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Retin-A Micro (tretinoin gel) microsphere, 0.1%, is a formulation containing 0.1% by weight tretinoin for the topical treatment of acne vulgaris. This formulation uses patented methy methacrylate/glycol dimethacrylate crosspolymer porous microspheres (MICROSPONGE® System) to enable inclusion of the active ingredient, tretinoin, in an aqueous gel. Other components of this formulation are purified water, carbomer 934P, glycerin, disodium EDTA, propylene glycol, sorbic acid, PPG-20 methyl glucose ether distearate, cyclomethicone and dimethicone copolyol, benzyl alcohol, trolamine, and butylated hydroxytoluene.
Chemically, tretinoin is all- trans -retinoic acid, also known as (all-E) 3,7-dimethyl-9-(2,6,6-trimethyl-1-cyclohexen-1-yl)-2,4,6,8-nonatetraenoic acid. It is a member of the retinoid family of compounds, and an endogenous metabolite of naturally occurring Vitamin A. Tretinoin has the following structure:
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Mode of Action: Although the exact mode of action of tretinoin is unknown, current evidence suggests that the effectiveness of tretinoin in acne is due primarily to its ability to modify abnormal follicular keratinization. Comedones form in follicles with an excess of keratinized epithelial cells. Tretinoin promotes detachment of cornified cells and the enhanced shedding of corneocytes from the follicle. By increasing the mitotic activity of follicular epithelia, tretinoin also increases the turnover rate of thin, loosely-adherent corneocytes. Through these actions, the comedo contents are extruded and the formation of the microcomedo, the precursor lesion of acne vulgaris, is reduced.
Additionally, tretinoin acts by modulating the proliferation and differentiation of epidermal cells. These effects are mediated by tretinoin' interaction with a family of nuclear retinoic acid receptors. Activation of these nuclear receptors causes changes in gene expression. The exact mechanisms whereby tretinoin-induced changes in gene expression regulate skin function are not understood.
In clinical trials with acne patients treated with Retin-A Micro (tretinoin gel) microsphere, 0.1%, analysis over the twelve week treatment period showed that cutaneous irritation scores for erytherna, peeling, burning/stinging, or itching peaked during the initial 2 weeks of therapy, decreasing thereafter. Throughout, no more than 3% of patients had scores indicative of a severe irritation rating; although, 6% (14/224) of patients treated with Retin-A Micro (tretinoin gel) microsphere, 0.1%, discontinued treatment due to irritation. Of these 14 patients, four had severe irritation after 3 to 5 days of treatment, with blistering in one patient.
Results in studies of 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 to decreased irritancy by the MICROSPONGE® System has not been established.
Tretinoin is an endogenous metabolite of Vitamin A metabolism in man. Percutaneous absorption, as determined by the cumulative excretion of radiolabeled drug into urine and feces, was assessed in 44 healthy men and women. Estimates of in vivo bioavailability, mean (SD) %, following both single and multiple daily applications, for a period of 28 days, were 0.82 (0.11)% and 1.41 (0.54)%, 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 relative to baseline levels.
Retin-A Micro (tretinoin gel) microsphere, 0.1%, is indicated for topical application in the treatment of acne vulgaris. The safety and efficacy of the use of this product in the treatment of other disorders have not been established.
In two vehicle-controlled clinical studies, Retin-A Micro (tretinoin gel) microsphere, 0.1%, applied once daily was significantly more effective than vehicle in reducing the severity of acne lesion counts. The mean reductions in lesion counts from baseline after treatment for 12 weeks are shown in the following table:
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Retin-A Micro (tretinoin gel) microsphere, 0.1%, was also significantly superior to the vehicle in the investigator's global evaluation of the clinical response. In study #1, thirty-five percent (35%) of patients using Retin-A Micro (tretinoin gel) microsphere, 0.1%, achieved an excellent result compared to eleven percent (11%) of patients on vehicle control. In study #2, twenty-eight percent (28%) of patients using Retin-A Micro (tretinoin gel) microsphere, 0.1%, achieved an excellent result compared to nine percent (9%) of patients on vehicle control.
This drug is contraindicated in individuals with a history of sensitivity reactions to any of its components. It should be discontinued if hypersensitivity to any of its ingredients is noted.
General: The skin of certain individuals may become excessively dry, red, swollen, or blistered. 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. Excessive skin dryness may also be experienced; if so, use of an appropriate emollient during the day may be helpful. Unprotected exposure to sunlight, including sunlamps, should be minimized during the use of Retin-A Micro (tretinoin gel) microsphere, 0.1%, 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 considerable sun exposure due to their occupation and those with inherent sensitivity to the sun should exercise particular caution. Use of sunscreen products (SPF 15) and protective clothing over treated areas are recommended when exposure cannot be avoided. Weather extremes, such as wind or cold, also may be irritating to patients being treated with tretinoin. Retin-A Micro (tretinoin gel) microsphere, 0.1%, should be kept away from the eyes, the mouth, paranasal creases of the nose, and mucous membranes. Tretinoin has been reported to cause severe irritation on eczematous skin and should be used with utmost caution in patients with this condition.
