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:

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

6.1 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.

8.1 Pregnancy

Pregnancy Category C

There are no adequate and well-controlled studies in pregnant women. Tretinoin Gel Microsphere should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Thirty human cases of temporally associated congenital malformations have been reported during two decades of clinical use of tretinoin products. Although no definite pattern of teratogenicity and no causal association has been established from these cases, five of the reports describe the rare birth defect category holoprosencephaly (defects associated with incomplete midline development of the forebrain). The significance of these spontaneous reports in terms of risk to the fetus is not known.

For purposes of comparison of the animal exposure to systemic human exposure, the MRHD applied topically is defined as 1 gram of Tretinoin Gel Microsphere, 0.1%, applied daily to a 60 kg person (0.017 mg tretinoin/kg body weight).

Pregnant rats were treated with Tretinoin Gel Microsphere, 0.1%, at daily dermal doses of 0.5 to 1.0 mg/kg/day tretinoin on gestation days 6-15. Alterations were seen in vertebrae and ribs of offspring at 5 to 10 times the MRHD based on the body surface area (BSA) comparison.

Pregnant New Zealand White rabbits were treated with Tretinoin Gel Microsphere, 0.1%, at daily dermal doses of 0.2, 0.5, and 1.0 mg/kg/day tretinoin on gestation days 7-19. Doses were administered topically for 24 hours a day while wearing Elizabethan collars to prevent ingestion of the drug. Increased incidences of certain alterations, including domed head and hydrocephaly, typical of retinoid-induced fetal malformations in this species, were observed at 0.5 and 1.0 mg/kg/day. Similar malformations were not observed at 0.2 mg/kg/day, 4 times the MRHD based on BSA comparison. Other pregnant rabbits exposed topically for six hours per day to 0.5 or 1.0 mg/kg/day tretinoin while restrained in stocks to prevent ingestion, did not show any malformations at doses up to 19 times (1.0 mg/kg/day) the MRHD based on BSA comparison, but fetal resorptions were increased at 0.5 mg/kg (10 times the MRHD based on BSA comparison).

Oral tretinoin has been shown to cause malformations in rats, mice, rabbits, hamsters, and nonhuman primates.

Tretinoin induced fetal malformations in Wistar rats when given orally at doses greater than 1 mg/kg/day (10 times the MRHD based on BSA comparison). In the cynomolgus monkey, fetal malformations were reported for doses of 10 mg/kg/day but none were observed at 5 mg/kg/day (95 times the MRHD based on BSA comparison), although increased skeletal variations were observed at all doses. Dose-related increases in embryolethality and abortion also were reported. Similar results have also been reported in pigtail macaques.

In oral peri- and postnatal development studies in rats with tretinoin, decreased survival of neonates and growth retardation were observed at doses in excess of 2 mg/kg/day (19 times the MRHD based on BSA comparison).

Nonteratogenic effects on fetus

Oral tretinoin has been shown to be fetotoxic in rats when administered at doses 24 times the MRHD based on BSA comparison.

Topical tretinoin has been shown to be fetotoxic in rabbits when administered at doses 10 times the MRHD based on BSA comparison.

8.3 Nursing Mothers

It is not known whether tretinoin and/or its metabolites are excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Tretinoin Gel Microsphere is administered to a nursing woman.

8.4 Pediatric Use

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

8.5 Geriatric Use

Safety and effectiveness in a geriatric population have not been established. Clinical trials of Tretinoin Gel Microsphere, 0.1%, 0.08% and 0.04%, did not include sufficient numbers of subjects aged 65 and over to determine whether they responded differently from younger subjects.

12.1 Mechanism of Action

Although tretinoin activates three members of the retinoic acid (RAR) nuclear receptors (RARα, RARβ, and RARγ) which may act to modify gene expression, subsequent protein synthesis, and epithelial cell growth and differentiation, it has not been established whether the clinical effects of tretinoin are mediated through activation of retinoic acid receptors and/or other mechanisms.

The exact mode of action of tretinoin is unknown. Current evidence suggests that topical tretinoin decreases cohesiveness of follicular epithelial cells with decreased microcomedone formation. Additionally, tretinoin stimulates mitotic activity and increased turnover of follicular epithelial cells causing extrusion of the comedones.

12.3 Pharmacokinetics

Tretinoin is a 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 after single and repeated daily applications of 500 mg of a 0.1% tretinoin gel formulation. Estimates of in vivo bioavailability, mean (SD)%, following both single and multiple daily applications, for a period of 28 days with the 0.1% gel, 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 of Tretinoin Gel Microsphere, 0.1%, relative to baseline levels. Clinical pharmacokinetic studies have not been performed with Tretinoin Gel Microsphere, 0.04%.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Dermal carcinogenicity testing has not been performed with Tretinoin Gel Microsphere, 0.1% or 0.04%.

