"The U.S. Food and Drug Administration today approved Differin Gel 0.1% (adapalene), a once-daily topical gel for the over-the-counter (OTC) treatment of acne. Differin Gel 0.1% is approved for use in people 12 years of age and older.
The skin of certain individuals may become dry, red, or exfoliated while using Atralin Gel. If the degree of irritation warrants, patients should be directed to temporarily reduce the amount or frequency of application of the medication, discontinue use temporarily, or discontinue use all together. Efficacy at reduced frequencies of application has not been established. If a reaction suggesting sensitivity occurs, use of the medication should be discontinued. Mild to moderate skin dryness may also be experienced; if so, use of an appropriate moisturizer during the day may be helpful.
Tretinoin has been reported to cause severe irritation on eczematous or sunburned skin and should be used with caution in patients with these conditions.
To help limit skin irritation, patients must:
- wash the treated skin gently, using a mild, non-medicated soap, and pat it dry
- avoid washing the treated skin too often and scrubbing the affected skin area
- avoid contact with the peels of limes
Ultraviolet Light And Environmental Exposure
Unprotected exposure to sunlight, including sunlamps, should be minimized during the use of Atralin 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 of at least SPF 15 and protective clothing over treated areas is recommended when exposer cannot be avoided.
Weather extremes, such as wind or cold, also may be irritating to tretinoin-treated skin.
Atralin Gel contains soluble fish proteins and should be used with caution in patients with known sensitivity or allergy to fish. Patients who develop pruritus or urticaria should contact their health care provider.
Patient Counseling Information
See FDA-Approved Patient Labeling (PATIENT INFORMATION)
Instruct patients to clean the affected areas with an appropriate cleanser before applying Atralin Gel.
Patients may use moisturizers that are non-comedogenic, and should avoid products that could be drying or irritating.
Patients may also wear cosmetics while being treated with Atralin Gel; however, they should be instructed to remove the cosmetics and clean the area thoroughly before applying Atralin Gel.
Warn patients of the drying and irritation effects often seen during treatment. Continue use of the medication if these effects are tolerable.
Caution patients against application of Atralin Gel around the eyes, mouth, paranasal creases, and mucous membranes as the skin is especially prone to irritation.
Minimize exposure to sunlight, including sunlamps. Recommend the use of sunscreen products and protective apparel (e.g., hat) when exposure cannot be avoided.
Carcinogenesis, Mutagenesis, Impairment Of Fertility
A 2-year dermal mouse carcinogenicity study was initiated with topical administration of 0.005%, 0.025% and 0.05% Atralin Gel. Although no drug-related tumors were observed in surviving animals, the irritating nature of the drug product precluded daily dosing, confounding data interpretation and reducing the biological significance of these results.
Studies in hairless albino mice with a different formulation suggest that concurrent exposure to tretinoin may enhance the tumorigenic potential of carcinogenic doses of UVB and UVA light from a solar simulator. This effect was confirmed in a later study in pigmented mice, and dark pigmentation did not overcome the enhancement of photocarcinogenesis by 0.05% tretinoin. Although the significance of these studies to humans is not clear, patients should minimize exposure to sunlight or artificial ultraviolet irradiation sources.
The genotoxic potential of tretinoin was evaluated in an in vitro bacterial reversion test, an in vitro chromosomal aberration assay in human lymphocytes and an in vivo rat micronucleus assay. All tests were negative. In dermal fertility studies of another tretinoin formulation in rats, slight (not statistically significant) decreases in sperm count and motility were seen at 0.5 mg/kg/day (3 mg/m², approximately 4 times the clinical dose based on body surface area comparison), and slight (not statistically significant) increases in the number and percent of nonviable embryos in females treated with 0.25 mg/kg/day and above (1.5 mg/m², approximately 2 times the clinical dose based on body surface area comparison), were observed.
Use In Specific Populations
Pregnancy Category C
There are no well-controlled trials in pregnant women treated with Atralin Gel. Atralin Gel should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Atralin Gel at doses of 0.1, 0.3 and 1 g/kg/day was tested for maternal and developmental toxicity in pregnant Sprague-Dawley rats by dermal application. The dose of 1 g/kg/day was approximately 4 times the clinical dose assuming 100% absorption and based on body surface area comparison. Possible tretinoin-associated teratogenic effects (craniofacial abnormalities (hydrocephaly), asymmetrical thyroids, variations in ossification, and increased supernumerary ribs) were noted in the fetuses of Atralin Gel treated animals. These finding were not observed in control animals. Other maternal and reproductive parameters in the Atralin Gel treated animals were not different from control. For purposes of comparison of the animal exposure to human exposure, the clinical dose is defined as 2 g of Atralin Gel applied daily to a 50 kg person.
Oral tretinoin has been shown to be teratogenic in rats, mice, rabbits, hamsters and nonhuman primates. Tretinoin was teratogenic in Wistar rats when given orally in doses greater than 1 mg/kg/day (approximately 8 times the clinical dose based on body surface area comparison). In the cynomolgus monkey, fetal malformations were reported for doses of 10 mg/kg/day, but none were observed at 5 mg/kg/day (approximately 80 times the clinical dose based on body surface area comparison), although increased skeletal variations were observed at all doses. Dose-related increases in embryolethality and abortion also were reported. Similar results have also been reported in pigtail macaques.
Topical tretinoin in a different formulation has generated equivocal results in animal teratogenicity tests. There is evidence for teratogenicity (shortened or kinked tail) of topical tretinoin in Wistar rats at doses greater than 1 mg/kg/day (approximately 8 times the clinical dose assuming 100% absorption and based on body surface area comparison). Anomalies (humerus: short 13%, bent 6%, os parietal incompletely ossified 14%) have also been reported when 10 mg/kg/day (approximately 160 times the clinical dose assuming 100% absorption and based on body surface areas comparison) was topically applied. Supernumerary ribs have been a consistent finding in rats when dams were treated topically or orally with retinoids.
With widespread use of any drug, a small number of birth defect reports associated temporally with the administration of the drug would be expected by chance alone. Cases of temporally associated congenital malformations have been reported with use of other topical tretinoin products. The significance of these spontaneous reports in terms of risk to the fetus is not known.
Nonteratogenic effects on fetuses
Oral tretinoin has been shown to be fetotoxic in rats when administered in doses 20 times the clinical dose based on body surface area comparison. Topical tretinoin has been shown to be fetotoxic in rabbits when administered in doses 8 times the clinical dose based on body surface area comparison.
It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Atralin Gel is administered to a nursing woman.
Safety and effectiveness in children below the age of 10 have not been established.
A total of 381 pediatric subjects (aged 10 to 16 years) treated with Atralin Gel were enrolled into the two clinical studies. Across these two studies, comparable safety and efficacy were observed between pediatric and adult subjects.
Safety and effectiveness in a geriatric population have not been established. Clinical studies of Atralin Gel did not include any subjects over age 65 to determine whether they respond differently from younger subjects.This monograph has been modified to include the generic and brand name in many instances.
Last reviewed on RxList: 9/10/2014
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