1 INDICATIONS AND USAGE Tretinoin gel (microsphere) is a retinoid indicated for topical application in the treatment of acne vulgaris.

Tretinoin gel (microsphere) is a retinoid, indicated for topical treatment of acne vulgaris.

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6 ADVERSE REACTIONS Most common adverse reactions are skin pain, pruritus, skin irritation/subcutaneous irritation, pharyngitis, and erythema.

( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Encube Ethicals Private Limited at 1-833-285-4151 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

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 acrylate copolymer microsphere 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.