TRETINOIN

5.3 Photosensitivity Tretinoin gel (microsphere) can cause photosensitivity. Advise patients to avoid or minimize unnecessary exposure to ultraviolet (UV) light, including sunlight and sunlamps, while using tretinoin gel (microsphere). Advise patients with sunburn to not use tretinoin gel (microsphere) until the sunburn fully recovers. Advise patients, especially those who may be required to have extended periods of UV light exposure (e.g., due to occupation or sports), those with inherent sensitivity to the sun, or those using drugs that cause photosensitivity, to use sun protection daily in the form of sunscreen (sun protection factor [SPF] ≥ 15) and sun- protective clothing, when UV exposure cannot be avoided, even on days when it is not sunny or inside activities are expected.

5 WARNINGS AND PRECAUTIONS Local Skin Irritation : Tretinoin gel (microsphere) can cause local skin irritation, including excessive dryness, redness, swelling, peeling, itching, blistering, burning, or stinging ( 5.1 ) Avoid use on eczematous skin or during weather extremes, such as severe wind or cold. To reduce the risk of local skin irritation, wash the treated skin gently, using a mild, non-medicated soap, avoid washing the treated skin too often or scrubbing it hard when washing, and apply a topical moisturizer. If severe local skin irritation occurs, discontinue use temporarily or permanently. Initial Worsening of Inflammatory Acne Vulgaris : During the early weeks of tretinoin gel (microsphere) treatment, an apparent exacerbation of inflammatory lesions may occur. If tretinoin gel (microsphere) is tolerated, this should not be considered a reason to discontinue therapy. ( 5.2 ) Photosensitivity : Tretinoin gel (microsphere) can cause photosensitivity. Advise patients to avoid or minimize unnecessary exposure to UV light, including sunlight and sunlamps. Advise patients to use sunscreen (SPF ≥15) and sun-protective clothing if UV light exposure cannot be avoided. Avoid use on sunburn skin. ( 5.3 ) 5.1 Local Irritation Tretinoin gel (microsphere) can cause local skin irritation, including excessive dryness, redness, swelling, peeling, itching, blistering, burning, or stinging [see Adverse Reactions ( 6.1 )] . Use of tretinoin gel (microsphere) in greater than the recommended dosage (more frequent than once daily application or excessive application) will not result in more rapid or improved acne results and may result in marked redness, peeling, or discomfort. Tretinoin has been reported to cause severe local skin irritation on eczematous skin. Weather extremes, such as severe wind or cold, may increase the risk of skin irritation in patients using tretinoin gel (microsphere). To reduce the risk of local skin irritation, instruct tretinoin gel (microsphere) - treated patients to: Avoid use of tretinoin gel (microsphere) in areas affected by eczema. Minimize or avoid use of tretinoin gel (microsphere) with weather extremes. Wash the treated skin gently, using a mild, non-medicated soap, pat it dry, and avoid washing the treated skin too often or scrubbing it hard when washing. Tretinoin gel (microsphere) is not recommended with concomitant use of medicated or abrasive soaps and cleansers, products that have a strong drying effect, products with high concentrations of alcohol, astringents, spices, or lime peels. Apply a topical moisturizer. Advise patients that concomitant use of topical over the counter (OTC) acne products containing benzoyl peroxide, sulfur, resorcinol, or salicylic acid with tretinoin gel (microsphere) may increase the risk for local skin irritation including dryness, erythema, and peeling. Consider withholding the use of topical OTC acne products if signs of skin irritation develop. Advise patients to allow the skin irritation effects of the topical OTC acne products to subside before initiation of tretinoin gel (microsphere) treatment . If severe local skin irritation occurs, discontinue tretinoin gel (microsphere) use temporarily or permanently. Efficacy of tretinoin gel (microsphere) at reduced frequencies of application has not been established. 5.2 Initial Worsening of Inflammatory Acne Vulgaris During the early weeks of tretinoin gel (microsphere) treatment, an apparent exacerbation of inflammatory acne vulgaris lesions may occur. If tretinoin gel (microsphere) is tolerated, initial worsening of inflammatory acne vulgaris lesions should not be considered a reason to discontinue therapy. 5.3 Photosensitivity Tretinoin gel (microsphere) can cause photosensitivity. Advise patients to avoid or minimize unnecessary exposure to ultraviolet (UV) light, including sunlight and sunlamps, while using tretinoin gel (microsphere). Advise patients with sunburn to not use tretinoin gel (microsphere) until the sunburn fully recovers. Advise patients, especially those who may be required to have extended periods of UV light exposure (e.g., due to occupation or sports), those with inherent sensitivity to the sun, or those using drugs that cause photosensitivity, to use sun protection daily in the form of sunscreen (sun protection factor [SPF] ≥ 15) and sun- protective clothing, when UV exposure cannot be avoided, even on days when it is not sunny or inside activities are expected.

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. Tretinoin gel (microsphere), 0.04% and 0.1% In a double-blind trial, 156 subjects with acne vulgaris were treated for 12-weeks with tretinoin gel (microsphere) 0.04% (n=78) or 0.1% (n=78) topically once daily. In this trial, the most frequently reported adverse events affected the skin and subcutaneous tissue (15% in the 0.04% group, and 21% in the 0.1% group). The most prevalent events in the 0.04% group were skin irritation (6%); and in the 0.1% group, skin burning (8%), erythema (5%), skin irritation (4%), and dermatitis (4%). In this trial, 63% of the adverse events were of mild intensity, and 34% were of moderate intensity. 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of tretinoin gel (microsphere) and other topical tretinoin products. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure: Hyper- or hypopigmentation has been reported with repeated application of tretinoin.