DIFFERIN (Page 2 of 4)

8.2 Lactation

Risk Summary
There are no data on the presence of topical adapalene 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). The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for DIFFERIN Gel and any potential adverse effects on the breastfed child from DIFFERIN Gel, or from the underlying maternal condition.
Clinical Considerations
To minimize potential exposure to the breastfed infant via breastmilk, use DIFFERIN Gel on the smallest area of skin and for the shortest duration possible while breastfeeding. Avoid application of DIFFERIN Gel to areas with increased risk for potential ingestion by or ocular exposure to the breastfeeding child.

8.4 Pediatric Use

Safety and effectiveness have not been established in pediatric patients below the age of 12.

8.5 Geriatric Use

Clinical studies of DIFFERIN Gel did not include subjects 65 years of age and older to determine whether they respond differently than younger subjects. Safety and effectiveness in geriatric patients age 65 and above have not been established.

10 OVERDOSAGE

Chronic ingestion of the drug may lead to the same side effects as those associated with excessive oral intake of vitamin A.

11 DESCRIPTION

DIFFERIN (adapalene) Gel contains adapalene 0.3% (3 mg/g) in a topical aqueous gel for use in the treatment of acne vulgaris, consisting of carbomer 940, edetate disodium, methylparaben, poloxamer 124, propylene glycol, purified water, and sodium hydroxide. May contain hydrochloric acid for pH adjustment.

The chemical name of adapalene is 6-[3-(1-adamantyl)-4-methoxyphenyl]-2-naphthoic acid. It is a white to off-white powder, which is soluble in tetrahydrofuran, very slightly soluble in ethanol, and practically insoluble in water. The molecular formula is C28 H28 O3 and molecular weight is 412.53. Adapalene is represented by the following structural formula.

adapalene-chem-structure
(click image for full-size original)

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

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.

12.2 Pharmacodynamics

Clinical pharmacodynamic studies have not been conducted for DIFFERIN Gel.

12.3 Pharmacokinetics

Systemic exposure of adapalene following topical application of DIFFERIN Gel was evaluated in a clinical trial. Sixteen acne subjects were treated once daily for 10 days with 2 grams of DIFFERIN Gel applied to the face, chest and back, corresponding to approximately 2 mg/cm2. Fifteen subjects had quantifiable (LOQ = 0.1 ng/mL) adapalene levels resulting in a mean Cmax of 0.553 ± 0.466 ng/mL on Day 10 of treatment. The mean AUC0-24hr was 8.37 ± 8.46 ng.h/mL as determined in 15 of the 16 subjects on Day 10. The terminal apparent half-life, determined in 15 of 16 subjects, ranged from 7 to 51 hours, with a mean of 17.2 ± 10.2 hours. Adapalene was rapidly cleared from plasma and was not detected 72 hours after the last application for all but one subject. Exposure of potential circulating metabolites of adapalene was not measured. Excretion of adapalene appears to be primarily by the biliary route.

In another clinical trial in subjects with moderate to moderately severe acne, DIFFERIN (adapalene) Gel, 0.3% or Adapalene Gel, 0.1% was applied to the face and optionally to the trunk, once daily for 12 weeks. Seventy-eight (78) subjects had plasma adapalene levels evaluated at Weeks 2, 8, and 12. Of the 209 plasma samples analyzed, adapalene concentrations were below the limit of detection (LOD = 0.15 ng/mL) of the method in all samples but three. For the three samples, traces of adapalene below the limit of quantification (LOQ = 0.25 ng/mL) of the method were found. One of these samples was taken at Week 12 from a male subject treated with DIFFERIN Gel, 0.3% who treated the face and the trunk for eight weeks (thereafter, only the face was treated). The second and third samples were from the Week 2 and 12 visits of a female subject treated with Adapalene Gel, 0.1% who treated only the face for 12 weeks. In this study, the average daily usage of product was 1 g/day.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

No carcinogenicity, genotoxicity, or impairment of fertility studies were conducted with DIFFERIN Gel.

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 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.

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).

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

14 CLINICAL STUDIES

The safety and efficacy of once daily use of DIFFERIN Gel for treatment of acne vulgaris were assessed in one 12 week, multi-center, controlled, clinical trial, conducted in a total of 653 subjects 12 to 52 years of age with acne vulgaris of mild to moderate severity. All female subjects of child-bearing potential enrolled in the trial were required to have a negative urine pregnancy test at the beginning of the trial and were required to practice a highly effective method of contraception during the trial. Female subjects who were pregnant, nursing or planning to become pregnant were excluded from the trial.

Subjects enrolled in the trial were Caucasian (72%), Hispanic (12%), African-American (10%), Asian (3%), and other (2%). An equal number of males (49.5%) and females (50.5%) enrolled. Success was defined as “Clear” or “Almost Clear” in the Investigator’s Global Assessment (IGA). The success rate, mean reduction, and percent reduction in acne lesion counts from Baseline after 12 weeks of treatment are presented in the following table:

Table 3: Clinical study primary efficacy results at Week 12
DIFFERIN(adapalene)Gel, 0.3% AdapaleneGel, 0.1% VehicleGel
N = 258 N = 261 N = 134
IGA Success Rate 53 (21%) 41 (16%) 12 (9%)
Inflammatory Lesions Mean Baseline Count Mean Absolute (%) Reduction 27.714.4 (51.6%) 28.113.9 (49.7%) 27.211.2 (40.7%)
Non-Inflammatory Lesions Mean Baseline Count Mean Absolute (%) Reduction 39.416.3 (39.7%) 41.015.2 (35.2%) 40.010.3 (27.2%)
Total Lesions Mean Baseline Count Mean Absolute (%) Reduction 67.130.6 (45.3%) 69.129.0 (41.8%) 67.221.4 (33.7%)

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