Retin-A Micro Product Monograph

CLINICAL PHARMACOLOGY

RETIN-A MICRO tretinoin gel (microsphere) is a novel formulation containing either 0.1% w/w or 0.04% w/w tretinoin by weight for the topical treatment of acne vulgaris.

Tretinoin is a member of the retinoid family of compounds, and an endogenous metabolite of Vitamin A.

Tretinoin is highly effective in the treatment of acne, although the exact mode of action of tretinoin is unknown. Current evidence suggests that this efficacy is due primarily to the ability of tretinoin to modify abnormal follicular keratinization. Comedones form in follicles due to abnormal keratinization and intercellular cohesiveness, with an excess of keratin retained in the follicle. 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 rates 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’s 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.

This formulation uses patented methyl methacrylate/glycol dimethacrylate crosspolymer porous microspheres (MICROSPONGE System) to enable inclusion of the active ingredient, tretinoin, in an aqueous gel.

Irritation Potential

Although tretinoin is intrinsically irritating to the skin, RETIN-A MICRO (microsphere) 0.1% w/w, was found to be significantly less irritating than RETIN-A Cream, 0.1% w/w, in a cumulative 21-day irritation test in subjects with normal skin. In addition, a half-face comparative irritation trial conducted for up to 14 days in women with sensitive skin, without acne, RETIN-A MICRO (microsphere) 0.1% w/w, was statistically less irritating than tretinoin cream, 0.1% w/w (Table 1). [See PHARMACOLOGY –Irritation Potential subsection.] There were no comparative studies conducted between RETIN-A MICRO (microsphere) 0.1% w/w and 0.04% w/w to assess comparative irritation potential.

Table 1: RETIN-A MICRO 0.04% w/w Overview of Cutaneous Treatment Effects. Percentage of patients experiencing symptoms

Pharmacokinetics

Tretinoin is an endogenous metabolite of Vitamin A metabolism in man. Percutaneous absorption of RETIN-A MICRO (microsphere), as determined by the cumulative excretion of radio-labelled 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.

Clinical Trials RETIN-A MICRO (microsphere) 0.04% w/w

In two large vehicle-controlled clinical studies, RETIN-A MICRO (microsphere) 0.04% w/w, applied once daily was significantly more effective than vehicle in reducing the severity of acne lesion counts. A total of 451 subjects with acne vulgaris were enrolled in the 2 controlled clinical studies. Of these 225 subjects applied RETIN-A MICRO (microsphere) 0.04% w/w. The severity of acne experienced by patients enrolled in these studies is shown in Table 2.

Table 2: Baseline severity of acne

The mean reductions in lesion counts from baseline after treatment for 12 weeks are shown in Table 3.

Table 3: Mean (LS Mean) Percent Reduction in Lesion Counts from BL to

Week 12 RETIN-A MICRO 0.04% w/w ITT/LOCF

Lesion Count

vehicle

It takes 6-8 weeks to see significant clinical benefit from applying RETIN-A MICRO (microsphere) 0.04% w/w to acne lesions. There are no comparative studies between RETIN-A MICRO (microsphere) 0.04% w/w and 0.1% w/w.

RETIN-A MICRO (microsphere) 0.04% w/w was also significantly superior to the vehicle in the investigator’s global evaluation of the clinical response. In study #1 14% of subjects using RETIN-A MICRO (microsphere) 0.04% w/w achieved an excellent result compared to 5% (p < 0.0001) of patients on vehicle control. In study #2, 19% of subjects using RETIN-A MICRO (microsphere) 0.04% w/w achieved an excellent result compared to 9% (p=0.0052) of subjects on vehicle control.

Clinical Trials RETIN-A MICRO (microsphere) 0.1% w/w

In two vehicle-controlled clinical studies, RETIN-A MICRO (microsphere) 0.1% w/w 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 Table 4.

Table 4: Mean percent reduction from BL to Week 12

RETIN-A MICRO 0.1% w/w studies

Lesion Count

Vehicle gel

Therapeutic results may be noticed after two weeks, but more than four weeks are required before consistent beneficial results are observed. In each study, at each return visit, there was a greater mean percent reduction in total lesion count with RETIN-A MICRO (microsphere) 0.1% w/w than with vehicle (Table 5).

