ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS. The most common adverse reactions (incidence >= 5%) with tretinoin gel are dry skin, peeling/scaling/flaking skin, skin burning sensation, and erythema. (6.1)To report SUSPECTED ADVERSE REACTIONS, contact Mylan Pharmaceuticals Inc. at 1-877-446-3679 (1-877-4-INFO-RX) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.. 6.1 Clinical Trials Experience. Because clinical trials are conducted under prescribed conditions, adverse reaction rates observed in the clinical trials of drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.In two randomized, controlled trials, 674 subjects received treatment for up to 12 weeks with tretinoin gel [see Clinical Studies (14) ]. In these studies, 50% of the subjects who were treated with tretinoin gel reported one or more adverse reactions; 30% of the subjects reported treatment-related adverse reactions. In the vehicle group, 29% of the 487 randomized subjects reported at least one adverse reaction; 5% of the subjects reported events that were treatment-related. There were no serious, treatment-related adverse reactions reported by subjects in any of the treatment groups.Selected adverse reactions that occurred in at least 1% of subjects in the two studies combined are shown in Table (below). Most skin-related adverse reactions first appear during the first two weeks of treatment with tretinoin gel, and the incidence rate for skin-related reactions peaks around the second and third week of treatment. In some subjects the skin-related adverse reactions persists throughout the treatment period.Table 1. Number of Subjects with Selected Adverse Reactions (Occurring in At Least 1% of Subjects)EventTretinoin Gel(n 674)Vehicle Gel(n 487)Dry Skin109 (16%)8 (2%)Peeling/Scaling/Flaking Skin78 (12%)7 (1%)Skin Burning Sensation53 (8%)8 (2%)Erythema47 (7%)1 (< 1%)Pruritus11 (2%)3 (1%)Pain of Skin7 (1%)0 (0%)Sunburn7 (1%)3 (1%). 6.2 Postmarketing Experience. The following adverse reactions have been identified during post-approval use of tretinoin gel. Because these reactions are reported voluntarily from population of uncertain size, it is not always possible to reliably estimate their frequency or establish causal relationship to drug exposure.Temporary hyper- or hypopigmentation has been reported with repeated application of tretinoin.

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. 2-year dermal mouse carcinogenicity study was initiated with topical administration of 0.005%, 0.025% and 0.05% tretinoin gel. Although no drug-related tumors were observed in surviving animals, the irritating nature of the drug product precluded daily dosing, confounding data interpretation and reducing the biological significance of these results.Studies in hairless albino mice with different formulation suggest that concurrent exposure to tretinoin may enhance the tumorigenic potential of carcinogenic doses of UVB and UVA light from solar simulator. This effect was confirmed in 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 to humans is not clear, patients should minimize exposure to sunlight or artificial ultraviolet irradiation sources.The genotoxic potential of tretinoin was evaluated in an in vitro bacterial reversion test, an in vitro chromosomal aberration assay in human lymphocytes and an in vivo rat micronucleus assay. All tests were negative.In dermal fertility studies of another tretinoin formulation in rats, slight (not statistically significant) decreases in sperm count and motility were seen at 0.5 mg/kg/day (3 mg/m2, approximately times the clinical dose based on body surface area comparison), and slight (not statistically significant) increases in the number and percent of nonviable embryos in females treated with 0.25 mg/kg/day and above (1.5 mg/m2, approximately times the clinical dose based on body surface area comparison), were observed.

