DIFFERIN

DIFFERIN — adapalene gel
Galderma Laboratories, L.P.

adapalene-chem-structure45g-tube-carton45-gram-carton-image

1 INDICATIONS AND USAGE

DIFFERIN Gel is indicated for the topical treatment of acne vulgaris in patients 12 years of age and older.

2 DOSAGE AND ADMINISTRATION

Wash affected areas gently with a non-medicated soap. Apply a thin film of DIFFERIN Gel to the entire face and any other affected areas of the skin once daily in the evening. Avoid application to the areas of skin around eyes, lips, and mucous membranes. A mild transitory sensation of warmth or slight stinging may occur shortly after the application of DIFFERIN Gel.
Instruct patients to minimize sun exposure and to use moisturizers for relief of dry skin or irritation.

If therapeutic results are not noticed after 12 weeks of treatment, therapy should be reevaluated.

For topical use only. Not for ophthalmic, oral or intravaginal use.

3 DOSAGE FORMS AND STRENGTHS

Each gram of DIFFERIN Gel, 0.3% contains 3 mg adapalene in an off-white aqueous gel.

4 CONTRAINDICATIONS

DIFFERIN Gel is contraindicated in patients who have known hypersensitivity to adapalene or any excipient of DIFFERIN Gel [see WARNINGS AND PRECAUTIONS (5.1) ].

5 WARNINGS AND PRECAUTIONS

5.1 Allergic/ Hypersensitivity Reactions

Adverse reactions including anaphylaxis angioedema, face edema, eyelid edema, lip swelling, and pruritus that sometimes required medical treatment have been reported during postmarketing use of adapalene. Advise a patient to stop using DIFFERIN Gel and seek medical attention if experiencing allergic or anaphylactoid/anaphylactic reactions during treatment.

5.2 Ultraviolet Light and Environmental Exposure

Exposure to sunlight, including sunlamps, should be minimized during use of DIFFERIN Gel. Patients who normally experience high levels of sun exposure, and those with inherent sensitivity to sun, should be warned to exercise caution. Use of sunscreen products and protective clothing over treated areas is recommended when exposure cannot be avoided. Weather extremes, such as wind or cold, also may be irritating to patients under treatment with DIFFERIN Gel.

5.3 Local Cutaneous Reactions

Cutaneous signs and symptoms such as erythema, scaling, dryness, and stinging/burning were reported with use of DIFFERIN Gel. These were most likely to occur during the first four weeks of treatment, were mostly mild to moderate in intensity, and usually lessened with continued use of the medication. Depending upon the severity of these side effects, patients should be instructed to either use a moisturizer, reduce the frequency of application of DIFFERIN Gel or discontinue use.

Avoid application 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.

As DIFFERIN Gel has the potential to induce local irritation in some patients, concomitant use of other potentially irritating topical products (medicated or abrasive soaps and cleansers, soaps and cosmetics that have a strong drying effect and products with high concentrations of alcohol, astringents, spices, or lime) should be approached with caution.

6 ADVERSE REACTIONS

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reactions rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

In the multi-center, controlled clinical trial, signs and symptoms of local cutaneous irritation were monitored in 258 acne subjects who used DIFFERIN Gel once daily for 12 weeks. Of the subjects who experienced cutaneous irritation (erythema, scaling, dryness, and/or burning/stinging), the majority of cases were mild to moderate in severity, occurred early in treatment and decreased thereafter. The incidence of local cutaneous irritation with DIFFERIN Gel from the controlled clinical trial is provided in the following table:

Table 1: Physician assessed local cutaneous irritation with DIFFERIN Gel
Incidence of Local Cutaneous Irritation with DIFFERIN Gel(N = 253*)Maximum Severity Scores Higher Than Baseline
Mild Moderate Severe
Erythema 66 (26.1%) 33 (13.0%) 1 (0.4%)
Scaling 110 (43.5%) 47 (18.6%) 3 (1.2%)
Dryness 113 (44.7%) 43 (17.0%) 2 (0.8%)
Burning/Stinging 72 (28.5%) 36 (14.2%) 9 (3.6%)

* Total number of subjects with local cutaneous data for at least one post-Baseline evaluation

Table 2: Patient reported local cutaneous reactions with DIFFERIN Gel
DIFFERIN (adapalene) Gel Vehicle Gel
N = 258 N = 134
Related* Adverse Reactions Dry Skin Skin Discomfort Desquamation 57 (22.1%)36 (14%)15 (5.8%)4 (1.6%) 6 (4.5%)2 (1.5%)0 (0%)0 (0%)

* Selected adverse reactions defined by investigator as Possibly, Probably or Definitely Related

The following adverse reactions occurred in less than 1% of subjects: acne flare, contact dermatitis, eyelid edema, conjunctivitis, erythema, pruritus, skin discoloration, rash, and eczema.

In a one-year, open-label safety trial of 551 subjects with acne who received DIFFERIN Gel, the pattern of adverse reactions was similar to the 12-week controlled study.

6.2 Post-Marketing Experience

The following adverse reactions have been identified during post approval use of adapalene:

Immune system disorders: angioedema, face edema, lip swelling
Skin disorders: application site pain
Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate the frequency or establish a causal relationship to drug exposure.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary
Available data from clinical trials with DIFFERIN Gel 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 40 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).
The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defects, loss, or other adverse outcomes. In the U.S. general population the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies are 2 to 4% and 15 to 20%, respectively.

Data

Animal Data
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 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 (40 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).

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