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 Adapalene gel, 0.3% 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 adapalene gel, 0.3%. 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 adapalene gel, 0.3%.

5.3 Local Cutaneous Reactions

Cutaneous signs and symptoms such as erythema, scaling, dryness, and stinging/ burning were reported with use of adapalene gel, 0.3%. 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 adapalene gel, 0.3% 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 adapalene gel, 0.3% 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.

6.1 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 Adapalene gel, 0.3% 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 Adapalene gel, 0.3% from the controlled clinical trial is provided in the following table:

Table 1: Physician assessed local cutaneous irritation with Adapalene gel

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

Table 2: Patient reported local cutaneous adverse reactions with Adapalene Gel

 
* 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 Adapalene gel, 0.3%, the pattern of adverse reactions was similar to the 12-week controlled study.

6.2 Postmarketing 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.

8.1 Pregnancy

Risk Summary
Available data from clinical trials with Adapalene 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).

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 adapalene gel, 0.3% and any potential adverse effects on the breastfed child from adapalene gel, 0.3% or from the underlying maternal condition.

 Clinical Considerations 
To minimize potential exposure to the breastfed infant via breastmilk, use adapalene gel, 0.3% on the smallest area of skin and for the shortest duration possible while breastfeeding. Avoid application of adapalene gel, 0.3% 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 adapalene gel, 0.3% 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.

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 Adapalene Gel,0.3%.

12.3 Pharmacokinetics

Systemic exposure of adapalene following topical application of adapalene gel was evaluated in a clinical trial. Sixteen acne subjects were treated once daily for 10 days with 2 grams of adapalene gel, 0.3% 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, 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 adapalene 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.

13.1 Carcinogenesis, Mutagenesis , Impairment of Fertility

No carcinogenicity, genotoxicity, or impairment of fertility studies were conducted with Adapalene gel, 0.3%.

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.