EPIDUO FORTE- adapalene and benzoyl peroxide gel
Galderma Laboratories, L.P.
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use EPIDUO FORTE safely and effectively. See full prescribing information for EPIDUO FORTE.
EPIDUO® FORTE (adapalene and benzoyl peroxide) topical gel.
Initial U.S. Approval: 2015
INDICATIONS AND USAGE
EPIDUO FORTE, is a combination of adapalene, a retinoid, and benzoyl peroxide and is indicated for the topical treatment of acne vulgaris in adults and pediatric patients 12 years of age and older. (1)
DOSAGE AND ADMINISTRATION
DOSAGE FORMS AND STRENGTHS
Topical Gel, 0.3%/2.5% (3)
EPIDUO FORTE is contraindicated in patients with a history of hypersensitivity reactions to benzoyl peroxide or any components of the formulation in EPIDUO FORTE. (4)
WARNINGS AND PRECAUTIONS
See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling.
FULL PRESCRIBING INFORMATION: CONTENTS*
EPIDUO FORTE is indicated for the topical treatment of acne vulgaris in adults and pediatric patients 12 years of age and older.
Each gram of EPIDUO FORTE topical gel contains 3 mg (0.3%) adapalene and 25 mg (2.5%) benzoyl peroxide in a white to very pale yellow, opaque gel. EPIDUO FORTE is available in pumps containing 15 g, 30 g, 45 g, 60 g or 70 g.
EPIDUO FORTE is contraindicated in patients with a history of hypersensitivity reactions to benzoyl peroxide or any components of the formulation in EPIDUO FORTE.
Hypersensitivity reactions, including anaphylaxis, angioedema, and urticaria, have been reported with the use of benzoyl peroxide products. If a serious hypersensitivity reaction occurs, discontinue EPIDUO FORTE immediately and initiate appropriate therapy.
Avoid exposure to sunlight, including sunlamps, during the use of EPIDUO FORTE. 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 EPIDUO FORTE.
Erythema, scaling, dryness, and stinging/burning may be experienced with use of EPIDUO FORTE. 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 FORTE, 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 FORTE.
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).
The following adverse reactions are discussed in greater detail elsewhere in the labeling:
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 EPIDUO FORTE. 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 EPIDUO FORTE and for which the rate with EPIDUO FORTE exceeded the rate for the vehicle are presented in Table 1:
|Adapalene and Benzoyl Peroxide Gel, 0.1%/2.5% |
|Skin burning sensation||1%||0%||0%|
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.
|End of Treatment Severity
|EPIDUO FORTE (N=213)|
|Adapalene and Benzoyl Peroxide Gel, 0.1%/2.5% (N=212)|
The following adverse reactions have been identified during postapproval use of EPIDUO FORTE. 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..
Available pharmacovigilance data with EPIDUO FORTE 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.
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 EPIDUO FORTE 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).
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 EPIDUO FORTE and any potential adverse effects on the breastfed child from EPIDUO FORTE or from the underlying maternal condition.
To minimize potential exposure to the breastfed infant via breastmilk, use EPIDUO FORTE on the smallest area of skin and for the shortest duration possible while breastfeeding. Advise breastfeeding women not to apply EPIDUO FORTE directly to the nipple and areola to avoid direct infant exposure.
Safety and effectiveness of EPIDUO FORTE in pediatric patients under the age of 12 have not been established.
EPIDUO FORTE (adapalene and benzoyl peroxide) topical gel, 0.3%/2.5% is a white to very pale yellow, opaque gel for topical use containing adapalene 0.3% and benzoyl peroxide 2.5%.
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:
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:
Molecular formula: C14H10O4 Molecular weight: 242.23
EPIDUO FORTE 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.
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 is an oxidizing agent with bactericidal and keratolytic effects.
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 EPIDUO FORTE 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.
No formal drug-drug interaction studies were conducted with EPIDUO FORTE.