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. Tretinoin is metabolite of Vitamin that binds with high affinity to specific retinoic acid receptors located in both the cytosol and nucleus, but cutaneous levels of tretinoin in excess of physiologic concentrations occur following application of tretinoin-containing topical drug product.Although tretinoin activates three members of the retinoic acid (RAR) nuclear receptors (RAR, RAR, and RAR) which act to modify gene expression, subsequent protein synthesis, and epithelial cell growth and differentiation, it has not been established whether the clinical effects of tretinoin are mediated through activation of retinoic acid receptors, other mechanisms, or both.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.. 12.3 Pharmacokinetics. In two (2) studies, the plasma levels of tretinoin and its major metabolites (13-cis-retinoic acid and 4-oxo-13-cis-retinoic acid) were investigated in total of 14 patients (age: 13 25 years) with severe acne, who applied g +- 0.5 (range 3.5 - 4.5 g) of tretinoin gel once daily to face, back and chest, as compared to mean of 0.71 (range of 0.07 3.71 g) applied in the controlled clinical trials. Blood samples were taken at baseline and immediately prior to treatment on days 1, 5, 10 and 14. On Day 14, the final study day, samples also were taken 1, 2, 4, 6, 8, 10, 12, 16, and 24 hours, post-treatment.The plasma concentrations of tretinoin and its metabolites could be measured (LOQ 0.5 ng/mL for all three analytes) in all patients at all time points. The range of plasma concentrations of tretinoin and its metabolites, 13-cis-retinoic acid and all-trans-4-oxo-retinoic acid at baseline and after multiple once daily applications of tretinoin gel 0.05% for 14 days are given in Table (below). Although some patients had increased concentrations of tretinoin or its metabolites over baseline values, no consistent increase in these concentrations were observed across patients.Table 2. Concentrations of Active and Metabolites at Baseline and at Day 14 After Exposure to Tretinoin Gel, 0.05%CompoundBaseline ConcentrationRange (ng/ml)Day 14 ConcentrationRange (ng/ml)Tretinoin0.68 1.620.69 2.8813-cis-retinoic acid0.67 1.790.51 2.264-oxo-13-cis-retinoic acid0.82 5.920.59 6.96.

CLINICAL STUDIES SECTION.

14 CLINICAL TRIALS. The safety and efficacy of tretinoin gel used once daily before bedtime for the treatment of mild to moderate acne vulgaris were assessed in two 12-week prospective, multi-center, randomized, controlled trials. Subjects in these two trials ranged from 10 to 65 years of age, were approximately 52% female, 48% male, and were 74% Caucasian, 15% Black or African American, 3% Asian, and 8% Other.Efficacy results at Week 12 are presented in Table 3. Success on the 6-point Global Severity Score is defined as score of (clear) or (very mild). In Trial 2, subjects were also required to have at least two grades reduction from baseline for success. Very mild acne is defined as: skin almost clear; rare non-inflammatory lesions present, with rare non-inflamed papules (papules may be hyperpigmented, though not pink-red, less than lesions). The database was not large enough to assess whether there were differences in effects in age, gender, or race subgroups.Table 3. Efficacy Results at Week 12 in Trials and 2Trial 1Tretinoin GelN 375VehicleN 185Global Severity Score SuccessSuccess was defined as (clear) or (very mild)78 (21%)23 (12%)Non-Inflammatory Facial Lesions Mean Baseline Count50.752.4 Mean Absolute Reduction21.810.3 Mean Percent Reduction43%21%Inflammatory Facial Lesions Mean Baseline Count23.423.9 Mean Absolute Reduction9.75.8 Mean Percent Reduction41%26%Total Facial Lesions Mean Baseline Count74.176.3 Mean Absolute Reduction31.416.1 Mean Percent Reduction43%22%Trial 2Tretinoin GelN 299VehicleN 302Global Severity Score SuccessSuccess was defined as (clear) or (very mild) with at least grades reduction from baseline69 (23%)42 (14%)Non-Inflammatory Facial Lesions Mean Baseline Count51.952.7 Mean Absolute Reduction18.710.8 Mean Percent Reduction37%20%Inflammatory Facial Lesions Mean Baseline Count22.923.4 Mean Absolute Reduction7.04.0 Mean Percent Reduction30%17%Total Facial Lesions Mean Baseline Count74.876.1 Mean Absolute Reduction25.714.7 Mean Percent Reduction35%19%.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. For topical use only. Not for ophthalmic, oral, or intravaginal use.Tretinoin gel should be applied once daily, before bedtime, to the skin where acne lesions appear, using thin layer to cover the entire affected area. Tretinoin gel should be kept away from the eyes, the mouth, paranasal creases, and mucous membranes. Application of excessive amounts of gel will not provide incremental efficacy. Patients treated with tretinoin gel may use cosmetics, but the areas to be treated should be cleansed thoroughly before the medication is applied.When treating with tretinoin gel, caution should be exercised with the use of concomitant topical over-the-counter preparations, topical medications, medicated or abrasive soaps and cleansers, products that have strong drying effect, and products with high concentrations of alcohol, astringents, spices, or lime. Particular caution should be exercised with acne preparations containing benzoyl peroxide, sulfur, resorcinol, or salicylic acid. Allow the effects of such preparations to subside before use of tretinoin gel has begun.. oApply thin layer of tretinoin gel once daily, before bedtime, to skin where lesions occur. Keep away from eyes, mouth, nasal creases, and mucous membranes. (2)oTretinoin gel is not for oral, ophthalmic, or intravaginal use. (2). oApply thin layer of tretinoin gel once daily, before bedtime, to skin where lesions occur. Keep away from eyes, mouth, nasal creases, and mucous membranes. (2). oTretinoin gel is not for oral, ophthalmic, or intravaginal use. (2).

