5.1 Local Skin Irritation

RETIN-A MICRO can cause local skin irritation, including excessive dryness, redness, swelling, peeling, itching, blistering, burning, or stinging [see Adverse Reactions (6.1)]. Use of RETIN-A MICRO 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 RETIN-A MICRO.

To reduce the risk of local skin irritation, instruct RETIN-A MICRO-treated patients to:

•

Avoid use of RETIN-A MICRO in areas affected by eczema.

•

Minimize or avoid use of RETIN-A MICRO 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. RETIN-A MICRO 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 RETIN-A MICRO 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 RETIN-A MICRO treatment.

If severe local skin irritation occurs, discontinue RETIN-A MICRO use temporarily or permanently.

Efficacy of RETIN-A MICRO at reduced frequencies of application has not been established.

5.2 Initial Worsening of Inflammatory Acne Vulgaris

During the early weeks of RETIN-A MICRO treatment, an apparent exacerbation of inflammatory acne vulgaris lesions may occur. If RETIN-A MICRO is tolerated, initial worsening of inflammatory acne vulgaris lesions should not be considered a reason to discontinue therapy.

5.3 Photosensitivity

RETIN-A MICRO can cause photosensitivity. Advise patients to avoid or minimize unnecessary exposure to ultraviolet (UV) light, including sunlight and sunlamps, while using RETIN-A MICRO. Advise patients with sunburn to not use RETIN-A MICRO 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.

6.1 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.

RETIN-A MICRO, 0.1%

The safety of RETIN-A MICRO, 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 RETIN-A MICRO, 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)]. RETIN-A MICRO 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 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 [see Warnings and Precautions (5.1)]. 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.

RETIN-A MICRO, 0.04%

The safety of RETIN-A MICRO, 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 RETIN-A MICRO, 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)]. RETIN-A MICRO 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 RETIN-A MICRO, 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 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.

RETIN-A MICRO, 0.04% and 0.1%

In a double-blind trial, 156 subjects with acne vulgaris were treated for 12-weeks with RETIN-A MICRO 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 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.

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 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 0.1% tretinoin gel (microsponge) 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 (microsponge) 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 (microsponge) 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 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.

8.2 Lactation

Risk Summary

There are no data on the presence of tretinoin or its metabolites in human milk, the effects on the breastfed infant, or the effects on milk production. It is not known whether topical administration of tretinoin could result in sufficient systemic absorption to produce detectable quantities in human milk (see Clinical Considerations).

The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for RETIN-A MICRO and any potential adverse effects on the breastfed infant from the RETIN-A MICRO or from the underlying maternal condition.

Clinical Considerations

To minimize potential exposure to the infant via human milk, during breastfeeding, use RETIN-A MICRO on the smallest area of skin with acne and for the shortest duration possible. Advise breastfeeding women not to apply RETIN-A MICRO directly to the nipple and areola to avoid direct infant exposure.

8.4 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 [see Clinical Studies (14)]. The safety and effectiveness of RETIN-A MICRO have not been established in pediatric patients younger than 12 years of age.

8.5 Geriatric Use

Clinical trials of RETIN-A MICRO did not include sufficient numbers of subjects aged 65 and over to determine whether they responded differently from younger adult subjects. Acne vulgaris is largely a disease of pediatric and young adult patients. Clinical studies of RETIN-A MICRO did not include patients 65 years of age and older.

12.1 Mechanism of Action

Although tretinoin activates three members of the retinoic acid (RAR) nuclear receptors (RARα, RARβ, and RARγ) which may 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 and/or other mechanisms.

The exact mechanism of action of topical tretinoin for treatment of acne vulgaris is unknown. Current evidence suggests that topical tretinoin decreases cohesiveness of follicular epithelial cells with decreased microcomedone formation. Additionally, tretinoin stimulates mitotic activity and increased turnover of follicular epithelial cells causing extrusion of the comedones.

12.3 Pharmacokinetics

Absorption

Tretinoin is a metabolite of Vitamin A. Percutaneous absorption, as determined by the cumulative excretion of radiolabeled drug into urine and feces, was assessed in 44 healthy males and females after single and repeated daily tretinoin applications up to 28 days of 500 mg of a 0.1% tretinoin gel product. In this assessment, estimates of in vivo bioavailability, mean (SD) were 0.82 (0.11)% and 1.41 (0.54)%, for single and multiple daily topical applications, respectively. The plasma concentrations of tretinoin and its metabolites, 13-cis-retinoic acid, all-trans-4-oxo-retinoic acid, and 13-cis-4-oxo-retinoic acid, generally ranged from 1 to 3 ng/mL and were essentially unaltered after either single or multiple daily applications of RETIN-A MICRO, 0.1%, relative to baseline levels.