Information for Patients: See Patient Information leaflet.
Drug Interactions: Concomitant topical medication, medicated or abrasive soaps and cleansers, products that have a strong drying effect, products with high concentrations of alcohol, astringents, or spices should be used with caution because of possible interaction with tretinoin. Avoid contact with the peel of limes. Particular caution should be exercised with the concomitant use of topical over-the-counter acne preparations containing benzoyl peroxide, sulfur, resorcinol, or salicylic acid with Retin-A Micro (tretinoin gel) microsphere, 0.1%. It also is advisable to allow the effects of such preparations to subside before use of Retin-A Micro (tretinoin gel) microsphere, 0.1%, is begun.
Carcinogenesis, Mutagenesis, Impairment of Fertility: In a life-time dermal study in CD-1 mice, there was no evidence of carcinogenic potential when tretinoin was administered topically at a dose of 1.25 times the recommended clinical dose. For purposes of comparisons of animal exposure to human exposure, the "recommended human clinical dose" is defined as 1.0 g of 0.1% Retin-A Micro (tretinoin gel) microsphere applied to a 50 kg person. In the same study, at 25 and 50 times the recommended human clinical dose, the dermal maximum tolerated dose (MTD) of tretinoin was exceeded, yet there were no biologically significant findings.
Dermal carcinogenicity testing has not been performed with the microspheres or Retin-A Micro (tretinoin gel) microsphere, 0.1%. The components of the microspheres have not demonstrated carcinogenic potential when evaluated individually. The components of the microspheres have shown mutagenic and teratogenic potential with chronic exposure at doses several orders of magnitude higher than the human clinical dose. The very low levels of these components in microsponge polymer (< 25 ppm), used in the drug formulation, indicate an insignificant human risk under usage conditions.
Studies in hairless albino mice suggest that tretinoin may enhance the tumorigenic potential of ultraviolet (UV) light from a solar simulator. In other studies, when lightly pigmented hairless mice treated with tretinoin were exposed to carcinogenic doses of UVA/UVB light, the incidence and rate of development of skin tumors were either reduced or no effect was seen. Due to significantly different experimental conditions, no strict comparison of these disparate data is possible. Although the significance of these studies to humans is not clear, patients should avoid or minimize exposure to sun.
Tretinoin had no mutagenic potential when evaluated in the Ames assay and the in vivo mouse micronucleus assay.
The microspheres had no mutagenic potential when evaluated in the Ames assay.
Dermal fertility and perinatal development studies with Retin-A Micro (tretinoin gel) microsphere, 0.1%, have not been performed in any species. In oral fertility and perinatal development studies in rats with tretinoin, decreased survival of neonates and growth retardation were observed at doses in excess of 2 mg/kg/day (> 100 times the recommended human clinical dose which is 1.0 g/50kg adult).
Pregnancy: Teratogenic effects. Pregnancy Category C. No teratogenic effects were seen in pregnant rats with topical application of Retin-A Micro (tretinoin gel) microsphere, 0.1%, at doses up to 50 times the recommended daily human topical dose. In one study in New Zealand white rabbits treated with Retin-A Micro (tretinoin gel) microsphere, 0.1%, where doses of 0.2, 0.5 and 1.0 mg/kg/day of tretinoin were administered topically for 24 hours a day to pregnant rabbits, there appeared to be an association of the dosages with increased incidences of domed head and hydrocephaly in some of the fetuses, typical of retinoid-induced fetal malformations in this species. No abnormalities were observed at 0.2 mg/kg/day, 10 times the normal human topical dose of tretinoin. In a repeat study of the highest topical dose (1.0 mg/kg/day) in pregnant rabbits, these effects were not seen. Other pregnant rabbits exposed to six hours of 0.5 or 1.0 mg/kg/day tretinoin with proper controls to prevent oral ingestion, did not show any teratogenic effects up to 50 times (1.0 mg/kg/day) the human topical dose. In addition, topical tretinoin in non Retin-A Micro (tretinoin gel) microsphere, 0.1%, formulations was not teratogenic in rats and rabbits when given in doses of 250 and 80 times the recommended human clinical topical dose, respectively, (assuming a 50 kg adult applied a daily dose of 1.0 g of 0.1% gel topically). At these topical doses, however, delayed ossification of several bones occurred in rabbits. In rats, a dose-dependent increase of supernumerary ribs was observed.
Oral tretinoin has been shown to be teratogenic in rats, mice, rabbits, hamsters, and subhuman primates. Tretinoin is teratogenic in rats when given orally in doses 500 times the human clinical topical dose. However, variations in teratogenic doses among various strains of rats have been reported. In the cynomolgus monkey, which metabolically is more similar to humans than other species in its handling of tretinoin, no malformations were reported at 5 mg/kg/day (250 times the recommended human clinical topical dose), although increased skeletal variations were observed. A dose-related increased embryolethality was also reported. Similar results have also been reported in pigtail macaques.
