgaris in patients 12
`years of age and older.
`
`2 DOSAGE AND ADMINISTRATION
`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.
`
`
`EPIDUO Gel is not for oral, ophthalmic, or intravaginal use.
`
`
`3 DOSAGE FORMS AND STRENGTHS
`Each gram of EPIDUO Gel contains 1 mg (0.1%) adapalene and 25 mg (2.5%)
`benzoyl peroxide in an aqueous based gel.
`
`4 CONTRAINDICATIONS
`
`None
`
`
`5 WARNINGS AND PRECAUTIONS
`5.1 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.
`
`
`5.2 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. Depending upon the severity of these side effects, 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
`
`3
`
`

`

`products with high concentrations of alcohol, astringents, spices, or limes).
`
`6 ADVERSE REACTIONS
`6.1 Clinical Studies Experience
`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 clinical trials, 1401 subjects were exposed to EPIDUO Gel. A total of
`1036 subjects with acne vulgaris, 12 years and older, were treated once daily for 12
`weeks to 12 months. Related adverse events reported within 12 weeks of treatment and in
`
`at least 1% of subjects treated with EPIDUO Gel and those reported in subjects treated
`with the vehicle gel are presented in Table 1:
`
`Table 1 Drug Related Adverse Events Reported in Clinical Trials by At Least 1% of
`Patients Treated For 12 Weeks
`
`System Organ Class/Preferred Term
`
`Subjects with AE(s)
`Dry skin
`
`Contact dermatitis
`
`Application site burning
`
`Application site irritation
`
`Skin irritation
`
`Epiduo
`Gel
`
`N = 564
`
`14%
` 7%
`3%
`
`2%
`
`1%
`1%
`
`Vehicle Gel
`
`
`N = 489
`
`4%
`2%
`<1%
`<1%
`<1%
`0%
`
`
`
`
`Local tolerability evaluations, presented in Table 2, were conducted at each study
`visit in clinical trials by assessment of erythema, scaling, dryness, burning, and stinging.
`
` Table 2 Incidence of Local Cutaneous Irritation in Controlled Clinical
`
`Studies (N=553) Treatment Emergent Signs and Symptoms
`
`
`
`
`Maximum Severity
`
`During Treatment
`
`End of Treatment
`Severity
`
`(12 Weeks)
`Mild Moderate Severe Mild Moderate Severe
`
`
`
`
`
`
`27%
`8%
`13%
`1%
`2%
`1%
`Erythema
`35%
`11%
`1%
`9%
`1%
`<1%
`Scaling
`41%
`13%
`1%
`10%
`2%
`<1%
`Dryness
`Stinging/burning 41%
`15%
`3%
`7%
`2%
`1%
`
`
`
`
`4
`
`

`

`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.
`
`
`
` Analysis over the 12-week period showed that local tolerability scores for
`
` erythema, scaling, dryness, and stinging/burning peaked at Week 1 of therapy and
`decreased thereafter.
`
`
`7 DRUG INTERACTIONS
`
`
`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 12
`have not been established.
`
`8.5 Geriatric Use
`Clinical studies of EPIDUO Gel did not include sufficient numbers of subjects
`
`5
`
`

`

`aged 65 and over to determine whether they respond differently from younger subjects
`
`11 DESCRIPTION
`
`
`EPIDUO Gel is a combination product for topical use containing adapalene (a
`synthetic retinoid) and benzoyl peroxide.
`
`
`Adapalene 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:
`
`Molecular formula: C28H28O3
`
`
`
`
`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:
`
`
`Molecular weight: 242.23
`
`Molecular formula: C14H10O4
`
`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
`
`6
`
`

`

`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 bacteriocidal and keratolytic effects
`12.2 Pharmacodynamics
`
`Pharmacodynamics of EPIDUO Gel is unknown.
`
`
`
`
`12.3 Pharmacokinetics
`A pharmacokinetic study was conducted in 24 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
`
`limit of quantification
`quantifiable adapalene plasma concentrations above
`the
`(LOQ=0.1ng/mL). The highest adapalene Cmax and AUC 0-24h was 0.21 ng/mL and
`1.99 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.
`
`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
`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.
`
`
`7
`
`

`

`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, 20mg adapalene/kg/day (120mg/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.
`
`
`8
`
`

`

`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.
`
`
`Table 3: Clinical Efficacy of EPIDUO Gel at Week 12
`Study 1
`
`
`
`
`
`
`IGA: Two Grade
`Improvement and
`Clear or Almost
`Clear
`Inflammatory
`Lesions: Mean
`Absolute
`(Percent) Change
`Non-inflammatory
`Lesions: Mean
`Absolute
`(Percent) Change
`
`
`
`
`
`Adapalene
`
`0.1% in
`Vehicle
`Gel
`
`Benzoyl
`Peroxide
`2.5% in
`Vehicle
`Gel
`
`Vehicle
`Gel
`
`(N=148)
`
`(N=149)
`
`(N = 71)
`
`EPIDUO
`Gel
`
`(N =
`149)
`
`32
`(21.5%)
`
`18
`(12.2%)
`
`18
`(12.1%)
`
`4
`(5.6%)
`
`16.0
`(52.4%)
`
`11.4
`(39.9%)
`
`10.5
`(35.8%)
`
`9.5
`(31.8%)
`
`23.4
`(45.9%)
`
`15.2
`(29.6%)
`
`13.7
`(32.2%)
`
`13.2
`(27.8%)
`
`Study 2
`
`
`Adapalene
`0.1% in
`Vehicle
`Gel
`
`Benzoyl
`Peroxide
`2.5% in
`Vehicle
`Gel
`
`Vehicle
`Gel
`
`(N=420)
`
`(N=415)
`
`(N = 418)
`
`EPIDUO
`Gel
`
`(N =
`415)
`
`IGA: Two Grade
`Improvement and
`Clear or Almost
`
`125
`(30.1%)
`
`83
`(19.8%)
`
`92
`(22.2%)
`
`47
`(11.3%)
`
`9
`
`

`

`Clear
`Inflammatory
`Lesions: Mean
`Absolute
`(Percent) Change
`Non-inflammatory
`Lesions: Mean
`Absolute
`(Percent) Change
`
`15.4
`(53.4%)
`
`12.3
`(41.7%)
`
`13.7
`(47.6%)
`
`8.7
`(30.2%)
`
`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.
`
`16 HOW SUPPLIED/STORAGE AND HANDLING
`EPIDUO (adapalene and benzoyl peroxide) Gel 0.1%/2.5% is supplied as
`follows:
`
`45 gram tube
`
`Storage and handling
`- Store at 25° C; excursions permitted to 15° – 30° C (59° – 86° F).
`- Protect from light.
`- Keep out of reach of children.
`- Keep away from heat.
`- Keep tube tightly closed.
`
`
`
`NDC 0299-5908-45
`
`
`17 PATIENT COUNSELING INFORMATION
`- 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.
`
`Marketed by:
`
`GALDERMA LABORATORIES, L.P., Fort Worth, Texas 76177 USA
`
`Manufactured by:
`
`Galderma Production Canada Inc., Baie d’Urfé, QC, H9X 3S4 Canada
`
`Made in Canada
`
`GALDERMA is a registered trademark.
`
`(Part Number)
`
`
`10
`
`