NONCLINICAL TOXICOLOGY SECTION.

13 NONCLINICAL TOXICOLOGY. 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. 2-year dermal mouse carcinogenicity study was initiated with topical administration of 0.005%, 0.025% and 0.05% tretinoin gel. Although no drug-related tumors were observed in surviving animals, the irritating nature of the drug product precluded daily dosing, confounding data interpretation and reducing the biological significance of these results.Studies in hairless albino mice with different formulation suggest that concurrent exposure to tretinoin may enhance the tumorigenic potential of carcinogenic doses of UVB and UVA light from solar simulator. This effect was confirmed in 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 to humans is not clear, patients should minimize exposure to sunlight or artificial ultraviolet irradiation sources.The genotoxic potential of tretinoin was evaluated in an in vitro bacterial reversion test, an in vitro chromosomal aberration assay in human lymphocytes and an in vivo rat micronucleus assay. All tests were negative.In dermal fertility studies of another tretinoin formulation in rats, slight (not statistically significant) decreases in sperm count and motility were seen at 0.5 mg/kg/day (3 mg/m2, approximately times the clinical dose based on body surface area comparison), and slight (not statistically significant) increases in the number and percent of nonviable embryos in females treated with 0.25 mg/kg/day and above (1.5 mg/m2, approximately times the clinical dose based on body surface area comparison), were observed.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

PRINCIPAL DISPLAY PANEL 0.05% NDC 0378-8090-45 Rx onlyTretinoinGel, USP0.05%For Topical Use OnlyNet Wt. 45 gIMPORTANT: The opening of this product is covered by metal seal. Do not use if seal has been punctured or is not visible.TO OPEN: To puncture the seal, reverse the cap and place the puncture-top onto the tube. Push down firmly until seal is open. To close, screw the cap back onto the tube.FOR TOPICAL USE ONLYUSUAL DOSAGE: Tretinoin gel should be applied oncedaily, before bedtime, using thin layer to cover the entireaffected area. See accompanying prescribing information.WARNING: KEEP THIS AND ALL MEDICATION OUT OF THE REACH OF CHILDREN.STORAGE AND HANDLING: Store at 20 to 25C (68 to 77F).[See USP Controlled Room Temperature.] Protect from freezing.See end flap for lot number and expiration date.CONTENTS DESCRIPTION: Tretinoin gel, USP is translucentto opaque, pale yellow topical gel containing 0.05% tretinoin,by weight. Other components of this formulation are benzylalcohol, butyl paraben, butylated hydroxytoluene, carbomer980, ethyl paraben, fish collagen hydrolyzates, glycerin,iso-butyl paraben, methylparaben, octoxynol 9,phenoxyethanol, propylparaben, purified water, sodiumhyaluronate, and trolamine.Manufactured for: Mylan Pharmaceuticals Inc. Morgantown, WV 26505 U.S.A.Manufactured by: Rockledge Pharmaceutical Manufacturing LLC Rockledge, FL 32955 U.S.A.RCK:8090:45:1C:R1Mylan.com. Tretinoin Gel 0.05% Carton Label.