Table 5: Mean percent reduction from baseline in total lesion counts over time, subjects valid for efficacy

RETIN-A MICRO 0.1% w/w studies

RETIN-A MICRO (microsphere) 0.1% w/w was also significantly superior to the vehicle in the investigator’s global evaluation of the clinical response. In study #1, 35% of patients using RETIN-A MICRO (microsphere) 0.1% w/w achieved an excellent result compared to 11% of patients on vehicle control. In study #2, 28% of patients using RETIN-A MICRO (microsphere) 0.1% w/w achieved an excellent result compared to 9% of patients on vehicle control.

INDICATIONS AND CLINICAL USE

RETIN-A MICRO tretinoin gel (microsphere) is indicated for topical application in the treatment of acne vulgaris.

CONTRAINDICATIONS

RETIN-A MICRO tretinoin gel (microsphere) 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.

WARNINGS

General

The skin of certain sensitive individuals may become excessively dry, red, swollen, or blistered. 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. Excessive skin dryness may also be experienced; if so, use of an appropriate emollient during the day may be helpful.

RETIN-A MICRO tretinoin gel (microsphere) should be kept away from the eyes, the mouth, angles 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. If a reaction suggesting sensitivity or chemical irritation occurs, use of the medication should be discontinued. [See PRECAUTIONS

• General Precautions subsection.]

Use in Pregnancy: Topical tretinoin should be used by women of childbearing years only after contraceptive counselling. It is recommended that topical tretinoin should not be used by pregnant women.

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 prospective 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 with babies born to women in the same cohort who were not similarly exposed.

Oral tretinoin has been shown to be teratogenic and fetotoxic in rats when given in doses 1000 and 500 times the topical human dose, respectively.

In nine (9) out of ten (10) teratology studies of topical tretinoin conducted in rats and rabbits using several formulations, there has been no evidence of teratogenicity. In one (1) out of ten (10) studies there was an increase in fetal malformations; however, a clear causal relationship of topical tretinoin in these findings could not be established. In a repeat of this study, there were no fetal malformations. Topical tretinoin can produce treatment-related fetal effects (delayed ossification of bones and an increase in supernumerary ribs). The fetal no-effect dose is 1.0 mg/kg/day (200 times the recommended clinical dose). [See TOXICOLOGY - Reproduction and Teratology subsection.]

Nursing Mothers

It is not known whether RETIN-A MICRO (microsphere) is excreted in human milk. Nevertheless, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Since many drugs are excreted in human milk, caution should be exercised when tretinoin is administered to a nursing mother.

PRECAUTIONS

General Precautions

RETIN-A MICRO tretinoin gel (microsphere) is for external use only.

Although recent studies have shown that RETIN-A MICRO (microsphere) does not cause phototoxicity or photoallergy, unprotected exposure to sunlight, including sunlamps, should be minimized during the use of RETIN-A MICRO (microsphere).

Patients with sunburn should be advised not to use the product until fully recovered because of the possibility of a 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 (at least SPF 15) and protective clothing over treated areas are recommended when exposure cannot be avoided. [See DOSAGE AND ADMINISTRATION Section.]

Local Irritation

Excessive skin dryness may be experienced; if so, use of an appropriate emollient during the day may be helpful.

The skin of certain sensitive individuals may become excessively dry, red, swollen, or blistered. 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.

RETIN-A MICRO (microsphere) should be kept away from the eyes, the mouth, angles 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.

Medicated or abrasive soaps and cleansers, soaps and cosmetics that have a strong drying effect, and products with high concentrations of alcohol, astringents, spices or lime should be used with caution because of possible interaction with tretinoin. Avoid contact with the peel of limes.

Patients will be able to remove hair as usual (e.g. plucking, electrolysis, depilatories) but should avoid these procedures at night before applying RETIN-A MICRO (microsphere) as they might result in skin irritation.

Weather extremes, such as wind or cold, also may be irritating to patients being treated with tretinoin.

