Tretinoin

ADVERSE REACTIONS The skin of certain sensitive individuals may become excessively red, edematous, blistered, or crusted. If these effects occur, the medication should either be discontinued until the integrity of the skin is restored, or the medication dosing frequency should be adjusted temporarily to a level the patient can tolerate. However, efficacy has not been established for lower dosing frequencies. True contact allergy to topical tretinoin is rarely encountered. Temporary hyper- or hypopigmentation has been reported with repeated application of tretinoin cream. Some individuals have been reported to have heightened susceptibility to sunlight while under treatment with tretinoin cream. Adverse effects of tretinoin cream have been reversible upon discontinuation of therapy (see DOSAGE AND ADMINISTRATION section).

CONTRAINDICATIONS The product should not be used if there is hypersensitivity to any of the ingredients.

DESCRIPTION Tretinoin Cream, USP a topical retinoid, contains tretinoin USP, 0.025% by weight in a hydrophilic cream vehicle of stearic acid, polyolprepolymer-2, isopropyl myristate, polyoxyl 40 stearate, propylene glycol, stearyl alcohol, xanthan gum, sorbic acid, butylated hydroxytoluene, and purified water. Chemically, tretinoin is all- trans- retinoic acid (C 20 H 28 0 2 ; molecular weight 300.44 vitamin A acid) and has the following structural formula: Description: C:\Documents and Settings\MBORTZ\Desktop\image.jpg

DOSAGE AND ADMINISTRATION Tretinoin Cream should be applied once a day, in the evening, to the skin where acne lesions appear, using enough to cover the entire affected area lightly. Application may cause a transient feeling of warmth or slight stinging. In cases where it has been necessary to temporarily discontinue therapy or reduce the frequency of application, therapy may be resumed or frequency of application increased when the patients become able to tolerate the treatment. Alterations of dose frequency should be closely monitored by careful observation of the clinical therapeutic response and skin tolerance. Efficacy has not been established for less than once-daily dosing frequencies. During the early weeks of therapy, an apparent increase in number and exacerbation of inflammatory acne lesions may occur. This is due, in part, to the action of the medication on deep, previously unseen lesions and should not be considered a reason to discontinue therapy. Therapeutic results should be noticed after two to three weeks but more than six weeks of therapy may be required before definite beneficial effects are seen. Patients treated with tretinoin cream may use cosmetics, but the areas to be treated should be cleansed thoroughly before the medication is applied (see PRECAUTIONS section).

INDICATIONS AND USAGE Tretinoin Cream, USP is indicated for topical application in the treatment of acne vulgaris. The safety and efficacy of this product in the treatment of other disorders have not been established.

OVERDOSAGE If medication is applied excessively, no more rapid or better results will be obtained 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.

Drug Interactions Concomitant topical medication, medicated or abrasive soaps and cleansers, soaps and cosmetics that have a strong drying effect, and products with high concentrations of alcohol, astringents, spices or lime should be used with caution because of possible interaction with tretinoin. Particular caution should be exercised in using preparations containing sulfur, resorcinol, or salicylic acid with tretinoin cream. It also is advisable to “rest” a patient’s skin until the effects of such preparations subside before use of tretinoin cream is begun.

CLINICAL PHARMACOLOGY Although the exact mode of action of tretinoin is unknown, current evidence suggests that topical tretinoin decreases cohesiveness of follicular epithelial cells with decreased microcomedo formation. Additionally, tretinoin stimulates mitotic activity and increased turnover of follicular epithelial cells causing extrusion of the comedones. Pharmacokinetics: In vitro and in vivo pharmacokinetic studies with tretinoin cream indicate that less than 0.3% of the topically applied dose is bioavailable. Circulating plasma levels of both tretinoin and isotretinoin are only slightly elevated above those found in healthy normal controls.

Pharmacokinetics: In vitro and in vivo pharmacokinetic studies with tretinoin cream indicate that less than 0.3% of the topically applied dose is bioavailable. Circulating plasma levels of both tretinoin and isotretinoin are only slightly elevated above those found in healthy normal controls.

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Tretinoin Tretinoin TRETINOIN TRETINOIN STEARIC ACID PPG-12/SMDI COPOLYMER ISOPROPYL MYRISTATE POLYOXYL 40 STEARATE PROPYLENE GLYCOL STEARYL ALCOHOL XANTHAN GUM SORBIC ACID BUTYLATED HYDROXYTOLUENE WATER

Carcinogenesis, Mutagenesis and Impairment of Fertility In a life-time dermal study in CD-1 mice with another tretinoin cream, 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 five 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 1.0 g of 0.025% Tretinoin Cream 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 vitamin A treated groups in the basal layer of the 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 UVA/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 III studies with tretinoin cream have 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 (> 400 times the average recommended human topical clinical dose).

NDA020404

Tretinoin

Tretinoin

50090-0651

HUMAN PRESCRIPTION DRUG

TOPICAL

Tretinoin Label Image

FOR TOPICAL USE ONLY Rx Only

Information for Patients See attached Patient Package Insert .

CLINICAL STUDIES In one vehicle-controlled clinical trial, Tretinoin Cream 0.025%, applied once daily was more effective than vehicle in the treatment of facial acne vulgaris of mild to moderate severity. Percent reductions in lesion count after treatment for 12 weeks in this study are shown in the following table: Tretinoin Cream, Vehicle 0.025% Cream N = Number of Subjects N = 75 N = 58 Noninflammatory Lesions 45% 27% Inflammatory Lesions 46% 32% Total Lesions 46% 28%

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 tretinoin cream is administered to a nursing woman.