No carcinogenicity, genotoxicity, or fertility studies were conducted with EPIDUO FORTE.
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, 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). The highest dose levels are 3.2 (mice) and 2.4 (rats) times the MRHD of EPIDUO FORTE 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 EPIDUO FORTE) 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.
The safety and efficacy of EPIDUO FORTE applied once daily for 12 weeks for the treatment of acne vulgaris were assessed in a multicenter, randomized, double-blind, vehicle-controlled trial, comparing EPIDUO FORTE to vehicle gel in subjects with acne vulgaris. The trial also evaluated adapalene and benzoyl peroxide gel, 0.1%/2.5%, a lower strength product than EPIDUO FORTE (adapalene and benzoyl peroxide) topical gel, 0.3%/2.5%. In this trial, 217 subjects were treated with EPIDUO FORTE, 217 subjects with adapalene and benzoyl peroxide, gel, 0.1%/2.5% and 69 subjects with the vehicle gel.
Treatment response was defined as the percent of subjects who were rated “clear” or “almost clear’ at Week 12 with at least a two-grade improvement 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 clear skin with no inflammatory or non-inflammatory lesions. An IGA score of “almost clear” corresponded to a few scattered comedones and a few small papules.
At baseline, 50% of subjects were graded as “moderate” (IGA Grade 3) and 50% were graded as “severe” (IGA Grade 4) on the IGA scale. Subjects had an average of 98 (range 51-226) total lesions of which the mean number of inflammatory lesions was 38 (range: 20-99) and the mean number of non-inflammatory lesions was 60 (range 30- 149). Subjects ranged in age from 12 to 57 years, with 273 (54%) of subjects 12 to 17 years of age. Approximately equal number of males (48%) and females (52%) were enrolled.
The IGA success rate, mean reduction, and percent reduction in acne lesion counts from baseline after 12 weeks of treatment are presented in the following table.
|Adapalene and Benzoyl|
Peroxide Gel, 0.1%/2.5%
|IGA: two-grade improvement and "clear" or "almost clear"||33.7%||27.3%||11.0%|
|Inflammatory lesions: mean absolute (percent) reduction||27.8 (68.7%)||26.5 (69.3%)||13.2 (39.2%)|
|Non-inflammatory lesions: mean absolute (percent) reduction||40.5 (68.3%)||40.0 (68.0%)||19.7 (37.4%)|
* This trial was not designed or powered to compare the efficacy of EPIDUO FORTE to the lower strength adapalene and benzoyl peroxide gel, 0.1%/2.5%, nor to compare the lower strength adapalene and benzoyl peroxide gel, 0.1%/2.5% to the vehicle control.
In subjects graded as “severe” (IGA Grade 4), efficacy was observed in the EPIDUO FORTE group.
EPIDUO FORTE (adapalene and benzoyl peroxide) gel 0.3%/2.5% is white to very pale yellow in color and opaque in appearance, and is supplied as follows:
15 gram pump NDC 0299-5906-15
30 gram pump NDC 0299-5906-30
45 gram pump NDC 0299-5906-45
60 gram pump NDC 0299-5906-60
70 gram pump NDC 0299-5906-70
Advise the patient to read the FDA approved patient labeling (Patient Information).
Inform patients that serious hypersensitivity reactions occurred with the use of benzoyl peroxide products. If a patient experiences a serious hypersensitivity reaction, instruct patient to discontinue EPIDUO FORTE immediately and seek medical help [see Warnings and Precautions (5.1)].
Advise patients to minimize or avoid exposure to natural or artificial light, including tanning beds or UVA/B treatment. Recommend the use of broad spectrum sunscreen products and protective apparel (e.g., hat) when exposure cannot be avoided [see Warnings and Precautions (5.2)].
Skin Irritation/Contact Dermatitis
Inform patients that EPIDUO FORTE may cause irritation such as erythema, scaling, dryness, stinging or burning [see Warnings and Precautions (5.3)].