Drug Interactions

Caution should be exercised with the simultaneous use of topical over-the-counter acne preparations containing benzoyl peroxide, sulfur, resorcinol, or salicylic acid with RETIN-A MICRO (microsphere). It also is advisable to allow the effects of such preparations to subside before use of RETIN-A MICRO (microsphere) is begun.

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.

Pediatric Use

Safety and effectiveness in children below the age of 12 have not been established.

ADVERSE REACTIONS

The skin of certain sensitive individuals treated with RETIN-A MICRO tretinoin gel (microsphere) 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. 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.].

SYMPTOMS AND TREATMENT OF OVERDOSAGE

RETIN-A MICRO tretinoin gel (microsphere) is intended for topical use only. In the event of accidental ingestion, if the ingestion is recent, the stomach should be emptied immediately by gastric lavage or by induction of emesis. All other treatment should be appropriately supportive. Oral ingestion of the drug may lead to the same side effects as those associated with excessive oral intake of Vitamin A including teratogenesis in women of childbearing years. Therefore, in such cases pregnancy testing should be carried out in females of childbearing age.

DOSAGE AND ADMINISTRATION

RETIN-A MICRO tretinoin gel (microsphere) should be applied once a day, to acne-prone skin areas, after washing with mild, non-medicated soap and dry skin gently. The gel may be applied at any time during the day or at bedtime. Use only a sufficient quantity of medication 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. RETIN-A MICRO (microsphere) applied once daily is effective in reducing the severity of acne and reducing the number of lesions. 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. This may be due to the action of the medication on deep, previously unseen lesions and should not be considered a reason to discontinue therapy.

Therapeutic results may be noticed after two weeks, but more than four weeks of therapy are required before consistent beneficial effects are observed. Patients in clinical trials were treated for 12 weeks.

Patients treated with RETIN-A MICRO (microsphere) may use cosmetics, but the areas to be treated should be cleansed thoroughly before the medication is applied.

Patients treated with RETIN-A MICRO (microsphere) should use effective sunscreens with a minimum SPF of 15 as well as protective clothing when exposure to sun cannot be avoided.

PHARMACEUTICAL INFORMATION

Drug Substance

Common Name: Tretinoin

Chemical Name: 3,7-dimethyl-9-(2,6,6-trimethyl-1-cyclo-hexen-1-yl) -2,4,6,8,

-no natetraenoic acid.

Structural Formula:

Molecular Formula: C₂₀H₂₈0₂

Molecular Weight: 300.44 g/mol

Physicochemical Properties

Description: Tretinoin is a yellow to orange crystalline powder having a characteristic odor.

Solubility: It is practically insoluble in water and propylene glycol, insoluble in glycerin, and slightly soluble in chloroform and ethanol.

Melting Point: It has a melting point of 182.8°C.

DRUG PRODUCT

Composition

RETIN-A MICRO tretinoin gel (microsphere) is a low irritancy formulation. This formulation uses patented acrylates copolymer porous microspheres (MICROSPONGE System) to enable inclusion of the active ingredient, tretinoin, in an aqueous gel, without the use of oils or organic solvents like ethanol or acetone, which themselves can contribute to irritation. It is a member of the retinoid family of compounds and an endogenous metabolite of Vitamin A. Other components of this formulation are Purified Water, Carbomer 934P in the 0.1% w/w strength and Carbomer 974P in the 0.04% w/w strength, Glycerin, Disodium EDTA, Propylene Glycol, Propylene Glycol Dicaprylate/Dicaprate, Sorbic Acid, PPG-20 Methyl Glucose Ether Distearate, Cyclomethicone and Dimethicone Copolyol, Benzyl Alcohol, Trolamine, and Butylated Hydroxytoluene.

STABILITY AND STORAGE RECOMMENDATIONS

Keep container closed when not in use. Store between 15^o C - 25^o C. Protect pump containers from heat.

AVAILABILITY OF DOSAGE FORMS

RETIN-A MICRO tretinoin gel (microsphere) 0.04% w/w and 0.1% w/w are supplied as 50 g pumps and 2 g tubes (samples).