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. In two (2) studies, the plasma levels of tretinoin and its major metabolites (13-cis-retinoic acid and 4-oxo-13-cis-retinoic acid) were investigated in total of 14 patients (age: 13 25 years) with severe acne, who applied g +- 0.5 (range 3.5 - 4.5 g) of tretinoin gel once daily to face, back and chest, as compared to mean of 0.71 (range of 0.07 3.71 g) applied in the controlled clinical trials. Blood samples were taken at baseline and immediately prior to treatment on days 1, 5, 10 and 14. On Day 14, the final study day, samples also were taken 1, 2, 4, 6, 8, 10, 12, 16, and 24 hours, post-treatment.The plasma concentrations of tretinoin and its metabolites could be measured (LOQ 0.5 ng/mL for all three analytes) in all patients at all time points. The range of plasma concentrations of tretinoin and its metabolites, 13-cis-retinoic acid and all-trans-4-oxo-retinoic acid at baseline and after multiple once daily applications of tretinoin gel 0.05% for 14 days are given in Table (below). Although some patients had increased concentrations of tretinoin or its metabolites over baseline values, no consistent increase in these concentrations were observed across patients.Table 2. Concentrations of Active and Metabolites at Baseline and at Day 14 After Exposure to Tretinoin Gel, 0.05%CompoundBaseline ConcentrationRange (ng/ml)Day 14 ConcentrationRange (ng/ml)Tretinoin0.68 1.620.69 2.8813-cis-retinoic acid0.67 1.790.51 2.264-oxo-13-cis-retinoic acid0.82 5.920.59 6.96.

PREGNANCY SECTION.

8.1 Pregnancy. Pregnancy Category C. There are no well-controlled studies in pregnant women treated with tretinoin gel. Tretinoin gel should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.Tretinoin gel at doses of 0.1, 0.3 and g/kg/day was tested for maternal and developmental toxicity in pregnant Sprague-Dawley rats by dermal application. The dose of g/kg/day was approximately times the clinical dose assuming 100% absorption and based on body surface area comparison. Possible tretinoin-associated teratogenic effects (craniofacial abnormalities (hydrocephaly), asymmetrical thyroids, variations in ossification, and increased supernumerary ribs) were noted in the fetuses of tretinoin gel treated animals. These findings were not observed in control animals. Other maternal and reproductive parameters in the tretinoin gel treated animals were not different from control. For purposes of comparison of the animal exposure to human exposure, the clinical dose is defined as g of tretinoin gel applied daily to 50 kg person.Oral tretinoin has been shown to be teratogenic in rats, mice, rabbits, hamsters and nonhuman primates. Tretinoin was teratogenic in Wistar rats when given orally in doses greater than mg/kg/day (approximately times the clinical dose based on body surface area comparison). In the cynomolgus monkey, fetal malformations were reported for doses of 10 mg/kg/day, but none were observed at mg/kg/day (approximately 80 times the clinical dose based on body surface area comparison), although increased skeletal variations were observed at all doses. Dose-related increases in embryolethality and abortion also were reported. Similar results have also been reported in pigtail macaques.Topical tretinoin in different formulation has generated equivocal results in animal teratogenicity tests. There is evidence for teratogenicity (shortened or kinked tail) of topical tretinoin in Wistar rats at doses greater than mg/kg/day (approximately times the clinical dose assuming 100% absorption and based on body surface area comparison). Anomalies (humerus: short 13%, bent 6%, os parietal incompletely ossified 14%) have also been reported when 10 mg/kg/day (approximately 160 times the clinical dose assuming 100% absorption and based on body surface area comparison) was topically applied. Supernumerary ribs have been consistent finding in rats when dams were treated topically or orally with retinoids.With widespread use of any drug, small number of birth defect reports associated temporally with the administration of the drug would be expected by chance alone. Cases of temporally associated congenital malformations have been reported with use of other topical tretinoin products. The significance of these spontaneous reports in terms of risk to the fetus is not known.. Nonteratogenic Effects on Fetus. Oral tretinoin has been shown to be fetotoxic in rats when administered in doses 20 times the clinical dose based on body surface area comparison. Topical tretinoin has been shown to be fetotoxic in rabbits when administered in doses times the clinical dose based on body surface area comparison.

SPL PATIENT PACKAGE INSERT SECTION.

