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• RENOVA (tretinoin cream) 0.02% is a dermal irritant, and the results of continued irritation of the skin for greater than 52 weeks in chronic use with RENOVA (tretinoin cream) are not known. There is evidence of atypical changes in melanocytes and keratinocytes and of increased dermal elastosis in some patients treated with RENOVA (tretinoin cream) 0.05% for longer than 48 weeks. The significance of these findings and their relevance for RENOVA (tretinoin cream) 0.02% are unknown.
• RENOVA (tretinoin cream) 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.

Exposure to sunlight (including sunlamps) should be avoided or minimized during use of RENOVA (tretinoin cream) because of heightened sunburn susceptibility. Patients should be warned to use sunscreens (minimum SPF of 15) and protective clothing when using RENOVA (tretinoin cream) . Patients with sunburn should be advised not to use RENOVA (tretinoin cream) until fully recovered. Patients who may have considerable sun exposure, e.g., due to their occupation, and those patients with inherent sensitivity to sunlight should exercise caution when using RENOVA (tretinoin cream) and follow the precautions outlined in the Patient Package Insert.

RENOVA (tretinoin cream) 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 and consider additional appropriate therapy. Tretinoin has been reported to cause severe irritation on eczema-tous skin and should be used only with caution in patients with this condition.

Application of larger amounts of medication than recommended has not been shown to lead to more rapid or better results, and marked redness, peeling, or discomfort may occur.

General

RENOVA (tretinoin cream) should be used only as an adjunct to a comprehensive skin care and sunlight avoidance program. (See INDICATIONS AND USAGE section.)

If a drug sensitivity, chemical irritation, or a systemic adverse reaction develops, use of RENOVA (tretinoin cream) should be discontinued. Weather extremes, such as wind or cold, may be more irritating to patients using tretinoin-containing products.

Information for Patients

RENOVA (tretinoin cream) 0.02% is to be used as described below unless otherwise directed by your physician:

1. it is for use on the face.
2. Avoid contact with the eyes, ears, nostrils, angles of the nose, and mouth. RENOVA (tretinoin cream) may cause severe redness, itching, burning, stinging, and peeling if used on these areas.
3. In the evening, gently wash your face with a mild soap. Pat skin dry and wait 20-30 minutes before applying RENOVA (tretinoin cream) . Apply only a small pearl-sized (about Va inch or 5 millimeter diameter) amount of RENOVA (tretinoin cream) to your face at one time. This should be enough to cover the entire affected area lightly.
4. Do not wash your face for at least one hour after applying RENOVA (tretinoin cream) .
5. For best results, you are advised not to apply another skin care product or cosmetic for at least one hour after applying RENOVA (tretinoin cream) .
6. In the morning, apply a moisturizing sunscreen, SPF15 or greater.
7. RENOVA (tretinoin cream) is a serious medication. Do not use RENOVA (tretinoin cream) if you are pregnant or attempting to become pregnant. If you become pregnant while using RENOVA (tretinoin cream) , please contact your physician immediately.
8. Avoid sunlight and other medicines that may increase your sensitivity to sunlight.
9. RENOVA (tretinoin cream) does not remove wrinkles or repair sun-damaged skin. Please refer to the Patient Package Insert for additional patient information.

Carcinogenesis, Mutagenesis, Impairment of Fertility

In a 91-week dermal study in which CD-1 mice were administered 0.017% and 0.035% formulations of tretinoin, cutaneous squamous cell carcinomas and papillomas in the treatment area were observed in some female mice. These concentrations are near the tretinoin concentration of this clinical formulation (0.02%). A dose-related incidence of liver tumors in male mice was observed at those same doses. The maximum systemic doses associated with the 0.017% and 0.035%o formulations are 0.5 and 1.0 mg/kg/day. These doses are 10 and 20 times the maximum human systemic dose, when adjusted for total body surface area. 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 0.025 mg/kg/day of tretinoin was administered topically to mice (0.5 times the maximum human systemic dose, adjusted for total body surface area). For purposes of comparisons of the animal exposure to systemic human exposure, the maximum human systemic dose is defined as 1 gram of 0.02% RENOVA applied daily to a 50 kg person (0.004 mg tretinoin/kg body weight).

Studies in hairless albino mice 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 has been confirmed in a later study in pigmented mice, and dark pigmentation did not overcome the enhancement of photocarcino-genesis 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 mutagenic potential of tretinoin was evaluated in the Ames assay and in the in vivo mouse micronucleus assay, both of which were negative.

In dermal Segment I fertility studies in rats, slight (not statistically significant) decreases in sperm count and motility were seen at 0.5 mg/kg/day (20 times the maximum human systemic dose adjusted for total body surface area), and slight (not statistically significant) increases in the number and percent of nonviable embryos in females treated with 0.25 mg/kg/day (10 times the maximum human systemic dose adjusted for total body surface area) and above were observed. A dermal Segment III study with RENOVA (tretinoin cream) has not been performed in any species. In oral Segment I and Segment III studies in rats with tretinoin, decreased survival of neonates and growth retardation were observed at doses in excess of 2 mg/kg/day (83 times the human topical dose adjusted for total body surface area).

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 Wistar rats when given orally or topically in doses greater than 1 mg/kg/day (42 times the maximum human systemic dose normalized for total body surface area). 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 (417 times the maximum human systemic dose adjusted for total body surface area), although increased skeletal variations were observed at all doses. A dose-related increase in 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 (42 times the maximum human systemic dose adjusted for total body surface area). 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 administered doses of greater than 0.2 mg/kg/day (17 times the maximum human systemic dose adjusted for total body surface area) 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 may be fetotoxic, but not overtly teratogenic, in rats and rabbits at doses of 1.0 and 0.5 mg/kg/day, respectively (42 times the maximum human systemic dose adjusted for total body surface area in both species).

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 human 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 0.5 mg/kg/day (42 times the maximum human systemic dose normalized for total body surface area). Oral tretinoin has been shown to be fetotoxic, resulting in skeletal variations and increased intrauterine death, in rats when administered 2.5 mg/kg/day (104 times the maximum human systemic dose adjusted for total body surface area).

There are, however, no adequate and well-controlled studies in pregnant women. RENOVA (tretinoin cream) should not be used during pregnancy.

Nursing Mothers

It is not known whether this drug is excreted in human milk. Since many drugs are excreted in human milk, mitigation of fine facial wrinkles with RENOVA (tretinoin cream) 0.02% may be postponed in nursing mothers until after completion of the nursing period.

Pediatric Use

Safety and effectiveness in patients less than 18 years of age have not been established.

Geriatric Use

In clinical studies with RENOVA (tretinoin cream) 0.02%, patients aged 65 to 71 did not demonstrate a significant difference for improvement in fine wrinkling when compared to patients under the age of 65. Patients aged 65 and over may demonstrate slightly more irritation, although the differences were not statistically significant in the clinical studies for RENOVA (tretinoin cream) 0.02%. Safety and effectiveness of RENOVA (tretinoin cream) 0.02% in individuals older than 71 years of age have not been established.

Last reviewed on RxList: 12/10/2008
This monograph has been modified to include the generic and brand name in many instances.