Renova

RENOVA (tretinoin emollient cream 0.05%) is available in these sizes:

NDC 0062-0185-0020 gram tube
NDC 0062-0185-0540 gram tube
NDA 0062-0185-0360 gram tube

Storage: Store at 25°C (77°F), excursions permitted to 15-30°C (59°F-86°F). DO NOT FREEZE.

QUESTIONS: Physicians and Pharmacists can call 1-800-462-7762, from 8:30 a.m. to 4:30 p.m. Eastern Time, Monday through Friday.

ORTHO DERMATOLOGICAL DIVISION, A division of ORTHO-McNEIL PHARMACEUTICAL CORPORATION, Raritan, New Jersey 08869. Revised July 2000. FDA rev date: 3/20/2001

(To understand fully the indication for this product, please read the entire INDICATIONS AND USAGE section of the labeling.)

RENOVA (tretinoin cream) 0.05% is indicated as an adjunctive agent (see second bullet point below) for use in the mitigation (palliation) of fine wrinkles, mottled hyperpigmentation, and tactile roughness of facial skin in patients who use comprehensive skin care and sunlight avoidance programs (see bullet point 3 for populations in which effectiveness has not been established). RENOVA (tretinoin emollient cream 0.05%) DOES NOT ELIMINATE WRINKLES, REPAIR SUN DAMAGED SKIN, REVERSE PHOTOAGING, or RESTORE MORE YOUTHFUL or YOUNGER SKIN. In double-blinded, vehicle-controlled clinical studies, many patients in the vehicle group achieved desired palliative effects on fine wrinkling, mottled hyperpigmentation, and tactile roughness of facial skin with the use of comprehensive skin care and sunlight avoidance programs including sunscreens, protective clothing, and non-prescription emollient creams.

• RENOVA (tretinoin emollient cream 0.05%) 0.05% has NOT DEMONSTRATED A MITIGATING EFFECT on significant signs of chronic sun exposure such as coarse or deep wrinkling, skin yellowing, lentigines, telangiectasia, skin laxity, keratinocytic atypia, melanocytic atypia, or dermal elastosis.
• RENOVA (tretinoin emollient cream 0.05%) should be used under medical supervision as an adjunct to a comprehensive skin care and sunlight avoidance program that includes the use of effective sunscreens (minimum SPF of 15) and protective clothing when desired results on fine wrinkles, mottled hyperpigmentation, and roughness of facial skin have not been achieved with a comprehensive skin care and sunlight avoidance program alone.
• The effectiveness of RENOVA (tretinoin emollient cream 0.05%) 0.05% in the mitigation of fine wrinkles, mottled hyperpigmentation, and tactile roughness of facial skin has not been established in people greater than 50 years of age OR in people with moderately to heavily pigmented skin. In addition, patients with visible actinic keratoses and patients with a history of skin cancer were excluded from clinical trials of RENOVA (tretinoin emollient cream 0.05%) 0.05%. Thus the effectiveness and safety of RENOVA (tretinoin emollient cream 0.05%) 0.05% in these populations are not known at this time.
• Neither the safety nor the effectiveness of RENOVA (tretinoin emollient cream 0.05%) for the prevention or treatment of actinic keratoses or skin neoplasms has been established.
• Neither the safety nor the efficacy of using RENOVA (tretinoin emollient cream 0.05%) 0.05% daily for greater than 48 weeks has been established, and daily use beyond 48 weeks has not been systematically and histologically investigated in adequate and well-controlled trials. (See WARNINGS section.)

• Do NOT use RENOVA (tretinoin emollient cream 0.05%) if the patient is pregnant or is attempting to become pregnant or is at high risk of pregnancy,
• Do NOT use RENOVA (tretinoin emollient cream 0.05%) if the patient is sunburned or if the patient has eczema or other chronic skin conditions of the face,
• Do NOT use RENOVA (tretinoin emollient cream 0.05%) if the patient is inherently sensitive to sunlight,
• Do NOT use RENOVA (tretinoin emollient cream 0.05%) if the patient is also taking drug(s) known to be photosensitizers (e.g., thiazides, tetracyclines, fluoroquinolones, phenothiazines, sulfonamides) because of the possibility of augmented phototoxicity.

