Tretinoin (Topical) Side Effects, Dosing and Safety

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.

(To understand fully the indication for this product, please read the entire INDICATIONS AND USAGE section of the labeling.) RENOVA (tretinoin cream) 0.02% is indicated as an adjunctive agent (see second bullet point below) for use in the mitigation (palliation) of fine facial wrinkles in patients who use comprehensive skin care and sunlight avoidance programs. RENOVA (tretinoin cream) 0.02% DOES NOT ELIMINATE WRINKLES, REPAIR SUN-DAMAGED SKIN, REVERSE PHOTOAGING, or RESTORE MORE YOUTHFUL or YOUNGER SKIN. In double-blind, vehicle-controlled clinical studies, many patients in the vehicle group achieved desired palliative effects on fine wrinkling 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 cream) 0.02% has NOT DEMONSTRATED A MITIGATING EFFECT on significant signs of chronic sunlight exposure such as coarse or deep wrinkling, tactile roughness, mottled hyperpigmentation, lentigines, telangiectasia, skin laxity, keratinocytic atypia, melanocytic atypia, or dermal elastosis.
• RENOVA (tretinoin cream) 0.02% 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.
• Patients with visible actinic keratosis and patients with a history of skin cancer were excluded from clinical trials of RENOVA (tretinoin cream) 0.02%. Thus the effectiveness and safety of RENOVA (tretinoin cream) 0.02% in these populations are not known at this time.
• Neither the safety nor the effectiveness of RENOVA (tretinoin cream) 0.02% for the prevention or treatment of actinic keratoses or skin neoplasms has been established.
• Neither the safety nor the efficacy of using RENOVA (tretinoin cream) 0.02% daily for greater than 52 weeks has been established, and daily use beyond 52 weeks has not been systematically and histologically investigated in adequate and well-controlled trials (see WARNINGS ). Clinical Trials Four adequate and well-controlled multi-center trials and one single-center randomized, controlled trial were conducted involving a total of 324 evaluable patients treated with RENOVA (tretinoin cream) 0.02% and 332 evaluable patients treated with the vehicle cream on the face for 24 weeks with a comprehensive skin care and sun avoidance program, to assess the effects on fine and coarse wrinkling, mottled hyperpigmentation, tactile skin roughness, and laxity. Patients were evaluated at baseline on a 10-unit scale and changes from that baseline rating were categorized as follows: Worsening: Increase of 1 unit or more. No improvement: No change. Minimal improvement: Reduction of 1 unit. Mild improvement: Reduction of 2 units. Moderate improvement: Reduction of 3 units or more. In these trials, the fine and coarse wrinkling, mottled hyperpigmentation, tactile roughness, and laxity of the facial skin were thought to be caused by multiple factors which included intrinsic aging or environmental factors, such as chronic sunlight exposure. Two of the five trials provided adequate demonstration of efficacy for mitigation of fine facial wrinkling. No two of the five trials adequately demonstrated efficacy for mitigation of coarse wrinkling, mottled hyperpigmentation, tactile skin roughness, and laxity. Data for fine wrinkling (the indication for which RENOVA (tretinoin cream) 0.02% demonstrated efficacy) from all five trials (four studies in lightly pigmented subjects with Fitzpatrick Skin Types I-III and one study in darkly pigmented subjects with Fitzpatrick Skin Types IV-VI) is provided below: FINE WRINKLING IN LIGHTLY PIGMENTED SUBJECTS Subjects Using RENOVA (tretinoin cream) 0.02% + CSP * (N=279) Vehicle + CSP * (N=280) A single-center study (N=107) in darkly pigmented, mostly African-American, subjects with Fitzpatrick Skin Types IV-VI demonstrated minimal or mild improvement in fine facial wrinkling in 43% of patients using Vehicle + CSP* compared to 29% of subjects using RENOVA (tretinoin cream) 0.02% + CSP*. Although fewer darkly pigmented subjects improved with RENOVA (tretinoin cream) 0.02% than with vehicle, these findings may reflect the small size of this study. * CSP = Comprehensive skin protection and sunlight avoidance programs including use of sunscreens, protective clothing, and non-prescription emollient creams. Worsened 1% 3% No Change 40% 58% Minimal Improvement 35% 27% Mild Improvement 15% 9% Moderate Improvement 10% 3% Self-assessment of fine wrinkles after 24 weeks of treatment with either RENOVA (tretinoin cream) 0.02% or Vehicle from the four studies in lightly pigmented patients showed the following: No studies have been conducted comparing the facial irritation or efficacy of RENOVA (tretinoin cream) 0.02% to RENOVA (tretinoin cream) 0.05% (older marketed formulation). Patients may lose some of the mitigating effects of RENOVA (tretinoin cream) 0.02% after 12 weeks of discontinuation of RENOVA (tretinoin cream) 0.02% from their comprehensive skin care and sunlight avoidance program. figure1.jpg

• 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) 0.02% 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) 0.02% 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) 0.02% because of heightened sunburn susceptibility. Patients should be warned to use sunscreens (minimum SPF of 15) and protective clothing when using RENOVA (tretinoin cream) 0.02%. Patients with sunburn should be advised not to use RENOVA (tretinoin cream) 0.02% 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) 0.02% and follow the precautions outlined in the Patient Package Insert. RENOVA (tretinoin cream) 0.02% 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.

(See WARNINGS and PRECAUTIONS .) In double-blind, vehicle-controlled studies involving 339 patients who applied RENOVA (tretinoin cream) 0.02% to their faces, adverse reactions associated with the use of RENOVA (tretinoin cream) 0.02% were limited primarily to the skin. Almost all patients reported one or more local reactions such as peeling, dry skin, burning, stinging, erythema, and pruritus. In 32% of all study patients, skin irritation was reported that was severe, led to temporary discontinuation of RENOVA (tretinoin cream) 0.02%, or led to use of a mild topical corticosteroid. About 7% of patients using RENOVA (tretinoin cream) 0.02%, compared to less than 1% of the control patients, had sufficiently severe local irritation to warrant short-term use of mild topical corticosteroids to alleviate local irritation. About 4% of patients had to discontinue use of RENOVA (tretinoin cream) 0.02% because of adverse reactions. Approximately 2% of spontaneous postmarketing adverse event reporting for RENOVA (tretinoin cream) 0.05% were for skin hypo- or hyperpigmentation. Other spontaneously reported adverse events for RENOVA (tretinoin cream) 0.05% predominantly appear to be local reactions similar to those seen in clinical trials. To report SUSPECTED ADVERSE REACTIONS, contact Bausch Health US, LLC at 1-800-321-4576 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

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 cream) 0.02% because they may increase irritation with RENOVA (tretinoin cream) 0.02%. RENOVA (tretinoin cream) 0.02% 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.

Pregnancy: Teratogenic Effects 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, five 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) 0.02% should not be used during pregnancy. Teratogenic Effects 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, five 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. 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.