Tretinoin

TRETINOIN- tretinoin gel
Oceanside Pharmaceuticals

1 INDICATIONS AND USAGE

Tretinoin Gel Microsphere is a retinoid indicated for topical application in the treatment of acne vulgaris.

2 DOSAGE AND ADMINISTRATION

For topical use only. Not for ophthalmic, oral, or intravaginal use.

Tretinoin Gel Microsphere should be applied once a day, in the evening, to the skin where acne lesions appear, using enough to cover the entire affected area in a thin layer. Areas to be treated should be cleansed thoroughly before the medication is applied. If medication is applied excessively, no more rapid or better results will be obtained and marked redness, peeling, or discomfort may occur. 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 [see Adverse Reactions (6.1)].

Therapeutic results may be noticed after two weeks, but more than seven weeks of therapy are required before consistent beneficial effects are observed.

Tretinoin Gel Microsphere should be kept away from the eyes, the mouth, paranasal creases of the nose, and mucous membranes.

Patients treated with Tretinoin Gel Microsphere may use cosmetics.

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 Tretinoin Gel Microsphere. It also is advisable to allow the effects of such preparations to subside before use of Tretinoin Gel Microsphere is begun.

3 DOSAGE FORMS AND STRENGTHS

Tretinoin Gel Microsphere is a white to very pale yellow opaque gel. Tretinoin Gel Microsphere is available in two strengths: 0.1% and 0.04%.

Each gram of Tretinoin Gel Microsphere, 0.1%, contains 1 mg of tretinoin.

Each gram of Tretinoin Gel Microsphere, 0.04%, contains 0.4 mg of tretinoin.

4 CONTRAINDICATIONS

None.

5 WARNINGS AND PRECAUTIONS

5.1 Local Irritation

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

Tretinoin has been reported to cause severe irritation on eczematous skin and should be used with utmost caution in patients with this condition.

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.

To help limit skin irritation, patients must

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wash the treated skin gently, using a mild, non-medicated soap, and pat it dry, and

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avoid washing the treated skin too often or scrubbing it hard when washing.

Patients should apply a topical moisturizer if dryness is bothersome.

5.2 Exposure to Ultraviolet Light or Weather Extremes

Unprotected exposure to sunlight, including sunlamps (UV light) should be avoided or minimized during the use of Tretinoin Gel Microsphere 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 extended periods of UV exposure (e.g., due to occupation or sports), or those with inherent sensitivity to the sun, or those using medications that cause photosensitivity, should exercise particular caution. Use of sunscreen products (SPF 15 or higher) and protective clothing over treated areas are recommended when exposure cannot be avoided [see Nonclinical Toxicology (13.1)].

Weather extremes, such as wind or cold, also may be irritating to tretinoin-treated skin.

6 ADVERSE REACTIONS

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.

Clinical Trials in Subjects with Acne

In separate clinical trials for each concentration, acne subjects treated with Tretinoin Gel Microsphere, 0.1% or 0.04%, over the twelve-week period showed that cutaneous irritation scores for erythema, peeling, dryness, burning/stinging, or itching peaked during the initial two weeks of therapy, decreasing thereafter.

Approximately half of the subjects treated with Tretinoin Gel Microsphere, 0.04%, had cutaneous irritation at Week 2. Of those subjects who did experience cutaneous side effects, 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 patients experienced moderate cutaneous irritation and there was no severe irritation at Week 2.

In trials of Tretinoin Gel Microsphere, 0.04%, throughout the treatment period the majority of subjects experienced some degree of irritation (mild, moderate, or severe) with 1% (2/225) of subjects having scores indicative of a severe irritation; 1.3% (3/225) of subjects treated with Tretinoin Gel Microsphere, 0.04%, discontinued treatment due to irritation, which included dryness in one patient and peeling and urticaria in another.

In trials of Tretinoin Gel Microsphere, 0.1%, no more than 3% of subjects had cutaneous irritation scores indicative of severe irritation; 6% (14/224) of subjects treated with Tretinoin Gel Microsphere, 0.1%, discontinued treatment due to irritation. Of these 14 subjects, four had severe irritation after 3 to 5 days of treatment, with blistering in one subject.

In a double-blind trial with 156 acne subjects comparing 12 weeks of treatment with Tretinoin Gel Microsphere, 0.04% or 0.1%, (78 subjects each group), the most frequently-reported adverse events affected the skin and subcutaneous tissue (15.4% in the 0.04% group, and 20.5% in the 0.1% group). The most prevalent of the dermatologic adverse events in the 0.04% group was skin irritation (6.4%); and in the 0.1% group skin burning (7.7%), erythema (5.1%), skin irritation (3.8%), and dermatitis (3.8%). Most adverse events were of mild intensity (63.4%), and 34.4% were moderate. One subject in each group had adverse events characterized as severe, neither were dermatologic findings and neither was characterized as related to drug by the investigator.

Trials in Subjects without Acne

In a half-face comparison trial conducted for up to 14 days in women with sensitive skin, but without acne, 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 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 Tretinoin Gel Microsphere, 0.1%, and tretinoin cream, 0.1%, has not been established. The lower irritancy of Tretinoin Gel Microsphere, 0.1%, in subjects without acne may be attributable to the properties of its vehicle. The contribution of decreased irritancy by the MICROSPONGE^® System has not been established. No irritation trials have been performed to compare Tretinoin Gel Microsphere, 0.04%, with either Tretinoin Gel Microsphere, 0.1%, or tretinoin cream, 0.1%.

6.2 Postmarketing Experience

The following adverse reactions have been identified during post-approval use of Tretinoin Gel Microsphere. 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.

Temporary hyper- or hypopigmentation has been reported with repeated application of tretinoin.