Patients require detailed instruction to obtain maximal benefits and to understand all the precautions necessary to use this product with greatest safety. The physician should review the Patient Package Insert.

RENOVA (tretinoin emollient cream 0.05%) should be applied to the face once a day in the evening, using only enough to cover the entire affected area lightly. Patients should gently wash their face with a mild soap, pat the skin dry, and wait 20 to 30 minutes before applying RENOVA (tretinoin emollient cream 0.05%). The patient should apply a pea-sized amount of cream to cover the entire affected face lightly. Caution should be taken when applying the cream to avoid the eyes, ears, nostrils, and mouth.

Application of RENOVA (tretinoin emollient cream 0.05%) may cause a transitory feeling of warmth or slight stinging.

Mitigation (palliation) of facial fine wrinkling, mottled hyperpigmentation and tactile roughness may occur gradually over the course of therapy. Up to six months of therapy may be required before the effects are seen. Most of the improvement noted with RENOVA (tretinoin emollient cream 0.05%) 0.05% is seen during the first 24 weeks of therapy. Thereafter, therapy primarily maintains the improvement realized during the first 24 weeks.

With discontinuation of RENOVA (tretinoin emollient cream 0.05%) 0.05% therapy, a majority of patients will lose most mitigating effects of RENOVA (tretinoin emollient cream 0.05%) 0.05% on fine wrinkles, mottled hyperpigmentation, and tactile roughness of facial skin; however, the safety and effectiveness of using RENOVA (tretinoin emollient cream 0.05%) 0.05% daily for greater than 48 weeks have not been established.

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

Patients treated with RENOVA (tretinoin emollient cream 0.05%) may use cosmetics but the areas to be treated should be cleansed before the medication is applied. (See PRECAUTIONS section.)

This drug is contraindicated in individuals with a history of sensitivity reactions to any of its components. It should be discontinued if hypersensitivity to any of its ingredients is noted.

WARNINGS

• RENOVA (tretinoin emollient cream 0.05%) is a dermal irritant, and the results of continued irritation of the skin for greater than 48 weeks in chronic use with RENOVA (tretinoin emollient cream 0.05%) 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 emollient cream 0.05%) for longer than 48 weeks. The significance of these findings is unknown.
• Safety and effectiveness of RENOVA (tretinoin emollient cream 0.05%) 0.05% in individuals with moderately or heavily pigmented skin have not been established.
• RENOVA (tretinoin emollient cream 0.05%) 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 emollient cream 0.05%) because of heightened sunburn susceptibility. Patients should be warned to use sunscreens (minimum SPF of 15) and protective clothing when using RENOVA (tretinoin emollient cream 0.05%). Patients with sunburn should be advised not to use RENOVA (tretinoin emollient cream 0.05%) 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 emollient cream 0.05%) and follow the precautions outlined in the Patient Package Insert.

RENOVA (tretinoin emollient cream 0.05%) 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 eczematous 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.

PRECAUTIONS

General

RENOVA (tretinoin emollient cream 0.05%) 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 emollient cream 0.05%) 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 emollient cream 0.05%) 0.05% is to be used as described below unless otherwise directed by your physician:

1. It is for use on the face only.
2. Avoid contact with the eyes, ears, nostrils, angles of the nose, and mouth. RENOVA (tretinoin emollient cream 0.05%) 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 emollient cream 0.05%). Apply only a pea-sized amount of RENOVA (tretinoin emollient cream 0.05%) 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 emollient cream 0.05%).
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 emollient cream 0.05%).
6. In the morning, apply a moisturizing sunscreen, SPF 15 or greater.
7. RENOVA (tretinoin emollient cream 0.05%) is a serious medication. Do not use RENOVA (tretinoin emollient cream 0.05%) if you are pregnant or attempting to become pregnant. If you become pregnant while taking RENOVA (tretinoin emollient cream 0.05%) , please contact your physician immediately.
8. Avoid sunlight and other medicines that may increase your sensitivity to sunlight.
9. RENOVA (tretinoin emollient cream 0.05%) 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 were observed in some female mice. These concentrations are lower than the concentration of tretinoin in the clinical formulation (0.05%). A dose related incidence of liver tumors in male mice was observed at those same doses. The maximum systemic doses associated with 0.017% and 0.035% formulations are 0.5 and 1.0 mg/kg/day. These doses are 4 and 8 times the maximum human systemic dose, when adjusted for total body surface area. The biological significance of the neoplastic findings is not clear because they occurred at doses that exceeded the maximally tolerated dermal dose 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 (1/5^th of the maximum human systemic dose, adjusted for total body surface area). For purposes of comparisons of the systemic animal exposure to the systemic human exposure, the maximum human systemic dose is 1 gram of 0.05% RENOVA applied daily to a 50 kg person (0.01 mg tretinoin/kg body weight, or 0.37 mg/m²total body surface area).

