Rejuva-A (Tretinoin)

REJUVA-A®

Stiefel

Tretinoin

Agent for the Treatment of Photodamaged Skin

Action And Clinical Pharmacology: Tretinoin, a member of the retinoid class of compounds, is both pharmacologically and structurally related to vitamin A which regulates epithelial cell growth and differentiation. Retinoic acid may exert its effects at the molecular level by binding to specific steroid-like nuclear receptors known as retinoic acid receptors. Binding of retinoic acid to a retinoic acid receptor will promote events at the cellular level by regulating gene transcription and affecting activities such as cellular differentiation and proliferation but the exact mechanism underlying these processes remain to be elucidated.

Topical tretinoin has been reported to correct many of the structural abnormalities of photoaged skin. Tretinoin has been shown to produce epidermal and dermal changes. At the epidermal level, tretinoin increased the epidermal thickness (acanthosis) and the mean granular layer, decreased tonofilament and desmosome strength and increased secretion of a glycosaminoglycan-like substance into the intercellular space. In addition, the cohesion of the epidermal cells and activity of the melanocytes are reduced.

Functional changes in the epidermis include an increase in trans-epidermal water loss and permeability. At the level of the dermis, vasodilatation and angiogenesis of the superficial vasculature, along with increased papillary dermal collagen, have been reported.

The long-term (1 year) safety and efficacy of tretinoin cream in the treatment of photoaging was evaluated during a double-blind, randomized, parallel group, multicentre, placebo controlled study. A total of 147 patients (110 active, 37 placebo) were entered; all were caucasian with chronic, moderate to severe actinically damaged facial skin. The patients applied the medication over their entire face once a day before retiring and were evaluated by the investigators after 1, 3, 6, 9 and 12 months of therapy.

Among the various expressions of the entity of the disease, significant clinical benefits were demonstrated for tretinoin cream versus placebo for the following: reduction in fine wrinkles from Month 3; reduction in moderate, moderately severe and severe coarse wrinkles from Month 6; reduction in the severity of dermatosis at Month 9.

In addition, histological findings demonstrated that skin treated with tretinoin cream showed significant decrease in the thickness of the stratum corneum and increases in the thickness of the stratum granulosum and spinulosum. Skin receiving the placebo cream showed no significant difference in the thickness of the different epidermal strata.

Indications And Clinical Uses: For the treatment of photodamaged skin (heliodermatitis).

The safety and efficacy of tretinoin cream (0.025%) for the prevention and treatment of actinic keratosis has not been established.

Contra-Indications: Patients with known hypersensitivity to retinoids or to any ingredient contained in the preparation.

Manufacturers’ Warnings In Clinical States: Tretinoin cream should be used as part of a comprehensive skin protection program, including use of sunscreen products and protective clothing.

Tretinoin cream is intended for external use only and should be kept away from the nostrils and other mucous membranes because of its irritant effect. Avoid the angles of the nose and nasolabial fold (if treatment in these areas is necessary, apply very sparingly). Topical use may induce severe local erythema and peeling at the site of application. If the degree of local irritation warrants, patients should be directed to use the medication less frequently, discontinue use temporarily or discontinue use altogether. Tretinoin has been reported to cause severe irritation of eczematous skin, and tretinoin cream should only be used with utmost caution in patients with this condition.

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

There have been rare reports of birth defects among babies born to women exposed to topical tretinoin during pregnancy. However, there are no well-controlled prospective studies of the use of topical tretinoin in pregnant women. A retrospective study of mothers exposed to topical tretinoin during the first trimester of pregnancy found no increase in the incidence of birth defects.

Topical retinoid teratology studies in rats and rabbits have been inconclusive. As with all retinoids, tretinoin administered orally at high doses is teratogenic.

Lactation: It is not known whether tretinoin 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.

Children: Safety and effectiveness in children have not been established.

Precautions: General: Care should be used when tretinoin cream is applied to treat wrinkles around the eyes (Crow’s feet) and mouth.

If a sunburn occurs, it is advisable to interrupt therapy until the severe erythema and peeling subside. Patients whose occupations require considerable exposure to the sun and those inherently sensitive to the sun should exercise particular caution and are advised to use a sunscreen of at least SPF 15. Protective clothing over treated areas is recommended when sun exposure cannot be avoided.

Carcinogenesis: Carcinogenic studies have not been conducted with tretinoin cream. Studies in hairless albino mice suggest that tretinoin may accelerate the tumorigenic potential of ultraviolet radiation. Although the significance of these studies to man is not clear, patients should avoid or minimize exposure to sun.

