5.1 Ultraviolet Light and Environmental Exposure

Exposure to sunlight, including sunlamps, should be avoided during the use of DIFFERIN Lotion. Patients with high levels of sun exposure and those with inherent sensitivity to sun should be warned to exercise 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 DIFFERIN Lotion.

5.2 Local Cutaneous Reactions

Signs and symptoms of local skin irritation (such as erythema, scaling, dryness, stinging/burning) may be experienced with use of DIFFERIN Lotion. These are most likely to occur during the first 2 weeks of treatment, are mostly mild to moderate in severity, and usually lessen with continued use of DIFFERIN Lotion. Depending upon the severity of these side effects, patients should be instructed to use a moisturizer, reduce the frequency of the application of DIFFERIN Lotion 0.1%, or discontinue use.

DIFFERIN Lotion 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 DIFFERIN Lotion.

Avoid concomitant use of other potentially irritating topical products (abrasive soaps and cleansers, soaps and cosmetics that have strong skin-drying effect and products with high concentrations of alcohol, astringents, spices, or limes).

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.

A total of 2141 subjects with acne vulgaris, 12 years and older, were treated once daily for 12 weeks. Of these, 1068 were exposed to DIFFERIN Lotion during the clinical trials. A total of 1057 subjects completed at least one post treatment evaluation.

Related adverse reactions that were reported in at least 1% of patients treated with DIFFERIN Lotion or with the Vehicle Lotion are presented in Table 1.

The majority of cases was transient, mild to moderate in severity and was managed with moisturizers.

Local tolerability evaluations, presented in Table 2, were conducted at each study visit in clinical trials. Erythema, scaling, dryness, burning/stinging were assessed:

Local tolerability scores for erythema, scaling, dryness, burning/stinging rose during the first two weeks of treatment and generally decreased thereafter.

7.1 Concomitant Topical Medications

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. Caution should be exercised in using preparation containing sulfur, resorcinol or salicylic acid in combination with DIFFERIN Lotion.

No formal drug-drug interaction studies were conducted with DIFFERIN Lotion.

8.1 Pregnancy

Pregnancy Category C. There are no well-controlled trials in pregnant women treated with DIFFERIN Lotion. Therefore, DIFFERIN Lotion should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Animal reproduction studies have not been conducted with DIFFERIN Lotion. Furthermore, such studies are not always predictive of human response.

Human Data

In clinical trials involving DIFFERIN Lotion, 0.1% in the treatment of acne vulgaris, women of childbearing potential initiated treatment only after a negative pregnancy test. Two women became pregnant while using DIFFERIN Lotion, 0.1%. One patient delivered a healthy full term baby and the other patient electively terminated her pregnancy.

Animal Data

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 DIFFERIN Lotion. 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.

Systemic exposure (AUC 0-24h) to adapalene at topical doses (6.0 mg/kg/day) in rats represented 101 times the exposure to adapalene in patients with acne treated with DIFFERIN Lotion applied to the face, chest and back (2 grams applied to 1000 cm² of acne-involved skin).

8.3 Nursing Mothers

It is not known whether adapalene is excreted in human milk following use of DIFFERIN Lotion. Because many drugs are excreted in human milk, caution should be exercised when DIFFERIN Lotion is administered to a nursing woman.

8.4 Pediatric Use

Safety and effectiveness of DIFFERIN Lotion in pediatric patients under the age of 12 have not been established.

8.5 Geriatric Use

Clinical studies of DIFFERIN Lotion did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.

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

Pharmacodynamics of DIFFERIN Lotion is unknown.

12.3 Pharmacokinetics

Systemic exposure of adapalene following a topical application of DIFFERIN Lotion was studied in one clinical study. Fourteen subjects at 18-29 years of age with severe acne were treated with 2 g of DIFFERIN Lotion once daily for 30 days to approximately 1000 cm2 of acne involved skin. Serial plasma samples were collected for 24 or 72 hours following application on days 1, 15 and 30. All plasma concentrations for 12 out of 14 patients were below the limit of quantification (LOQ=0.1 ng/mL). One patient had one sample above LOQ at day 30 and the other patient had four plasma samples above LOQ on both days 1 and 15, which ranged from 0.102 and 0.131 ng/mL. Due to the limited number of available data points, PK analysis was not undertaken.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

No carcinogenicity, mutagenicity and impairment of fertility studies were conducted with DIFFERIN Lotion.

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 DIFFERIN Lotion. In the rat study, an increased incidence of benign and malignant pheochromocytomas in the adrenal medulla of male rats was observed.

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).

In rat oral studies, 20 mg adapalene/kg/day (120 mg/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.

Additional barcode labeling by:
Physicians Total Care, Inc.
Tulsa, Oklahoma        74146