There have been isolated reports of birth defects among babies born to women exposed to topical tretinoin during pregnancy. To date, there have been no adequate and well-controlled studies performed in pregnant women, and the teratogenic blood level of tretinoin is not known. However, a well-conducted retrospective cohort study of babies born to women exposed to topical tretinoin during the first trimester of pregnancy found no excess birth defects among these babies when compared to babies born to women in the same cohort who were not similarly exposed. Nevertheless, topical tretinoin should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Pregnancy: Non-teratogenic Effects: Oral tretinoin has been shown to be fetotoxic in rats when administered in doses 125 times the recommended human clincal topical dose.
Preclinical toxicity studies: In male mice treated topically with Retin-A Micro (tretinoin gel) microsphere, 0.1%, at 0.5, 2.0 or 5.0 mg/kg/day tretinoin (25, 100 or 250 times the recommended human dose) for 90 days, a reduction in testicular weight, but with no pathological changes, was observed at 100 and 250 times the human topical dose. Similarly, in female mice, there was a reduction in ovarian weights, but without any underlying pathological changes, at 5.0 mg/kg/day (250 times the recommended human dose). In this study there was a dose-related increase in the plasma concentration of tretinoin 4 hours after the first dose. A separate toxicokinetic study in mice indicates that systemic exposure is greater after topical application to unrestrained animals than to restrained animals, suggesting that the systemic toxicity observed is probably related to oral ingestion. Male and female dogs treated with Retin-A Micro (tretinoin gel) microsphere, 0.1%, at 0.2, 0.5 or 1.0 mg/kg/day tretinoin (10, 25 or 50 times the human dose, respectively) for 90 days showed no evidence of reduced testicular or ovarian weights or pathological changes.
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%, is administered to a nursing woman.
Pediatric Use: Safety and effectiveness in children below the age of 12 have not been established.
Geriatric Use: Safety and effectiveness in a geriatric population have not been established.
The skin of certain sensitive individuals may become excessively red, edematous, blistered, or crusted. If these effects occur, the medication should be either discontinued until the integrity of the skin is restored, or the medication should be adjusted temporarily to a level the patient can tolerate. However, efficacy has not been established for lower dosing frequencies. True contact allergy to topical tretinoin is rarely encountered. Temporary hyper- or hypopigmentation has been reported with repeated application of tretinoin. Some individuals have been reported to have heightened susceptibility to sunlight while under treatment with tretinoin. To date, all adverse effects of tretinoin have been reversible upon discontinuance of therapy (see Dosage and Administration Section).
Retin-A Micro (tretinoin gel) microsphere, 0.1%, is intended for topical use only. If medication is applied excessively, no more rapid or better results will be obtained, and marked redness, peeling, or discomfort may occur. Oral ingestion of large amounts of the drug may lead to the same side effects as those associated with excessive oral intake of Vitamin A.
Retin-A Micro (tretinoin gel) microsphere, 0.1%, should be applied once a day, before retiring, to the skin areas where acne lesions appear, using enough to cover the entire affected area lightly. Application of excessive amounts of gel may result in "caking" of the gel, and will not provide incremental efficacy.
A transitory feeling of warmth or slight stinging may be noted on application. In cases where it has been necessary to temporarily discontinue therapy or to reduce the frequency of application, therapy may be resumed or the frequency of application increased as the patient becomes able to tolerate the treatment. Frequency of application should be closely monitored by careful observation of the clinical therapeutic response and skin tolerance. Efficacy has not been established for less than once daily dosing frequencies.
During the early weeks of therapy, an apparent exacerbation of inflammatory lesions may occur. If tolerated, this should not be considered a reason to discontinue therapy.
Therapeutic results may be noticed after two weeks, but more than seven weeks of therapy are required before consistent beneficial effects are observed.
Patients treated with Retin-A Micro (tretinoin gel) microsphere, 0.1%, may use cosmetics, but the areas to be treated should be cleansed thoroughly before the medication is applied.
Retin-A Micro (tretinoin gel) microsphere, 0.1%, is supplied as:
20g (NDC 0062-0190-02) and 45g (NDC 0062-0190-03) tubes.
Storage Conditions: Store at 15°-25°C (59°-77°F).
Rx only.
Ortho Dermatological
Division of Ortho-McNeil Pharmaceutical, Inc.
Skillman, New Jersey 08558
©OPC 1999 Revised November 1999 643-11-477-4
Retin-A® Micro® is a registered trademark of Ortho-McNeil Pharmaceutical, Inc.
MICROSPONGE® is a registered trademark of Advanced Polymer Systems, Inc., Redwood City, CA
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