Clinical pharmacokinetic studies have not been performed with RETIN-A MICRO, 0.08%, 0.06% and 0.04%.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Dermal carcinogenicity testing has not been performed with RETIN-A MICRO (tretinoin) gel microsphere, 0.04%, 0.06%, 0.08%, or 0.1%.

In a 91-week dermal study in which CD-1 mice were administered 0.017% and 0.035% formulations of tretinoin, cutaneous squamous cell carcinomas and papillomas in the treatment area were observed in some female mice. These concentrations are near the tretinoin concentration of the 0.04% and 0.1% clinical formulations. A dose-dependent incidence of liver tumors in male mice was observed at those same doses. The maximum systemic doses associated with the administered 0.017% and 0.035% formulations are 0.5 and 1 mg/kg/day tretinoin, respectively. These doses are two and four times the MRHD based on BSA comparison.

The biological significance of these findings is not clear because they occurred at doses that exceeded the dermal maximally tolerated dose of tretinoin and because they were within the background natural occurrence rate for these tumors in this strain of mice. There was no evidence of carcinogenic potential when 0.025 mg/kg/day of tretinoin was administered topically to mice (0.1 times the MRHD based on BSA comparison). Studies in hairless albino mice suggest that concurrent exposure to tretinoin may enhance the tumorigenic potential of carcinogenic doses of UVB and UVA light from a solar simulator. This effect has been confirmed in a later study in pigmented mice, and dark pigmentation did not overcome the enhancement of photocarcinogenesis by 0.05% tretinoin. Although the significance of these studies to humans is not clear, patients should minimize exposure to sunlight or artificial ultraviolet irradiation sources [see Warnings and Precautions (5.3)].

The genotoxic potential of tretinoin was evaluated in the Ames assay and an in vivo mouse micronucleus assay. Both tests were negative.

The components of the microspheres have shown potential for genetic toxicity and fetal malformation. EGDMA, a component of the excipient acrylates copolymer, was positive for induction of structural chromosomal aberrations in an in vitro chromosomal aberration assay in mammalian cells in the absence of metabolic activation, and negative for genetic toxicity in the Ames assay, and an in vivo mouse micronucleus assay.

In fertility studies in rats with oral tretinoin, the no-observable effect level was 2 mg/kg/day (19 times the MRHD based on BSA comparison).

14.1 Clinical Studies with RETIN-A MICRO, 0.1%

The efficacy of RETIN-A MICRO, 0.1 was evaluated in two double-blind, randomized, vehicle-controlled trials in adult and pediatric subjects 11 years of age and older with acne vulgaris (Studies 1 and 2). RETIN-A MICRO is not approved for use in pediatric patients younger than 12 years of age [see Indications and Usage (1)]. RETIN-A MICRO, 0.1%, applied topically once daily in the evening, was superior to vehicle gel, applied topically once daily, in reducing the acne lesion counts. The mean reduction in lesion counts from baseline after treatment for 12 weeks are shown in Table 1:

Efficacy was also assessed by the investigator’s global evaluation, which included categories of “excellent”, “good”, “fair”, “no change”, and “poor”. RETIN-A MICRO 0.1%, was significantly superior (p<0.001) to the vehicle in the investigator’s global evaluation of the clinical response:

•

In Study #1, 35% of RETIN-A MICRO 0.1% -treated subjects achieved an “excellent” result, as compared to 11% of vehicle-treated subjects.

•

In Study #2, 28% of RETIN-A MICRO 0.1%-treated subjects achieved an “excellent” result, as compared to 9% of vehicle-treated subjects.

14.2 Clinical Studies with RETIN-A MICRO, 0.04%

 

In two vehicle-controlled clinical trials in adult and pediatric subjects 11 years of age and older with acne vulgaris (Studies 3 and 4). RETIN-A MICRO is not approved for use in pediatric patients younger than 12 years of age [see Indications and Usage (1)]. RETIN-A MICRO, 0.04%, applied topically once daily in the evening, was more effective (p<0.05) than vehicle gel, applied topically once daily, in reducing the acne lesion counts. The mean reduction in lesion counts from baseline after treatment for 12 weeks are shown in Table 2:

Table 2: Mean Percent Reduction in Lesion Counts in Subjects with Acne Vulgaris at Week 12 in Studies 3 and 4

Efficacy was also assessed by the investigator’s global evaluation, which included categories of “excellent”, “good”, “fair”, “no change”, and “poor”. RETIN-A MICRO 0.04% was superior (p<0.05) to the vehicle in the investigator's global evaluation of the clinical response:

•

In Study #3, 14% of RETIN-A MICRO 0.04%-treated subjects achieved an “excellent” result, as compared to 5% of vehicle-treated subjects.

•

In Study #4, 19% of RETIN-A MICRO 0.04%-treated subjects achieved an “excellent” result, as compared to 9% of vehicle-treated subjects.

Patient Information