WARNINGS:
- RENOVA is a dermal irritant, and the results of continued irritation of the skin for greater than 48 weeks in chronic, long term use are not known. There is evidence of atypical changes in melanocytes and keratinocytes, and of increased dermal elastosis in some patients treated with RENOVA for longer than 48 weeks. The significance of these findings is unknown.
- Safety and effectiveness of RENOVA in individuals with moderately or heavily pigmented skin have not been established.
- RENOVA should not be administered if the patient is also taking drugs known to be photosensitizers (e.g., thiazides, tetracyclines, fluoroquinolones, phenothiazines, sulfonamides) because of the possibility of augmented phototoxicity.
Because of heightened burning susceptibility, exposure to sunlight (including sunlamps) should be avoided or minimized during use of RENOVA. Patients must be warned to use sunscreens (minimum SPF of 15) and protective clothing when using RENOVA. Patients with sunburn should be advised not to use RENOVA until fully recovered. Patients who may have considerable sun exposure due to their occupation and those patients with inherent sensitivity to sunlight should exercise particular caution when using RENOVA and assure that the precautions outlined in the Patient Package Insert are observed.
RENOVA should be kept out of the eyes, mouth, angles of the nose, and mucous membranes. Topical use may cause severe local erythema, pruritus, burning, stinging, and peeling at the site of application. If the degree of local irritation warrants, patients should be directed to use less medication, decrease the frequency of application, discontinue use temporarily, or discontinue use altogether.
Tretinoin has been reported to cause severe irritation on eczematous skin and should be used only with utmost caution in patients with this condition.
Application of larger amounts of medication than recommended will not lead to more rapid or better results, and marked redness, peeling, or discomfort may occur.
PRECAUTIONS:
General: RENOVA should only be used as an adjunct to a comprehensive skin care and sun avoidance program. (See INDICATIONS AND USAGE section.)
If a drug sensitivity, chemical irritation, or a systemic adverse reaction develops, use of RENOVA should be discontinued.
Weather extremes, such as wind or cold, may be more irritating to patients using RENOVA.
Information for Patients: See Patient Package Insert.
Drug Interactions: Concomitant topical medications, medicated or abrasive soaps, shampoos, cleansers, cosmetics with a strong drying effect, products with high concentrations of alcohol, astringents, spices or lime, permanent wave solutions, electrolysis, hair depilatories or waxes, and products that may irritate the skin should be used with caution in patients being treated with RENOVA because they may increase irritation with RENOVA.
RENOVA should not be administered if the patient is also taking drugs known to be photosensitizers (e.g., thiazides, tetracyclines, fluoroquinolones, phenothiazines, sulfonamides) because of the possibility of augmented phototoxicity.
Carcinogenesis, Mutagenesis, Impairment of Fertility: In a lifetime dermal study in CD-1 mice, at 100 and 200 times the average recommended human topical clinical dose, a few skin tumors in the female mice and liver tumors in male mice were observed. The biological significance of these findings is not clear because they occurred at doses that exceeded the dermal maximally 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 tretinoin was administered topically at a dose 5 times the average recommended human topical clinical dose. For purposes of comparisons of the animal exposure to human exposure, the "recommended human topical clinical dose" is defined as 500 mg of 0.05% RENOVA applied daily to a 50 kg person.
In a chronic, two-year bioassay of Vitamin A acid in mice performed by Tsubura and Yamamoto, generalized amyloid deposition was reported in all groups in the basal layer of the Vitamin A treated skin. In CD-1 mice, a similar study reported hyalinization at the treated skin sites and the incidence of this finding was 0/50, 3/50, 3/50, and 2/50 in male mice and 1/50, 0/50, 4/50, and 2/50 in female mice from the vehicle control, 0.25 mg/kg, 0.5 mg/kg, and 1 mg/kg groups, respectively.
Studies in hairless albino mice suggest that tretinoin may enhance the tumorigenic potential of carcinogenic doses of UVB and UVA light from a solar simulator. In other studies, when lightly pigmented hairless mice treated with tretinoin were exposed to carcinogenic doses of UVB light, the incidence and rate of development of skin tumors were either reduced or no effect was seen. Due to significantly different experimental conditions, no strict comparison of these disparate data is possible at this time. Although the significance of these studies to humans is not clear, patients should minimize exposure to sun.
The mutagenic potential of tretinoin was evaluated in the Ames assay and in the in vivo mouse micronucleus assay, both of which were negative.
Dermal Segment I and Ill studies with RENOVA have not been performed in any species. In oral Segment I and Segment Ill studies in rats with tretinoin, decreased survival of neonates and growth retardation were observed at doses in excess of 2 mg/kg/day (>400 times the average recommended human topical clinical dose).
Pregnancy:
Teratogenic effects: Pregnancy Category C.
ORAL tretinoin has been shown to be teratogenic in rats, mice, rabbits, hamsters, and subhuman primates. It was teratogenic and fetotoxic in rats when given orally in doses 1000 times the average recommended human topical clinical dose. However, variations in teratogenic doses among various strains of rats have been reported. In the cynomolgus monkey, which, metabolically, is closer to humans for tretinoin than the other species examined, fetal malformations were reported at doses of 10 mg/kg/day or greater, but none were observed at 5 mg/kg/day (1000 times the average recommended human topical clinical dose), although increased skeletal variations were observed at all doses. A dose-related increased embryolethality and abortion was reported. Similar results have also been reported in pigtail macaques.
TOPICAL tretinoin in animal teratogenicity tests has generated equivocal results. There is evidence for teratogenicity (shortened or kinked tail) of topical tretinoin in Wistar rats at doses greater than 1 mg/kg/day (200 times the recommended human topical clinical dose). Anomalies (humerus: short 13%, bent 6%, os parietal incompletely ossified 14%) have also been reported when 10 mg/kg/day was dermally applied.
There are other reports in New Zealand White rabbits with doses of approximately 80 times the recommended human topical clinical dose of an increased incidence of domed head and hydrocephaly, typical of retinoid-induced fetal malformations in this species.
In contrast, several well-controlled animal studies have shown that dermally applied tretinoin was not teratogenic at doses of 100 and 200 times the recommended human topical clinical dose, in rats and rabbits, respectively.
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. Thirty cases of temporally-associated congenital malformations have been reported during two decades of clinical use of another formulation of topical tretinoin (Retin-A). Although no definite pattern of teratogenicity and no causal association has been established from these cases, 5 of the reports describe the rare birth defect category holoprosencephaly (defects associated with incomplete midline development of the forebrain). The significance of these spontaneous reports in terms of risk to the fetus is not known.
Non-teratogenic effects:
Dermal tretinoin has been shown to be fetotoxic in rabbits when administered in doses 100 times the recommended topical human clinical dose. Oral tretinoin has been shown to be fetotoxic in rats when administered in doses 500 times the recommended topical human clinical dose.
There are, however, no adequate and well-controlled studies in pregnant women. RENOVA should not be used during pregnancy.
Nursing Mothers: 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 RENOVA is administered to a nursing woman.
Pediatric Use: Safety and effectiveness in patients less than 18 years of age have not been established.
Geriatric Use: Safety and effectiveness in individuals older than 50 years of age have not been established.
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