Adapalene and Benzoyl Peroxide Gel

Name: Adapalene and Benzoyl Peroxide Gel

Warnings

Included as part of the PRECAUTIONS section.

Clinical pharmacology

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 EPIDUO gel is unknown.

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.

Clinical Studies

The safety and efficacy of EPIDUO gel applied once daily for the treatment of acne vulgaris were assessed in two 12week, 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 or 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 Gel
N=142
Vehicle Gel
N=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%

Warnings and Precautions

Ultraviolet Light and Environmental Exposure

Exposure to sunlight, including sunlamps, should be minimized during the use of Adapalene and Benzoyl Peroxide 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 Adapalene and Benzoyl Peroxide gel.

Local Cutaneous Reactions

Erythema, scaling, dryness, and stinging/burning may be experienced with use of Adapalene and Benzoyl Peroxide 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 Adapalene and Benzoyl Peroxide 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 Adapalene and Benzoyl Peroxide 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).

Use in specific populations

Pregnancy

Pregnancy Category C. There are no well-controlled trials in pregnant women treated with Adapalene and Benzoyl Peroxide 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, Adapalene and Benzoyl Peroxide 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 Adapalene and Benzoyl Peroxide 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 Adapalene and Benzoyl Peroxide gel.  Because many drugs are excreted in human milk, caution should be exercised when  Adapalene and Benzoyl Peroxide gel is administered to a nursing woman.

Pediatric Use

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

Geriatric Use

Clinical studies of  Adapalene and Benzoyl Peroxide gel did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.

Clinical Studies

The safety and efficacy of  Adapalene and Benzoyl Peroxide gel applied once daily for the treatment of acne vulgaris were assessed in two 12-week, multicenter, controlled clinical studies of similar design, comparing Adapalene and Benzoyl Peroxide 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 Adapalene and Benzoyl Peroxide 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 Adapalene and Benzoyl Peroxide 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 Adapalene and Benzoyl Peroxide 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.

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

How Supplied/Storage and Handling

Adapalene and Benzoyl Peroxide Gel, 0.1% / 2.5% is white to very pale yellow in color and opaque in appearance, and is supplied as follows:


45 gram pump NDC 66993-869-48

Storage and handling

 - Store at 25ºC; excursions permitted to 15º - 30ºC (59º - 86ºF).

 - Protect from light.

 - Keep out of reach of children.

 - Keep away from heat.

 - Keep tube tightly closed.

What happens if i miss a dose (epiduo)?

Apply the missed dose as soon as you remember. If it is almost time for your next dose, wait until then to apply the medicine and skip the missed dose. Do not use extra medicine to make up the missed dose.

Side effects

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 EPIDUO gel
N = 564
Vehicle gel
N = 489
Subjects with AE (s) 14% 4%
Dry Skin 7% 2%
Contact dermatitis 3% < 1%
Application site burning 2% < 1%
Application site irritation 1% < 1%
Skin irritation 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 Trials (N = 553) Treatment Emergent Signs and Symptoms

  Maximum Severity During Treatment End of Treatment Severity (12 Weeks)
Mild Moderate Severe Mild Moderate Severe
Erythema 27% 13% 1% 8% 2% 1%
Scaling 35% 11% 1% 9% 1% < 1%
Dryness 41% 13% 1% 10% 2% < 1%
Stinging/burning 41% 15% 3% 7% 2% 1%

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.

During a pediatric clinical trial, 285 children with acne vulgaris, 9 to 11 years of age were treated with EPIDUO gel or with the vehicle gel once daily for 12 weeks. Overall, the safety profile of EPIDUO gel in these subjects is comparable to the safety profile observed in older subjects 12 years of age and above, both in the nature and frequency of the observed events.

Analysis of local tolerability evaluations shows similar incidence of treatment emergent signs and symptoms as in subjects 12 years of age and above, with local tolerability signs and symptoms peaking during the first week and decreasing over time.

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.

Read the entire FDA prescribing information for Epiduo (Adapalene and Benzoyl Peroxide Gel)

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