Patient Information Tretinoin Gel USP, 0.05%(tret noyn)For topical useImportant information: Tretinoin gel is for use on skin only. Do not get tretinoin gel in your mouth, eyes, vagina, or the corners of your nose.What is tretinoin gelTretinoin gel is prescription medicine used on the skin (topical) to treat acne. Acne is condition in which the skin has blackheads, whiteheads, and other pimples. It is not known if tretinoin gel is safe and effective in children under 10 years of age.What should tell my healthcare provider before using tretinoin gel Before using tretinoin gel, tell your doctor about all of your medical conditions, including if you:oare allergic to fish. Tretinoin gel contains fish proteins. Tell your healthcare provider if you get hives or itching during treatment with tretinoin gel.ohave skin condition called eczemaohave sunburnoare pregnant or plan to become pregnant. It is not known if tretinoin gel will harm your unborn baby. oare breastfeeding or plan to breastfeed. It is not known if tretinoin passes into breast milk.Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, herbal supplements, and any skin products that you use. Especially tell your healthcare provider if you use any other medicines to treat your acne, including medicated cleansers or soaps. Using other topical acne products may increase the irritation of your skin when used with tretinoin gel. How should use tretinoin geloUse tretinoin gel exactly as your healthcare provider tells you to use it. oBefore you apply tretinoin gel, gently wash the affected skin area with mild, non-medicated soap. Rinse and pat your skin dry. oApply tretinoin gel time day before bedtime.oApply thin layer of tretinoin gel to cover the affected skin areas. Gently rub tretinoin gel into your skin.oDo not use more tretinoin gel than you need to cover the affected area and do not apply tretinoin gel more than time day. Using too much tretinoin gel may irritate or increase the irritation of your skin, and will not give faster or better results.oYou may use moisturizers and cosmetics.What should avoid while using tretinoin geloAvoid washing your skin too often and scrubbing the affected skin area. oYou should avoid sunlamps, tanning beds, and ultraviolet light during treatment with tretinoin gel. oMinimize exposure to sunlight. oIf you have to be in the sunlight or are sensitive to sunlight, use sunscreen with SPF (sun protection factor) of 15 or more and wear protective clothing, and wide brimmed hat to cover the treated areas. oIf you do get sunburned, stop using tretinoin gel until your skin has healed and is back to normal.oCold weather and wind may irritate skin treated with tretinoin gel. Skin treated with tretinoin gel may dry out or get wind burned more easily. Talk to your healthcare provider/doctor about ways to manage skin irritation.oAvoid contact with the peels of limes.What are the possible side effects of tretinoin gelTretinoin gel may cause skin irritation, including: skin dryness, burning, redness, excessive flaking or peeling. If you develop these symptoms, your healthcare provider may tell you to stop using tretinoin gel for while, decrease the number of times you apply tretinoin gel, or completely stop treatment with tretinoin gel. It is not known if tretinoin gel is effective when used less than time day. Tell your healthcare provider if you have any side effect that bothers you or that does not go away. These are not all of the side effects possible with tretinoin gel. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.How do store tretinoin geloStore tretinoin gel at room temperature, 20 to 25C (68 to 77F). oProtect from freezing.Keep tretinoin gel and all medicines out of the reach of children.General information about the safe and effective use of tretinoin gelMedicines are sometimes prescribed for purposes other than those listed in Patient Information Leaflet. Do not use tretinoin gel for condition for which it was not prescribed. Do not give tretinoin gel to other people, even if they have the same symptoms you have. It may harm them. You can ask your pharmacist or healthcare provider for information about tretinoin gel that is written for health professionals.What are the ingredients of tretinoin gelActive ingredient: tretinoinInactive ingredients: benzyl alcohol, butyl paraben, butylated hydroxytoluene, carbomer 980, ethyl paraben, fish collagen hydrolyzates, glycerin, iso-butyl paraben, methylparaben, octoxynol 9, phenoxyethanol, propylparaben, purified water, sodium hyaluronate, and trolamine. Manufactured for: Mylan Pharmaceuticals Inc., Morgantown, WV 26505 U.S.A.Manufactured by: Rockledge Pharmaceutical Manufacturing LLC, Rockledge, FL 32955 U.S.A.For more information, call Mylan Pharmaceuticals Inc. at 1-877-446-3679 (1-877-4-INFO-RX).This Patient Information has been approved by the U.S. Food and Drug Administration. Manufactured for: Mylan Pharmaceuticals Inc. Morgantown, WV 26505 U.S.A.Manufactured by: Rockledge Pharmaceutical Manufacturing LLC Rockledge, FL 32955 U.S.A.Revised: 1/2018RCK:PL:TRET5G:R1. oare allergic to fish. Tretinoin gel contains fish proteins. Tell your healthcare provider if you get hives or itching during treatment with tretinoin gel.. ohave skin condition called eczema. ohave sunburn. oare pregnant or plan to become pregnant. It is not known if tretinoin gel will harm your unborn baby. oare breastfeeding or plan to breastfeed. It