PATIENT COUNSELING INFORMATION
[See FDA-Approved Patient Labeling]
Instruct female patients to inform the treating physician of any plans to become pregnant. If the patient becomes pregnant, discontinue use and inform the treating physician immediately. Atralin (tretinoin) Gel should be used in pregnancy only if the potential benefit justifies the potential risk to the fetus.
Warn patients of the drying and irritation effects often seen during treatment. Direct patients to continue use of the medication if these effects are tolerable.
Caution patients against application of Atralin (tretinoin) Gel around the eyes, mouth, paranasal creases, and mucous membranes as this skin is especially prone to irritation.
Skin Care Regimen
Instruct patients to clean the affected areas with an appropriate cleanser before applying Atralin (tretinoin) 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 (tretinoin) Gel. However, they should be instructed to remove the cosmetics and clean the area thoroughly before applying Atralin (tretinoin) Gel.
Instruct patients to avoid direct exposure to the sun or sunlamps and to use sunscreen.
The skin of certain individuals may become dry, red, or exfoliated while using Atralin (tretinoin) 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.
Topical over-the-counter acne preparations, concomitant topical medication, medicated cleansers, topical products with alcohol or astringents, when used with Atralin (tretinoin) Gel, should be used with caution. [see DRUG INTERACTIONS].
Ultraviolet Light and Environmental Exposure
Unprotected exposure to sunlight, including sunlamps, should be minimized during the use of Atralin (tretinoin) 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 exposure cannot be avoided.
Weather extremes, such as wind or cold, also may be irritating to patients under treatment with tretinoin.
Atralin (tretinoin) 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.
Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenicity, photocarcinogenicity and mutagenicity testing of Atralin (tretinoin) Gel have not been performed in any species.
In a 91-week dermal study in which mice were administered 0.017% and 0.035% formulations of tretinoin in a different formulation, cutaneous squamous cell carcinomas and papillomas in the treatment area were observed in some female mice. These concentrations are near the tretinoin concentration of Atralin (tretinoin) Gel. A dose-related incidence of liver tumors in male mice was observed at those same doses. The maximum systemic doses associated with the administered 0.017% and 0.035% formulations are 0.5 and 1 mg/kg/day, (1.5 and 3 mg/m², respectively, approximately 2 and 4 times the clinical dose based on body surface area comparison). The biological significance of these findings is not clear because they occurred at doses that exceeded the dermal maximum tolerated dose (MTD) of tretinoin and because they were within the background natural occurrence rate for these tumors in this strain of mice. There was no evidence of carcinogenic potential when 0.025 mg/kg/day (0.075 mg/m² approximately 0.1 times the clinical dose, based on body surface area comparison) of tretinoin was administered topically to mice.
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 in 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 (tretinoin) Gel. Atralin (tretinoin) Gel should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Atralin (tretinoin) 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 (tretinoin) Gel treated animals. These findings were not observed in control animals. Other maternal and reproductive parameters in the Atralin (tretinoin) 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 (tretinoin) 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 area 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 a 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 a 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 (tretinoin) 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 (tretinoin) 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 (tretinoin) Gel did not include any subjects over age 65 to determine whether they respond differently from younger subjects.
Last reviewed on RxList: 8/16/2007
This monograph has been modified to include the generic and brand name in many instances.
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