Use EPIDUO FORTE on the smallest part of the skin and for the shortest duration possible while breastfeeding. Advise breastfeeding women not to apply EPIDUO FORTE directly to the nipple and areola to avoid direct infant exposure [see Use in Specific Populations (8.2)].
GALDERMA LABORATORIES, L.P.
Fort Worth, Texas 76177 USA
Made in Canada
All trademarks are the property of their respective owners.
EPIDUO FORTE (Ep-E-Do-Oh For-Tay)
(adapalene and benzoyl peroxide)
Important Information: EPIDUO FORTE is for use on the skin only (topical). Do not use EPIDUO FORTE
in or on your mouth, eyes, or vagina.
What is EPIDUO FORTE?
EPIDUO FORTE is a prescription medicine used on the skin (topical) to treat acne vulgaris. It is not known whether EPIDUO FORTE is safe and effective in children under 12 years of age.
Do not use EPIDUO FORTE if you have had an allergic reaction to benzoyl peroxide or any of the ingredients in EPIDUO FORTE. See the end of this Patient Information leaflet for a complete list of ingredients in EPIDUO FORTE.
Before using EPIDUO FORTE, tell your doctor about all of your medical conditions, including if you:
Tell your doctor about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.
How should I use EPIDUO FORTE?
Applying EPIDUO FORTE:
What should I avoid while using EPIDUO FORTE?
What are the possible side effects of EPIDUO FORTE?
EPIDUO FORTE may cause serious side effects including:
These are not all of the possible side effects of EPIDUO FORTE.
Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
How should I store EPIDUO FORTE?
Keep EPIDUO FORTE and all medicines out of the reach of children.
General information about the safe and effective use of EPIDUO FORTE
Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use EPIDUO FORTE for a condition for which it was not prescribed. Do not give EPIDUO FORTE to other people, even if they have the same symptoms you have. It may harm them. You can ask your doctor or pharmacist for information about EPIDUO FORTE that is written for health professionals.
What are the ingredients in EPIDUO FORTE?
Active ingredient: adapalene and benzoyl peroxide
Inactive ingredients: acrylamide/sodium acryloydimethyltaurate copolymer, docusate sodium, edetate disodium, glycerin, isohexadecane, polaxamer 124, polysorbate 80, propylene glycol, purified water and sorbitan oleate
Marketed by: GALDERMA LABORATORIES, L.P., Fort Worth, Texas 76177 USA
Made in Canada
All trademarks are the property of their respective owners.
For more information, call GALDERMA LABORATORIES, L.P. at 1-866-735-4137.
This Patient Information has been approved by the U.S. Food and Drug Administration.
Rx only NDC 0299-5906-45
(adapalene and benzoyl peroxide) Topical Gel 0.3%/2.5%
FOR TOPICAL USE ONLY
For topical use only. Not for ophthalmic, oral or intravaginal use.
Usual dosage: Apply a thin layer once a day to affected areas. See package insert for complete prescribing information.
Each gram contains: Active: adapalene 0.3% and benzoyl peroxide 2.5% in a gel. Inactive: acrylamide/sodium acryloyldimethyltaurate copolymer, docusate sodium, edetate disodium, glycerin, isohexadecane, poloxamer 124, polysorbate 80, propylene glycol, purified water, and sorbitan oleate.
Storage: Store at controlled room temperature 68° to 77°F (20° to 25°C) with excursions permitted between 59° and 86°F (15° and 30°C).
See carton closure for lot number and expiration date.
GALDERMA LABORATORIES, L.P.
14501 North Freeway
Fort Worth, Texas 76177 USA
Made in Canada.
All trademarks are the property of their respective owners
adapalene and benzoyl peroxide gel
|Labeler - Galderma Laboratories, L.P. (047350186)|
|G Production Inc.||251676961||manufacture(0299-5906)|