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 photocarcinogenesis by 0.05% tretinoin. Although the significance of these studies in 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 (8 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 (4 times the maximum human systemic dose adjusted for total body surface area) and above were observed. A dermal Segment III study with RENOVA (tretinoin emollient cream 0.05%) 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 ( > 33 times the maximum human systemic 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 (17 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 (167 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 (17 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 (7 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 (17 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 twenty-five years 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 (17 times the human topical 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 (42 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 emollient cream 0.05%) 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 wrinkles, mottled hyperpigmentation, and tactile roughness on the face with RENOVA (tretinoin emollient cream 0.05%) 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

Clinical studies of RENOVA (tretinoin emollient cream 0.05%) 0.05% did not include sufficient number of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between elderly and younger patients.

SIDE EFFECTS

(See WARNINGS and PRECAUTIONS sections.)

In double-blind, vehicle-controlled studies involving 179 patients who applied RENOVA (tretinoin emollient cream 0.05%) 0.05% to their face, adverse reactions associated with the use of RENOVA (tretinoin emollient cream 0.05%) 0.05% were limited primarily to the skin. During these trials, 4% of patients had to discontinue use of RENOVA (tretinoin emollient cream 0.05%) 0.05% because of adverse reactions. These discontinuations were due to skin irritation or related cutaneous adverse reactions.

Local reactions such as peeling, dry skin, burning, stinging, erythema, and pruritus were reported by almost all subjects during therapy with RENOVA (tretinoin emollient cream 0.05%) 0.05%. These signs and symptoms were usually of mild to moderate severity and generally occurred early in therapy. In most patients the dryness, peeling, and redness recurred after an initial (24 week) decline.

In spontaneous post-marketing adverse event reporting for RENOVA (tretinoin emollient cream 0.05%) 0.05%, approximately 2% of those were for skin hypo- or hyperpigmentation. Other spontaneously reported adverse events predominantly appear to be local reactions similar to those seen in clinical trials.

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 (tretinoin emollient cream 0.05%) because they may increase irritation with RENOVA (tretinoin emollient cream 0.05%).

RENOVA (tretinoin emollient cream 0.05%) 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.

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 (17 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 (167 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 (17 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 (7 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 (17 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 twenty-five years 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 (17 times the human topical 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 (42 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 emollient cream 0.05%) should not be used during pregnancy.

(See WARNINGS and PRECAUTIONS sections.)

In double-blind, vehicle-controlled studies involving 179 patients who applied RENOVA (tretinoin emollient cream 0.05%) 0.05% to their face, adverse reactions associated with the use of RENOVA (tretinoin emollient cream 0.05%) 0.05% were limited primarily to the skin. During these trials, 4% of patients had to discontinue use of RENOVA (tretinoin emollient cream 0.05%) 0.05% because of adverse reactions. These discontinuations were due to skin irritation or related cutaneous adverse reactions.

Local reactions such as peeling, dry skin, burning, stinging, erythema, and pruritus were reported by almost all subjects during therapy with RENOVA (tretinoin emollient cream 0.05%) 0.05%. These signs and symptoms were usually of mild to moderate severity and generally occurred early in therapy. In most patients the dryness, peeling, and redness recurred after an initial (24 week) decline.

In spontaneous post-marketing adverse event reporting for RENOVA (tretinoin emollient cream 0.05%) 0.05%, approximately 2% of those were for skin hypo- or hyperpigmentation. Other spontaneously reported adverse events predominantly appear to be local reactions similar to those seen in clinical trials.

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. Oral ingestion of the drug may lead to the same side effects as those associated with excessive oral intake of Vitamin A.