is not known if tretinoin passes into breast milk.. oUse tretinoin gel exactly as your healthcare provider tells you to use it. oBefore you apply tretinoin gel, gently wash the affected skin area with mild, non-medicated soap. Rinse and pat your skin dry. oApply tretinoin gel time day before bedtime.. oApply thin layer of tretinoin gel to cover the affected skin areas. Gently rub tretinoin gel into your skin.. oDo not use more tretinoin gel than you need to cover the affected area and do not apply tretinoin gel more than time day. Using too much tretinoin gel may irritate or increase the irritation of your skin, and will not give faster or better results.. oYou may use moisturizers and cosmetics.. oAvoid washing your skin too often and scrubbing the affected skin area. oYou should avoid sunlamps, tanning beds, and ultraviolet light during treatment with tretinoin gel. oMinimize exposure to sunlight. oIf you have to be in the sunlight or are sensitive to sunlight, use sunscreen with SPF (sun protection factor) of 15 or more and wear protective clothing, and wide brimmed hat to cover the treated areas. oIf you do get sunburned, stop using tretinoin gel until your skin has healed and is back to normal.. oCold weather and wind may irritate skin treated with tretinoin gel. Skin treated with tretinoin gel may dry out or get wind burned more easily. Talk to your healthcare provider/doctor about ways to manage skin irritation.. oAvoid contact with the peels of limes.. oStore tretinoin gel at room temperature, 20 to 25C (68 to 77F). oProtect from freezing.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. 8.1 Pregnancy. Pregnancy Category C. There are no well-controlled studies in pregnant women treated with tretinoin gel. Tretinoin gel should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.Tretinoin gel at doses of 0.1, 0.3 and g/kg/day was tested for maternal and developmental toxicity in pregnant Sprague-Dawley rats by dermal application. The dose of g/kg/day was approximately times the clinical dose assuming 100% absorption and based on body surface area comparison. Possible tretinoin-associated teratogenic effects (craniofacial abnormalities (hydrocephaly), asymmetrical thyroids, variations in ossification, and increased supernumerary ribs) were noted in the fetuses of tretinoin gel treated animals. These findings were not observed in control animals. Other maternal and reproductive parameters in the tretinoin gel treated animals were not different from control. For purposes of comparison of the animal exposure to human exposure, the clinical dose is defined as g of tretinoin gel applied daily to 50 kg person.Oral tretinoin has been shown to be teratogenic in rats, mice, rabbits, hamsters and nonhuman primates. Tretinoin was teratogenic in Wistar rats when given orally in doses greater than mg/kg/day (approximately times the clinical dose based on body surface area comparison). In the cynomolgus monkey, fetal malformations were reported for doses of 10 mg/kg/day, but none were observed at mg/kg/day (approximately 80 times the clinical dose based on body surface area comparison), although increased skeletal variations were observed at all doses. Dose-related increases in embryolethality and abortion also were reported. Similar results have also been reported in pigtail macaques.Topical tretinoin in different formulation has generated equivocal results in animal teratogenicity tests. There is evidence for teratogenicity (shortened or kinked tail) of topical tretinoin in Wistar rats at doses greater than mg/kg/day (approximately times the clinical dose assuming 100% absorption and based on body surface area comparison). Anomalies (humerus: short 13%, bent 6%, os parietal incompletely ossified 14%) have also been reported when 10 mg/kg/day (approximately 160 times the clinical dose assuming 100% absorption and based on body surface area comparison) was topically applied. Supernumerary ribs have been consistent finding in rats when dams were treated topically or orally with retinoids.With widespread use of any drug, small number of birth defect reports associated temporally with the administration of the drug would be expected by chance alone. Cases of temporally associated congenital malformations have been reported with use of other topical tretinoin products. The significance of these spontaneous reports in terms of risk to the fetus is not known.. Nonteratogenic Effects on Fetus. Oral tretinoin has been shown to be fetotoxic in rats when administered in doses 20 times the clinical dose based on body surface area comparison. Topical tretinoin has been shown to be fetotoxic in rabbits when administered in doses times the clinical dose based on body surface area comparison. 8.3 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 gel is administered to nursing woman.. 8.4 Pediatric Use. Safety and effectiveness in children below the age of 10 have not been established.A total of 381 pediatric subjects (aged 10 to 16 years), treated with tretinoin gel were enrolled into the two clinical studies. Across these two studies, comparable safety and efficacy were observed between pediatric and adult subjects.. 8.5 Geriatric Use. Safety and effectiveness in geriatric population have not been established. Clinical studies of tretinoin gel did not include any subjects over age 65 to determine whether they respond differently from younger subjects.

