1 INDICATIONS AND USAGE Retin-A Micro® (tretinoin) Gel microsphere, 0.1%, 0.08% and 0.04%, is a retinoid indicated for topical application in the treatment of acne vulgaris. Retin-A Micro (tretinoin) Gel microsphere, 0.1%, 0.08% and 0.04%, is a retinoid, indicated for topical treatment of acne vulgaris. (1)
3 DOSAGE FORMS AND STRENGTHS Retin-A Micro is a white to very pale yellow opaque gel. Retin-A Micro is available in three strengths: 0.04%, 0.08% and 0.1%. Each gram of Retin-A Micro Gel 0.1% contains 1 mg of tretinoin. Each gram of Retin-A Micro Gel 0.08% contains 0.8 mg of tretinoin. Each gram of Retin-A Micro Gel 0.04% contains 0.4 mg of tretinoin. Gel, 0.04%, 0.08% and 0.1% (3)
4 CONTRAINDICATIONS None. None. (4)
5 WARNINGS AND PRECAUTIONS •Retin-A Micro should not be used on eczematous or sunburned skin due to potential for severe irritation. (5.1) •Avoid unprotected exposure to sunlight including sunlamps (UV light), when using Retin-A Micro due to potential for increased photosensitization. Use sunscreen of at least SPF 15 and protective clothing during exposure. (5.2) • Avoid use of Retin-A Micro with weather extremes, such as wind or cold due to potential for increased irritation. (5.2) 5.1 Local Irritation The skin of certain individuals may become excessively dry, red, swollen, or blistered. Tretinoin has been reported to cause severe irritation on eczematous skin and should be used with utmost caution in patients with this condition. 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 a reaction suggesting sensitivity occurs, use of the medication should be discontinued. To help limit skin irritation, patients must •wash the treated skin gently, using a mild, non-medicated soap, and pat it dry, and •avoid washing the treated skin too often or scrubbing it hard when washing. Patients should apply a topical moisturizer if dryness is bothersome. 5.2 Exposure to Ultraviolet Light or Weather Extremes Unprotected exposure to sunlight, including sunlamps (UV light) should be avoided or minimized during the use of Retin-A Micro (tretinoin) Gel microsphere, 0.1%, 0.08% and 0.04%, 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 extended periods of UV exposure (e.g., due to occupation or sports), or those with inherent sensitivity to the sun, or those using medications that cause photosensitivity, should exercise particular caution. Use of sunscreen products (SPF15 or higher) and protective clothing over treated areas are recommended when exposure cannot be avoided [see Nonclinical Toxicology (13.1) ]. Weather extremes, such as wind or cold, also may be irritating to tretinoin-treated skin.
6 ADVERSE REACTIONS Most common adverse reactions are skin pain, pruritus, skin irritation/subcutaneous irritation, pharyngitis, and erythema. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Valeant Pharmaceuticals North America LLC at 1-800-321-4576 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. Clinical Trials in Subjects with Acne In separate clinical trials for each concentration, acne subjects treated with Retin-A Micro (tretinoin) Gel microsphere 0.1% or 0.04%, over the twelve week period showed that cutaneous irritation scores for erythema, peeling, dryness, burning/stinging, or itching peaked during the initial two weeks of therapy, decreasing thereafter. Approximately half of the subjects treated with Retin-A Micro 0.04% had cutaneous irritation at Week 2. Of those subjects who did experience cutaneous side effects, 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 patients experienced moderate cutaneous irritation and there was no severe irritation at Week 2. In trials of Retin-A Micro (tretinoin) Gel microsphere 0.04%, throughout the treatment period the majority of subjects experienced some degree of irritation (mild, moderate, or severe) with 1% (2/225) of subjects having scores indicative of a severe irritation; 1.3% (3/225) of subjects treated with Retin-A Micro (tretinoin) Gel microsphere, 0.04%, discontinued treatment due to irritation, which included dryness in one patient and peeling and urticaria in another. In trials of Retin-A Micro (tretinoin) Gel microsphere 0.1%, no more than 3% of subjects had cutaneous irritation scores indicative of severe irritation; 6% (14/224) of subjects treated with Retin-A Micro (tretinoin) Gel microsphere, 0.1% discontinued treatment due to irritation. Of these 14 subjects, four had severe irritation after 3 to 5 days of treatment, with blistering in one subject. In a double-blind trial with 156 acne subjects comparing 12 weeks of treatment with Retin-A Micro (tretinoin) Gel 0.04% or 0.1% (78 subjects each group), the most frequently-reported adverse events affected the skin and subcutaneous tissue (15.4% in the 0.04% group, and 20.5% in the 0.1% group). The most prevalent of the dermatologic adverse events in the 0.04% group was skin irritation (6.4%); and in the 0.1% group skin burning (7.7%), erythema (5.1%), skin irritation (3.8%), and dermatitis (3.8%). Most adverse events were of mild intensity (63.4%), and 34.4% were moderate. One subject in each group