Information Provided to the Patient: A patient information leaflet has been prepared and is included with each package of Rejuva-A (see Blue Section – Information for the Patient “Rejuva-A”).

Drug Interactions: Concomitant topical medication should be used with caution during therapy with tretinoin cream because of possible intensified reactions. Particular caution should be exercised when using cosmetics with a strong drying effect and products with high concentration of alcohol, as well as those containing a peeling agent concomitantly (such as sulfur, resorcinol, benzoyl peroxide or salicylic acid) with tretinoin cream. It may be advisable to “rest” a patient’s skin until the effects of previously used peeling agents subside before initiating tretinoin cream therapy.

Tretinoin is compatible with almost all oral drugs except for photosensitizers. In treating thin-skinned, sensitive regions such as the neck area with tretinoin, it is recommended to apply tretinoin cream thinly every third night, in the beginning, and then every other night as tolerance develops.

Excessive exposure to sunlight or ultraviolet rays (sunlamps) should be avoided during tretinoin cream treatment because the additional irradiation may lead to a more intense action.

If a sunburn occurs, it is advisable to interrupt therapy until the severe erythema and peeling subside. Patients whose occupations require considerable exposure to the sun should exercise particular caution and advised to use a sunscreen of at least SPF 15.

Adverse Reactions: In the long-term clinical trial with tretinoin cream, erythema and peeling/dryness were the most reported side effects in the tretinoin cream group with only 5 of 110 patients from this group withdrawing because of adverse events (erythema and peeling).

The skin of certain sensitive individuals, particularly those with fair complexions, may become excessively red, edematous, blistered or crusted when exposed to tretinoin cream. Pain, burning sensation, tenderness, irritation or pruritus have also been occasionally reported. If any of these effects occur, the medication should be discontinued until the integrity of the skin has been restored or the treatment schedule adjusted to the level the patient can tolerate. Temporary hyper- or hypopigmentation has been reported with repeated application of tretinoin. To date, all adverse clinical effects of tretinoin encountered have been reversible upon discontinuance of therapy. In many instances, reinstitution of therapy with tretinoin failed to produce the adverse effect previously experienced.

Symptoms And Treatment Of Overdose: Symptoms and Treatment: Topical: If medication is applied excessively, marked redness, peeling or discomfort may occur.

Inadvertent oral ingestion of tretinoin cream may lead to the same adverse 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 women of childbearing years.

Dosage And Administration: Tretinoin cream is especially suitable for the treatment of sun sensitive Type I and II skin types e.g., fair skinned people with red or blond hair and blue or hazel eyes, who always burn easily, severely with no or minimal tanning.

Tretinoin cream should be applied to the affected area once a day just before retiring. The area under treatment should be thoroughly cleansed with a mild soap and water and patted dry with a soft towel followed by application of tretinoin cream with a gentle rubbing motion using the fingertips.

It is recommended to start the therapy by applying one pea-size amount to the forehead and spread it evenly over the entire face. After tolerance to the medication is established, the dose may be doubled by applying a pea-size amount to each temple. For those patients who experience excessive irritation or discomfort, the frequency of application should be decreased to every other night or even every third night.

Treatment should be discontinued if a severe local inflammatory response is experienced. In cases where it has been necessary to discontinue therapy or to reduce the frequency of application, therapy may be reinstituted when the adverse effects have ceased.

Therapeutic results will occur gradually. Nine to twelve months of therapy may be required before beneficial effects are seen. At that time, frequency of application may be reduced to 2 or 3 times/week.

Availability And Storage: Rejuva-A Cream is available in Rejuva-A Skin Revitalizing System which also contains Rejuva Moisturizing Day Cream SPF 15.

Rejuva-A: Each g of cream contains: tretinoin 0.025% in a moisturizing cream base. Nonmedicinal ingredients: butylated hydroxytoluene, carbomer 934, cyclomethicone, diisopropyl adipate, germaben II, glycerin, light mineral oil, phenyl trimethicone, polysorbate 60, purified water, sodium hydroxide, sorbitan monostearate and stearyl alcohol. Tubes of 20 g.

Rejuva Moisturizing Day Cream SPF 15: Each g of cream contains: parsol 1989, parsol MCX. Nonmedicinal ingredients: butylated hydroxytoluene, carbomer 934, cyclomethicone, diisopropyl adipate, germaben II, glycerin, isoarachidyl neopentanoate, light mineral oil, phenyl trimethicone, poly-sorbate 60, purified water, sodium hydroxide and stearyl alcohol. Tubes of 20 g.

REJUVA-A® Stiefel Tretinoin Agent for the Treatment of Photodamaged Skin

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