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. oTretinoin gel should not be used on eczematous or sunburned skin due to potential for severe irritation. (5.1)oTopical over-the-counter acne preparations, concomitant topical medications, medicated cleansers, topical products with alcohol or astringents: Use with caution, irritation may occur. (5.1)oAvoid unprotected exposure to sunlight including sunlamps (UV light) when using tretinoin gel due to potential for increased photosensitization. Use sunscreen of at least SPF 15 and protective clothing during exposure. (5.2)oAvoid use of tretinoin gel with weather extremes, such as wind or cold due to potential for increased irritation. (5.2)oUse tretinoin gel with caution if allergic to fish due to potential for allergenicity to fish protein. Patients who develop pruritus or urticaria should contact their health care provider. (5.3). oTretinoin gel should not be used on eczematous or sunburned skin due to potential for severe irritation. (5.1). oTopical over-the-counter acne preparations, concomitant topical medications, medicated cleansers, topical products with alcohol or astringents: Use with caution, irritation may occur. (5.1). oAvoid unprotected exposure to sunlight including sunlamps (UV light) when using tretinoin gel due to potential for increased photosensitization. Use sunscreen of at least SPF 15 and protective clothing during exposure. (5.2). oAvoid use of tretinoin gel with weather extremes, such as wind or cold due to potential for increased irritation. (5.2). oUse tretinoin gel with caution if allergic to fish due to potential for allergenicity to fish protein. Patients who develop pruritus or urticaria should contact their health care provider. (5.3). 5.1 Skin Irritation. The skin of certain individuals may become dry, red, or exfoliated while using tretinoin gel. If the degree of irritation warrants, patients should be directed to temporarily reduce the amount or frequency of application of the medication, discontinue use temporarily, or discontinue use all together. Efficacy at reduced frequencies of application has not been established. If reaction suggesting sensitivity occurs, use of the medication should be discontinued. Mild to moderate skin dryness may also be experienced; if so, use of an appropriate moisturizer during the day may be helpful.Tretinoin has been reported to cause severe irritation on eczematous or sunburned skin and should be used with utmost caution in patients with these conditions.To help limit skin irritation, patients must:owash the treated skin gently, using mild, non-medicated soap, and pat it dryoavoid washing the treated skin too often and scrubbing the affected skin areaoavoid contact with the peels of limes. owash the treated skin gently, using mild, non-medicated soap, and pat it dry. oavoid washing the treated skin too often and scrubbing the affected skin area. oavoid contact with the peels of limes. 5.2 Ultraviolet Light and Environmental Exposure. Unprotected exposure to sunlight, including sunlamps, should be minimized during the use of tretinoin gel. Patients who normally experience high levels of sun exposure, and those with inherent sensitivity to sun, should be warned to exercise caution. Use of sunscreen products of at least SPF 15 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 tretinoin-treated skin.. 5.3 Fish Allergies. Tretinoin gel contains soluble fish proteins and should be used with caution in patients with known sensitivity or allergy to fish. Patients who develop pruritus or urticaria should contact their health care provider.