Tretinoin

1 INDICATIONS AND USAGE Tretinoin gel (microsphere) is indicated for the topical treatment of acne vulgaris in adults and pediatric patients 12 years of age and older. Tretinoin gel (microsphere) is a retinoid indicated for the topical treatment of acne vulgaris in adults and pediatric patients 12 years of age and older. (1)

2 DOSAGE AND ADMINISTRATION For topical use only. Not for ophthalmic, oral, or intravaginal use. Tretinoin gel (microsphere) should be applied once a day, in the evening, to the skin where acne lesions appear, using enough to cover the entire affected area in a thin layer. Areas to be treated should be cleansed thoroughly before the medication is applied. If medication is applied excessively, no more rapid or better results will be obtained and marked redness, peeling, or discomfort may occur. A transitory feeling of warmth or slight stinging may be noted on application. In cases where it has been necessary to temporarily discontinue therapy or to reduce the frequency of application, therapy may be resumed or the frequency of application increased as the patient becomes able to tolerate the treatment. Frequency of application 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 exacerbation of inflammatory lesions may occur. If tolerated, this should not be considered a reason to discontinue therapy [see Adverse Reactions (6.1) ]. Therapeutic results may be noticed after two weeks, but more than seven weeks of therapy are required before consistent beneficial effects are observed. Tretinoin gel (microsphere) should be kept away from the eyes, the mouth, paranasal creases of the nose, and mucous membranes. Patients treated with tretinoin gel microsphere may use cosmetics. Concomitant topical medication, medicated or abrasive soaps and cleansers, products that have a strong drying effect, products with high concentrations of alcohol, astringents, or spices should be used with caution because of possible interaction with tretinoin. Avoid contact with the peel of limes. Particular caution should be exercised with the concomitant use of topical over-the-counter acne preparations containing benzoyl peroxide, sulfur, resorcinol, or salicylic acid with tretinoin gel (microsphere). It also is advisable to allow the effects of such preparations to subside before use of tretinoin gel (microsphere) is begun. Apply a thin layer of tretinoin gel microsphere once daily, before bedtime, to skin where lesions occur. Keep away from eyes, mouth, nasal creases, and mucous membranes. (2) Not for oral, ophthalmic, or intravaginal use. (2)

3 DOSAGE FORMS AND STRENGTHS Tretinoin gel, USP (microsphere), 0.08% is a white to very pale-yellow opaque gel. Tretinoin gel, USP is available in one strength: 0.08%. Each gram of tretinoin gel, USP (microsphere), 0.08%, contains 0.8 mg of tretinoin, USP. Gel, 0.08% (3)

Contraindications: Use of the product should be discontinued if hypersensitivity to any of the ingredients is noted.

