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 oral, ophthalmic, or intravaginal use. Prior to tretinoin gel (microsphere) use, thoroughly cleanse area(s) with a mild, non-medicated cleanser then pat the skin dry. When applying tretinoin gel (microsphere), keep away from the eyes, the mouth, paranasal creases of the nose, and mucous membranes. Apply a thin layer of tretinoin gel (microsphere), 0.08% to skin where acne lesions appear (cover the entire affected area), once daily in the evening. Do not apply more than a thin layer [see Warning and Precautions (5.1) ] . Improvements in acne lesions may be noticed after two weeks of tretinoin gel (microsphere) therapy, but more than seven weeks of therapy may be needed for sustained benefit. If tretinoin gel (microsphere) was temporarily discontinued due to local adverse reactions, tretinoin gel (microsphere) therapy may be resumed upon resolution of local adverse reactions. For topical use only. Not for oral, ophthalmic, or intravaginal use. (2) Keep away from eyes, mouth, paranasal creases of the nose, and mucous membranes. (2) Apply a thin layer of tretinoin gel (microsphere) to skin where acne lesions appear (cover the entire affected area) once daily in the evening. (2)

5 WARNINGS AND PRECAUTIONS Local Skin Irritation: Tretinoin gel 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 treatment, an apparent exacerbation of inflammatory lesions may occur. If tretinoin gel is tolerated, this should not be considered a reason to discontinue therapy. (5.2) Photosensitivity: Tretinoin gel 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 Skin Irritation Tretinoin gel 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 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. To reduce the risk of local skin irritation, instruct tretinoin gel treated patients to: Avoid use of tretinoin gel in areas affected by eczema. Minimize or avoid use of tretinoin gel 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 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 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 treatment. If severe local skin irritation occurs, discontinue tretinoin gel use temporarily or permanently. Efficacy of tretinoin gel at reduced frequencies of application has not been established. 5.2 Initial Worsening of Inflammatory Acne Vulgaris During the early weeks of tretinoin gel treatment, an apparent exacerbation of inflammatory acne vulgaris lesions may occur. If tretinoin gel is tolerated, initial worsening of inflammatory acne vulgaris lesions should not be considered a reason to discontinue therapy. 5.3 Photosensitivity Tretinoin gel can cause photosensitivity. Advise patients to avoid or minimize unnecessary exposure to ultraviolet (UV) light, including sunlight and sunlamps, while using tretinoin gel. Advise patients with sunburn to not use tretinoin gel 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 …

4 CONTRAINDICATIONS None. None. (4)

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 (microsponge) 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 (microsponge) 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 (microsponge) at daily dermal doses of 0.2, 0.5, and 1 mg/kg/day tretinoin on gestation days 6 to 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 (microsponge) at daily dermal doses of 0.2, 0.5, and 1 mg/kg/day tretinoin on gestation days 7 to 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 (microsponge) at daily dermal doses of 0.5 or 1 mg/kg/day tretinoin on gestation days 7 to 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 administration of tretinoin du…

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 Amneal Pharmaceuticals at 1-877-835-5472 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, 0.1% The safety of tretinoin gel, 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, 0.1% and 175 subjects received vehicle, applied topically once daily in the evening, for 12 weeks. Mean age was 19 years (range 11 to 40) and 55% were female [see Clinical Studies (14.1) ] . Tretinoin gel 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, 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, 0.1%-treated subjects had cutaneous irritation scores indicative of severe cutaneous irritation and 6% (14/224) of tretinoin gel, 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, 0.04% The safety of tretinoin gel, 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, 0.04% and 226 subjects received vehicle, applied once daily in the evening, for 12 weeks. Mean age was 19 years (range 11 to 49) and 57% were female [see Clinical Studies (14.2) ] . Tretinoin gel 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, 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, 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, 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, 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, 0.04% and 0.1% In a double-blind trial, 156 subjects with acne vulgaris were treated for 12-weeks with tretinoin gel, 0.04% (n=78) or 0.1% (n=78) topically once daily. In this trial, the most freque…