Micro Drug Information

RETIN-A MICRO ® is indicated for the topical treatment of acne vulgaris in adults and pediatric patients 12 years of age and older.

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

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. Mean age was 19 years (range 11-40) and 55% were female. RETIN-A MICRO is not approved for use in pediatric patients younger than 12 years of age.

In Studies 1 and 2, subjects treated with RETIN-A MICRO, 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. During the 12-week treatment period, no more than 3% of RETIN-A MICRO, 0.1%-treated subjects had cutaneous irritation scores indicative of severe cutaneous irritation and 6% (14/224) of RETIN-A MICRO 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.

Mean age was 19 years (range 11-49) and 57% were female. Approximately half of the 225 subjects in the RETIN-A MICRO, 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 RETIN-A MICRO, 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 RETIN-A MICRO, 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. In this trial, 63% of the adverse events were of mild intensity, and 34% were of moderate intensity.

Postmarketing Experience

The following adverse reactions have been identified during post-approval use of RETIN-A MICRO 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.

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.

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 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 Retin-A Micro (tretinoin) Gel microsphere, 0.1%, applied daily to a 60 kg person (0.017 mg tretinoin/kg body weight).

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. 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. Doses were administered topically for six hours per day while pregnant rabbits were restrained in stocks to prevent ingestion. 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).

Supernumerary ribs have been a consistent finding in newborn rats when dams were treated topically or orally with retinoids. Oral administration of tretinoin during organogenesis has been shown to cause malformations in the offspring of rats, mice, rabbits, hamsters, and nonhuman primates. Fetal malformations and death were observed when tretinoin was orally administered to pregnant rats during organogenesis at doses greater than 1 mg/kg/day (10 times the MRHD based on BSA comparison).

Fetal malformations were reported at doses of 10 mg/kg/day or greater when administered to pregnant cynomolgus monkeys, 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-dependent increases in embryolethality and abortion also were reported. Similar results have also been reported in pigtail macaques.

In peri- and postnatal development studies in rats with oral 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). Oral tretinoin has been shown to be fetotoxic in rats when administered at doses 24 times the MRHD based on BSA comparison. Topical tretinoin has been shown to be fetotoxic in rabbits when administered at doses 10 times the MRHD based on BSA comparison.

Pediatric Use The safety and effectiveness of RETIN-A MICRO for topical application for the treatment of acne vulgaris have been established in pediatric patients aged 12 years and older. The safety and effectiveness of RETIN-A MICRO have not been established in pediatric patients younger than 12 years of age.

Oral ingestion of large amounts of RETIN-A MICRO 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.