6 ADVERSE REACTIONS Most common adverse reactions were skin irritation, skin burning, erythema, peeling, dryness, itching, and dermatitis. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Encube Ethicals Private Limited at 1-833-285-4151 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Tretinoin gel (microsphere), 0.1% The safety of tretinoin gel (microsphere), 0.1% for the treatment of acne vulgaris was evaluated in two multicenter, double-blind, randomized, vehicle-controlled clinical trials (Studies 1 and 2). A total of 347 subjects with acne vulgaris were treated in Studies 1 and 2 in which 172 subjects received tretinoin gel (microsphere), 0.1% and 175 subjects received vehicle, applied topically once daily in the evening, for 12 weeks. Mean age was 19 years (range 11-40) and 55% were female [see Clinical Studies (14.1) ]. Tretinoin gel (microsphere) is not approved for use in pediatric patients younger than 12 years of age [see Indications and Usage (1) ]. In Studies 1 and 2, subjects treated with tretinoin gel (microsphere), 0.1% had increased cutaneous irritation scores for erythema, peeling, dryness, burning/stinging, or itching that peaked during the initial two weeks of therapy and decreased thereafter, compared to those treated with vehicle [see Warnings and Precautions (5.1) ]. During the 12-week treatment period, no more than 3% of tretinoin gel (microsphere), 0.1%-treated subjects had cutaneous irritation scores indicative of severe cutaneous irritation and 6% (14/224) of tretinoin gel (microsphere) 0.1%-treated subjects discontinued treatment due to cutaneous irritation. Of these 14 subjects, four had severe cutaneous irritation after 3 to 5 days of treatment, with blistering in one subject. Tretinoin gel (microsphere), 0.04% The safety of tretinoin gel (microsphere), 0.04% for the treatment of acne vulgaris was evaluated in two multicenter, double-blind, randomized, vehicle-controlled clinical trials (Studies 3 and 4). A total of 451 subjects with acne vulgaris were treated in Studies 3 and 4 in which 225 subjects received tretinoin gel (microsphere), 0.04% and 226 subjects received vehicle, applied once daily in the evening, for 12 weeks. Mean age was 19 years (range 11-49) and 57% were female [see Clinical Studies (14.2) ]. Tretinoin gel (microsphere) is not approved for use in pediatric patients younger than 12 years of age [see Indications and Usage (1) ]. In Studies 3 and 4, subjects treated with tretinoin gel (microsphere), 0.04% had increased cutaneous irritation scores for erythema, peeling, dryness, burning/stinging, or itching that peaked during the initial two weeks of therapy and decreased thereafter, compared to those treated with vehicle [see Warnings and Precautions (5.1) ]. Approximately half of the 225 subjects in the tretinoin gel (microsphere), 0.04%-treated group had cutaneous irritation at Week 2. Of the subjects who experienced cutaneous irritation, most had signs or symptoms that were mild in severity (severity was ranked on a 4-point ordinal scale: 0=none, 1=mild, 2=moderate, and 3=severe). Less than 10% of tretinoin gel (microsphere), 0.04%-treated subjects experienced moderate cutaneous irritation, and none had severe cutaneous irritation at Week 2. In Studies 3 and 4, during the 12-week treatment period, the majority of tretinoin gel (microsphere), 0.04%-treated subjects experienced cutaneous irritation (mild, moderate, or severe), of which, 1% (2/225) of subjects had cutaneous irritation scores indicative of a severe irritation and 1.3% (3/225) of subjects discontinued treatment due to cutaneous irritation, which included dryness in one subject and peeling and urticaria in another. Tret …

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 gel. It also is advisable to “rest” a patient's skin until the effects of such preparations subside before use of tretinoin gel is begun.

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary Available data from published prospective observational studies and retrospective cohort studies over decades of use of topical tretinoin in pregnant women have not established a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes (see Data) . In animal reproduction studies with pregnant rats, alterations in the vertebrae and ribs of offspring were observed with daily topical dosing of 0.1% tretinoin gel (microsphere) during organogenesis at 5 to 10 times the maximum recommended human dose (MRHD). In animal reproduction studies with pregnant rabbits, fetal malformations, such as domed head and hydrocephaly, were observed in the offspring with daily topical dosing of 0.1% tretinoin gel (microsphere) during organogenesis at 10 to 19 times the MRHD [ see Data ]. The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the US general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4%, and 15% to 20%, respectively. Data Human Data: Published data from prospective observational studies and retrospective cohort studies on the use of topical tretinoin products during pregnancy have not identified an association with topical tretinoin and major birth defects or miscarriage. The available studies have methodologic limitations, including potential misclassification of exposure, small sample size and in some cases, lack of physical exam by an expert in birth defects. Animal Data: For purposes of comparison of the animal exposure to systemic human exposure, the MRHD applied topically is defined as 1 gram of tretinoin gel (microsphere), 0.1%, applied daily to a 60 kg person (0.017 mg tretinoin/kg body weight). Pregnant rats were treated with 0.1% tretinoin gel (microsphere) at daily dermal doses of 0.2, 0.5, and 1 mg/kg/day tretinoin on gestation days 6-15. Alterations were seen in the vertebrae and ribs of the affected offsprings at 0.5 mg/kg/day tretinoin, 5 to 10 times the MRHD based on body surface area (BSA) comparison. Pregnant rabbits were treated with 0.1% tretinoin gel (microsphere) at daily dermal doses of 0.2, 0.5, and 1 mg/kg/day tretinoin on gestation days 7-19. Doses were administered topically for 24 hours a day while wearing Elizabethan collars to prevent ingestion of the drug. Increased incidences of certain alterations, including domed head and hydrocephaly, typical of retinoid-induced fetal malformations in this species were observed at doses of 0.5 and 1 mg/kg/day. Similar malformations were not observed in the offspring at 0.2 mg/kg/day, 4 times the MRHD based on BSA comparison. In a second rabbit study, pregnant rabbits were treated with 0.1% tretinoin gel (microsphere) at daily dermal doses of 0.5 or 1 mg/kg/day tretinoin on gestation days 7-19. Doses were administered topically for six hours per day while pregnant rabbits were restrained in stocks to prevent ingestion. The offspring of pregnant rabbits exposed to 0.5 or 1 mg/kg/day tretinoin did not show any malformations at doses up to 19 times (1.0 mg/kg/day) the MRHD based on BSA comparison, but fetal resorptions were increased at 0.5 mg/kg (10 times the MRHD based on BSA comparison). Malformations (shortened or kinked tail) were observed in the offspring of pregnant rats treated with topical tretinoin at doses greater than 1 mg/kg/day during the period of organogenesis (10 times the MRHD based on BSA comparison). Anomalies (humerus: short 13%, bent 6%, os parietal incompletely ossified 14%) have also been reported in offspring when 10 mg/kg/day was topically applied to pregnant rats during the period of organogenesis. Supernumerary ribs have been a consistent finding in newborn rats when dams were treated topically or orally with retinoids. Oral administ …