had adverse events characterized as severe, neither were dermatologic findings and neither was characterized as related to drug by the investigator. Trials in Subjects Without Acne In a half-face comparison trial conducted for up to 14 days in women with sensitive skin, but without acne, Retin-A Micro (tretinoin) Gel microsphere, 0.1% was statistically less irritating than tretinoin cream, 0.1%. In addition, a cumulative 21 day irritation evaluation in subjects with normal skin showed that Retin-A Micro (tretinoin) Gel microsphere, 0.1%, had a lower irritation profile than tretinoin cream, 0.1%. The clinical significance of these irritation studies for patients with acne is not established. Comparable effectiveness of Retin-A Micro (tretinoin) Gel microsphere, 0.1% and tretinoin cream, 0.1%, has not been established. The lower irritancy of Retin-A Micro (tretinoin) Gel microsphere, 0.1% in subjects without acne may be attributable to the properties of its vehicle. The contribution of decreased irritancy by the MICROSPONGE System has not been established. No irritation trials have been performed to compare Retin-A Micro (tretinoin) Gel microsphere, 0.04%, with either Retin-A Micro (tretinoin) Gel microsphere, 0.1%, or tretinoin cream, 0.1%. 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of Retin-A Micro Gel. 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 casual relationship to drug exposure. Temporary hyper- or hypopigmentation has been reported with repeated application of tretinoin.
8 USE IN SPECIFIC POPULATIONS •Retin-A Micro should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. There are no adequate and well-controlled studies in pregnant and nursing women. (8.1) 8.1 Pregnancy There are no adequate and well-controlled studies in pregnant women. Retin-A Micro® should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Thirty human cases of temporally associated congenital malformations have been reported during two decades of clinical use of Retin-A Micro® (tretinoin) Gel microsphere, 0.1% and 0.04%. Although no definite pattern of teratogenicity and no causal association has 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. For purposes of comparison of the animal exposure to systemic human exposure, the Maximum Recommended Human Dose (MRHD) applied topically is defined as 1 gram of Retin-A Micro® (tretinoin) Gel microsphere 0.1% applied daily to a 60 kg person (0.017 mg tretinoin/kg body weight). Pregnant rats were treated with Retin-A Micro (tretinoin) Gel microsphere, 0.1%, at daily dermal doses of 0.5 to 1 mg/kg/day on gestation days 6-15. Alterations were seen in vertebrae and ribs of offspring at 5 to 10 times the MRHD based on the body surface area (BSA) comparison. Pregnant New Zealand White rabbits were treated with Retin-A Micro (tretinoin) Gel microsphere, 0.1%, at daily dermal doses of 0.2, 0.5, and 1.0 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 0.5 and 1.0 mg/kg/day. Similar malformations were not observed at 0.2 mg/kg/day, 4 times the MRHD based on BSA comparison. Other pregnant rabbits exposed topically for six hours per day to 0.5 or 1.0 mg/kg/day tretinoin while restrained in stocks to prevent ingestion, did not show any teratogenic effects 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). 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 1 mg/kg/day (10 times the MRHD based on BSA comparison). In the cynomolgus monkey, fetal malformations were reported for doses of 10 mg/kg/day but none were observed at 5 mg/kg/day (95 times the MRHD based on BSA 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. There is evidence for teratogenicity (shortened or kinked tail) of topical tretinoin in Wistar rats at doses greater than 1 mg/kg/day (10 times the MRHD based on BSA comparison). Anomalies (humerus: short 13%, bent 6%, os parietal incompletely ossified 14%) have also been reported when 10 mg/kg/day was topically applied. Supernumerary ribs have been a consistent finding in rats when dams were treated topically or orally with retinoids. In oral peri- and postnatal development studies in rats with tretinoin, decreased survival of neonates and growth retardation were observed at doses in excess of 2 mg/kg/day (19 times the MRHD based on BSA comparison). Nonteratogenic effects on fetus Oral tretinoin has been shown to be fetotoxic when administered (in doses 24 times the MRHD based on BSA comparison). Topical tretinoin has been shown to be fetotoxic in rabbits when administered in doses 10 times the MRHD based on BSA 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 Retin-A Micro (tretinoin) Gel microsphere, 0.1%, 0.08% or 0.04%, is administered to a nursing woman. 8.4 Pediatric Use Safety and effectiveness in children below the age of 12 have not been established. 8.5 Geriatric Use Safety and effectiveness in a geriatric population have not been established. Clinical trials of Retin-A Micro® (tretinoin) Gel microsphere 0.1% and 0.04% did not include sufficient numbers of subjects aged 65 and over to determine whether they responded differently from younger subjects.