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Chemically, tretinoin is all-trans-retinoic acid, also known as (all-E)-3,7-dimethyl-9-(2,6,6-trimethyl-1cyclohexen-1-yl)-2,4,6,8-nonatetraenoic acid. Tretinoin is a retinoid and a metabolite of naturally occurring Vitamin A. Tretinoin has a molecular weight of 300.44, a molecular formula of C20H28O2 and the following chemical structure:
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RETIN-A MICRO (tretinoin) gel is for topical use. Each gram of RETIN-A MICRO gel:
The formulation contains methyl methacrylate/glycol dimethacrylate crosspolymer (MICROSPONGE® System), propylene glycol dicaprylate/dicaprate and butylated hydroxytoluene. Other components consist of benzyl alcohol, butylated hydroxytoluene, carbomer 974P, cyclomethicone and dimethicone copolyol, disodium EDTA, glycerin, PPG-20 methyl glucose ether distearate, propylene glycol, purified water, sorbic acid, and trolamine.
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.
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.
Gel (white to very pale yellow and opaque):
RETIN-A MICRO (tretinoin) gel is opaque and white to very pale yellow in color and is supplied as follows:
| Strength | Amount of Tretinoin in One Gram of Gel | Quantity/Package Type | NDC |
| 0.04% | 0.4 mg | 20 gram tube | 0187-5144-20 |
| 45 gram tube | 0187-5144-45 | ||
| 50 gram pump | 0187-5144-50 | ||
| 0.06% | 0.6 mg | 50 gram pump | 0187-5146-50 |
| 0.08% | 0.8 mg | 50 gram pump | 0187-5148-50 |
| 0.1% | 1 mg | 20 gram tube | 0187-5140-20 |
| 45 gram tube | 0187-5140-45 | ||
| 50 gram pump | 0187-5140-50 |
Store at 20° to 25°C (68° to 77°F); excursions permitted from 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature].
Store pump upright.
Distributed by:Bausch Health US, LLC Bridgewater, NJ 08807 USA
Included as part of the PRECAUTIONS section.
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 RETINA MICRO.
To reduce the risk of local skin irritation, instruct RETIN-A MICRO-treated patients to:
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.
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.
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 sunprotective clothing, when UV exposure cannot be avoided, even on days when it is not sunny or inside activities are expected.
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. 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 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).
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. 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.
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.
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.
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).
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.
Pharmacodynamics
The pharmacodynamics of RETIN-A MICRO is unknown.
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-cisretinoic 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%.
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. 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:
Table 1: Mean Percent Reduction in Lesion Counts in Subjects with Acne Vulgaris at Week 12 in Studies
1 and 2
| Retin-A Micro (tretinoin gel) microsphere, 0.1% | Vehicle Gel | |||
| Study #1 72 pts |
Study #2 71 pts |
Study #1 72 pts |
Study #2 67 pts |
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| Non-inflammatory lesion counts | 49% | 32% | 22% | 3% |
| Inflammatory lesion counts | 37% | 29% | 18% | 24% |
| Total lesion counts | 45% | 32% | 23% | 16% |
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