12.1 Mechanism of Action Tretinoin is a metabolite of Vitamin A 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 a tretinoin-containing topical drug product. Although tretinoin activates three members of the retinoid acid (RAR) nuclear receptors (RARα, RARβ, and RARγ) 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.

11 DESCRIPTION Chemically, tretinoin is all-trans-retinoic acid, also known as (all-E)-3,7-dimethyl-9-(2,6,6-trimethyl-1-cyclohexen-1-yl)-2,4,6,8-nonatetraenoic acid. Tretinoin is a retinoid and a metabolite of naturally occurring Vitamin A. Tretinoin has a molecular weight of 300.44, a molecular formula of C 20 H 28 O 2 and the following chemical structure: Tretinoin Gel Microsphere (tretinoin) gel is for topical use. Each gram of Tretinoin Gel Microsphere gel: • 0.04%, contains 0.4 mg of tretinoin • 0.08%, contains 0.8 mg of tretinoin • 0.1%, contains 1 mg of tretinoin The formulation contains methyl methacrylate/glycol dimethacrylate crosspolymer (MICROSPONGE ® System), propylene glycol dicaprylate/dicaprate and butylated hydroxytoluene. Other components consist of benzyl alcohol, butylated hydroxytoluene, carbomer 974P, cyclomethicone and dimethicone copolyol, disodium EDTA, glycerin, PPG-20 methyl glucose ether distearate, propylene glycol, purified water, sorbic acid, and trolamine. A structure of a chemical formula AI-generated content may be incorrect.

10 OVERDOSAGE Oral ingestion of large amounts of tretinoin gel (microsphere) may lead to the same adverse reactions as those associated with excessive oral intake of Vitamin A. Consider contacting the Poison Help Line (1-800-222-1222) or a medical toxicologist for overdose recommendations.

16 HOW SUPPLIED/STORAGE AND HANDLING How Supplied Tretinoin Gel Microsphere (tretinoin) is opaque and white to very pale yellow in color and is supplied as follows: Strength Amount of Tretinoin in One Gram of Gel Quantity/Package Type NDC 0.04% 0.4 mg 20 gram tube 68682-514-92 45 gram tube 68682-514-94 50 gram pump 68682-514-95 0.08% 0.8 mg 50 gram pump 68682-515-95 0.1% 1 mg 20 gram tube 68682-513-82 45 gram tube 68682-513-84 50 gram pump 68682-513-85 Storage and Handling Store at 20° to 25°C (68° to 77°F); excursions permitted from 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature]. Store pump upright.