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 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 other species examined, fetal malformations were reported at oral 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. Dose-related increased embryolethality and abortion were 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 in rats when 10 mg/kg/day was dermally applied. Topical tretinoin (Tretinoin Cream, 0.1%) has been shown to be teratogenic in rabbits when given in doses 91 times the topical human dose for cream (assuming a 50 kg adult applies 1.0 g of 0.1% cream topically). In this study, increased incidence of cleft palate and hydrocephaly was reported in the tretinoin-treated animals. 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. When given subcutaneously to rabbits, tretinoin was teratogenic at 2 mg/kg/day but not at 1 mg/kg/day. These doses are approximately 400 and 200 times, respectively, the human topical dose of tretinoin cream, 0.025% (assuming a 50 kg adult applies 1.0 g of 0.025% cream topically). 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 have 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. Nonteratogenic 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. Tretinoin Cream, 0.025% 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 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 other species examined, fetal malformations were reported at oral 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. Dose-related increased embryolethality and abortion were 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 in rats when 10 mg/kg/day was dermally applied. Topical tretinoin (Tretinoin Cream, 0.1%) has been shown to be teratogenic in rabbits when given in doses 91 times the topical human dose for cream (assuming a 50 kg adult applies 1.0 g of 0.1% cream topically). In this study, increased incidence of cleft palate and hydrocephaly was reported in the tretinoin-treated animals. 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. When given subcutaneously to rabbits, tretinoin was teratogenic at 2 mg/kg/day but not at 1 mg/kg/day. These doses are approximately 400 and 200 times, respectively, the human topical dose of tretinoin cream, 0.025% (assuming a 50 kg adult applies 1.0 g of 0.025% cream topically). 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 have 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.

HOW SUPPLIED Product: 50090-0651 NDC: 50090-0651-0 20 g in a TUBE / 1 in a CARTON

General If a reaction suggesting sensitivity or chemical irritation occurs, use of the medication should be discontinued. Exposure to sunlight, including sunlamps or artificial sunlight, should be minimized during the use of tretinoin cream, and patients with sunburn should be advised not to use the product until fully recovered because of heightened susceptibility to sunlight as a result of the use of tretinoin. Patients who may be required to have considerable sun exposure due to occupation and those with inherent sensitivity to the sun should exercise particular caution. Use of sunscreen products 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. Tretinoin Cream, 0.025% should be kept away from the eyes, the mouth, the paranasal creases, and mucous membranes. Topical use may induce severe local erythema and peeling at the site of application. If the degree of local irritation warrants, patients should be directed to temporarily use the medication less frequently, discontinue use temporarily, or discontinue use altogether. Efficacy at reduced frequencies of application has not been established. Tretinoin has been reported to cause severe irritation on eczematous skin and should be used with utmost caution in patients with this condition.

PRECAUTIONS General If a reaction suggesting sensitivity or chemical irritation occurs, use of the medication should be discontinued. Exposure to sunlight, including sunlamps or artificial sunlight, should be minimized during the use of tretinoin cream, and patients with sunburn should be advised not to use the product until fully recovered because of heightened susceptibility to sunlight as a result of the use of tretinoin. Patients who may be required to have considerable sun exposure due to occupation and those with inherent sensitivity to the sun should exercise particular caution. Use of sunscreen products 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. Tretinoin Cream, 0.025% should be kept away from the eyes, the mouth, the paranasal creases, and mucous membranes. Topical use may induce severe local erythema and peeling at the site of application. If the degree of local irritation warrants, patients should be directed to temporarily use the medication less frequently, discontinue use temporarily, or discontinue use altogether. Efficacy at reduced frequencies of application has not been established. Tretinoin has been reported to cause severe irritation on eczematous skin and should be used with utmost caution in patients with this condition. Information for Patients See attached Patient Package Insert . Drug Interactions Concomitant topical medication, medicated or abrasive soaps and cleansers, soaps and cosmetics that have a strong drying effect, and products with high concentrations of alcohol, astringents, spices or lime should be used with caution because of possible interaction with tretinoin. Particular caution should be exercised in using preparations containing sulfur, resorcinol, or salicylic acid with tretinoin cream. It also is advisable to “rest” a patient’s skin until the effects of such preparations subside before use of tretinoin cream is begun. Carcinogenesis, Mutagenesis and Impairment of Fertility In a life-time dermal study in CD-1 mice with another tretinoin cream, 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 five 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 1.0 g of 0.025% Tretinoin Cream 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 vitamin A treated groups in the basal layer of the 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 UVA/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 III studies with tretinoin cream have 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 (> 400 times the average recommended human topical clinical dose). 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 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 other species examined, fetal malformations were reported at oral 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. Dose-related increased embryolethality and abortion were 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 in rats when 10 mg/kg/day was dermally applied. Topical tretinoin (Tretinoin Cream, 0.1%) has been shown to be teratogenic in rabbits when given in doses 91 times the topical human dose for cream (assuming a 50 kg adult applies 1.0 g of 0.1% cream topically). In this study, increased incidence of cleft palate and hydrocephaly was reported in the tretinoin-treated animals. 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. When given subcutaneously to rabbits, tretinoin was teratogenic at 2 mg/kg/day but not at 1 mg/kg/day. These doses are approximately 400 and 200 times, respectively, the human topical dose of tretinoin cream, 0.025% (assuming a 50 kg adult applies 1.0 g of 0.025% cream topically). 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 have 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. Nonteratogenic 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. Tretinoin Cream, 0.025% 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 tretinoin cream is administered to a nursing woman.