In a 91-week dermal study in which CD-1 mice were administered 0.017% and 0.035% formulations of tretinoin, cutaneous squamous cell carcinomas and papillomas in the treatment area were observed in some female mice. These concentrations are near the tretinoin concentration of the 0.04% and 0.1% clinical formulations. A dose-related incidence of liver tumors in male mice was observed at those same doses. The maximum systemic doses associated with the administered 0.017% and 0.035% formulations are 0.5 and 1.0 mg/kg/day tretinoin, respectively. These doses are two and four times the MRHD based on BSA comparison.

The biological significance of these findings is not clear because they occurred at doses that exceeded the dermal maximally tolerated dose of tretinoin and because they were within the background natural occurrence rate for these tumors in this strain of mice.

There was no evidence of carcinogenic potential when 0.025 mg/kg/day of tretinoin was administered topically to mice (0.1 times the MRHD based on BSA comparison). Studies in hairless albino mice suggest that concurrent exposure to tretinoin may enhance the tumorigenic potential of carcinogenic doses of UVB and UVA light from a solar simulator. This effect has been confirmed in a later study in pigmented mice, and dark pigmentation did not overcome the enhancement of photocarcinogenesis by 0.05% tretinoin. Although the significance of these studies to humans is not clear, patients should minimize exposure to sunlight or artificial ultraviolet irradiation sources [see Warnings and Precautions (5.2)].

The genotoxic potential of tretinoin was evaluated in the Ames assay and in the in vivo mouse micronucleus assay, both of which were negative.

The components of the microspheres have shown potential for genetic toxicity and fetal malformation. EGDMA, a component of the excipient acrylates copolymer, was positive for induction of structural chromosomal aberrations in the in vitro chromosomal aberration assay in mammalian cells in the absence of metabolic activation, and negative for genetic toxicity in the Ames assay, and the in vivo mouse micronucleus assay.

In oral fertility studies in rats with tretinoin, the no-observable effect level was 2 mg/kg/day (19 times the MRHD based on BSA comparison).

14.1 Tretinoin Gel Microsphere, 0.1%

In two vehicle-controlled trials, Tretinoin Gel Microsphere, 0.1%, applied once daily was significantly more effective than vehicle in reducing the acne lesion counts. The mean reductions in lesion counts from baseline after treatment for 12 weeks are shown in the following table:

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 subjects using Tretinoin Gel Microsphere, 0.1%, achieved an excellent result, as compared to eleven percent (11%) of subjects on the vehicle control. In Study #2, twenty-eight percent (28%) of patients using Tretinoin Gel Microsphere, 0.1%, achieved an excellent result, as compared to nine percent (9%) of the subjects on the vehicle control.

14.2 Tretinoin Gel Microsphere, 0.04%

In two vehicle-controlled clinical trials, Tretinoin Gel Microsphere, 0.04%, applied once daily, was more effective (p<0.05) than vehicle in reducing the acne lesion counts. The mean reductions in lesion counts from baseline after treatment for 12 weeks are shown in the following table:

Tretinoin Gel Microsphere, 0.04%, was also superior (p<0.05) to the vehicle in the investigator’s global evaluation of the clinical response. In Study #3, fourteen percent (14%) of subjects using Tretinoin Gel Microsphere, 0.04%, achieved an excellent result compared to five percent (5%) of subjects on vehicle control. In Study #4, nineteen percent (19%) of subjects using Tretinoin Gel Microsphere, 0.04%, achieved an excellent result compared to nine percent (9%) of subjects on vehicle control.

16.1 How Supplied

Tretinoin Gel Microsphere is opaque and white to very pale yellow in color.

Tretinoin Gel Microsphere, 0.1%, is supplied in

20 gram tube (NDC 68682-513-82),

45 gram tube (NDC 68682-513-84) and

50 gram pump (NDC 68682-513-85).

Tretinoin Gel Microsphere, 0.08%, is supplied in

50 gram pump (NDC 68682-515-95).

Tretinoin Gel Microsphere, 0.04%, is supplied in

20 gram tube (NDC 68682-514-92),

45 gram tube (NDC 68682-514-94) and

50 gram pump (NDC 68682-514-95).

16.2 Storage Conditions

Store at 20° to 25°C (68° to 77°F); excursions permitted from 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature].

Store pump upright.

Keep out of reach of children.