Tretinoin (Page 2 of 3)

8.3 Nursing Mothers

It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Tretinoin Gel is administered to a nursing woman.

8.4 Pediatric Use

Safety and effectiveness in children below the age of 10 have not been established.

A total of 381 pediatric subjects (aged 10 to 16 years) treated with Tretinoin Gel were enrolled into the two clinical studies. Across these two studies, comparable safety and efficacy were observed between pediatric and adult subjects.

8.5 Geriatric Use

Safety and effectiveness in a geriatric population have not been established. Clinical studies of Tretinoin Gel did not include any subjects over age 65 to determine whether they respond differently from younger subjects.

11 DESCRIPTION

Tretinoin Gel, 0.05% is a translucent to opaque, pale yellow gel containing 0.05% tretinoin, by weight for topical administration.

Chemically, tretinoin is all-trans -retinoic acid, also known as (all-E)-3,7-dimethyl-9-(2,6,6-trimethyl-1- cyclohexen-1-yl)-2,4,6,8-nonatetraenoic acid. It is a member of the retinoid class of compounds, and a metabolite of Vitamin A. Tretinoin has a molecular weight of 300.44, a molecular formula of C20 H28 O2 and the following structure:

chemstructure
(click image for full-size original)

Each gram of Tretinoin Gel, 0.05% contains 0.5 mg of tretinoin.

Other components of this formulation are benzyl alcohol, butylparaben, butylated hydroxytoluene, carbomer homopolymer Type C, ethylparaben, fish collagen hydrolyzates, glycerin, isobutylparaben, methylparaben, octoxynol 9, phenoxyethanol, propylparaben, purified water, sodium hyaluronate, and trolamine. The contribution to efficacy of individual components of the vehicle has not been evaluated.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Tretinoin is a metabolite of Vitamin A that binds with high affinity to specific retinoic acid receptors located in both the cytosol and nucleus, but cutaneous levels of tretinoin in excess of physiologic concentrations occur following application of a tretinoin-containing topical drug product.

Although tretinoin activates three members of the retinoid acid (RAR) nuclear receptors (RARα, RARβ, and RARγ) which 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, other mechanisms, or both.

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

12.3 Pharmacokinetics

In two (2) studies, the plasma levels of tretinoin and its major metabolites (13-cis-retinoic acid and 4-oxo-13-cis-retinoic acid) were investigated in a total of 14 patients (age: 13 – 25 years) with severe acne, who applied 4 g ± 0.5 g (range 3.5 g – 4.5 g) of Tretinoin Gel once daily to face, back and chest, as compared to a mean of 0.71 g (range of 0.07 – 3.71 g) applied in the controlled clinical trials. Blood samples were taken at baseline and immediately prior to treatment on days 1, 5, 10 and 14. On Day 14, the final study day, samples also were taken 1, 2, 4, 6, 8, 10, 12, 16, and 24 hours, post-treatment.

The plasma concentrations of tretinoin and its metabolites could be measured (LOQ = 0.5 ng/mL for all three analytes) in all patients at all time points. The range of plasma concentrations of tretinoin and its metabolites, 13-cis-retinoic acid and all-trans-4-oxo-retinoic acid at baseline and after multiple once daily applications of Tretinoin Gel, 0.05% for 14 days are given in Table 2 (below). Although some patients had increased concentrations of tretinoin or its metabolites over baseline values, no consistent increase in these concentrations were observed across patients.

Table 2: Concentrations of Active and Metabolites at Baseline and at Day 14 After Exposure to Tretinoin Gel, 0.05%
Compound Baseline Concentration Range (ng/mL) Day 14 Concentration Range (ng/mL)

Tretinoin

0.68-1.62

0.69-2.88

13-cis-retinoic acid

0.67-1.79

0.51-2.26

4-oxo-13-cis-retinoic acid

0.82-5.92

0.59-6.96

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

A 2-year dermal mouse carcinogenicity study was initiated with topical administration of 0.005%, 0.025% and 0.05% Tretinoin Gel. Although no drug-related tumors were observed in surviving animals, the irritating nature of the drug product precluded daily dosing, confounding data interpretation and reducing the biological significance of these results.

Studies in hairless albino mice with a different formulation 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 was 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.

The genotoxic potential of tretinoin was evaluated in an in vitro bacterial reversion test, an in vitro chromosomal aberration assay in human lymphocytes and an in vivo rat micronucleus assay. All tests were negative.

In dermal fertility studies of another tretinoin formulation in rats, slight (not statistically significant) decreases in sperm count and motility were seen at 0.5 mg/kg/day (3 mg/m2 , approximately 4 times the clinical dose based on body surface area comparison), and slight (not statistically significant) increases in the number and percent of nonviable embryos in females treated with 0.25 mg/kg/day and above (1.5 mg/m2 , approximately 2 times the clinical dose based on body surface area comparison) were observed.

14 CLINICAL STUDIES

The safety and efficacy of Tretinoin Gel used once daily before bedtime for the treatment of mild to moderate acne vulgaris were assessed in two 12-week prospective, multi-center, randomized, controlled trials. Subjects in these two trials ranged from 10 to 65 years of age, were approximately 52% female, 48% male, and were 74% Caucasian, 15% Black or African American, 3% Asian, and 8% Other.

Efficacy results at Week 12 are presented in Table 3. Success on the 6-point Global Severity Score is defined as a score of 0 (clear) or 1 (very mild). In Trial 2, subjects were also required to have at least two grades reduction from baseline for success. ‘Very mild’ acne is defined as: skin almost clear; rare non-inflammatory lesions present, with rare non-inflamed papules (papules may be hyperpigmented, though not pink-red, less than 4 lesions). The database was not large enough to assess whether there were differences in effects in age, gender, or race subgroups.

Table 3: Efficacy Results at Week 12 in Trials 1 and 2
*
Success was defined as 0 (clear) or 1 (very mild)
Success was defined as 0 (clear) or 1 (very mild) with at least 2 grades reduction from baseline

Trial 1

Tretinoin Gel N=375

Vehicle N=185

Global Severity Score Success *

78 (21%)

23 (12%)

Non-Inflammatory Facial Lesions

Mean Baseline Count

50.7

52.4

Mean Absolute Reduction

21.8

10.3

Mean Percent Reduction

43%

21%

Inflammatory Facial Lesions

Mean Baseline Count

23.4

23.9

Mean Absolute Reduction

9.7

5.8

Mean Percent Reduction

41%

26%

Total Facial Lesions

Mean Baseline Count

74.1

76.3

Mean Absolute Reduction

31.4

16.1

Mean Percent Reduction

43%

22%

Trial 2

Tretinoin Gel N=299

Vehicle N=302

Global Severity Score Success

69 (23%)

42 (14%)

Non-Inflammatory Facial Lesions

Mean Baseline Count

51.9

52.7

Mean Absolute Reduction

18.7

10.8

Mean Percent Reduction

37%

20%

Inflammatory Facial Lesions

Mean Baseline Count

22.9

23.4

Mean Absolute Reduction

7.0

4.0

Mean Percent Reduction

30%

17%

Total Facial Lesions

Mean Baseline Count

74.8

76.1

Mean Absolute Reduction

25.7

14.7

Mean Percent Reduction

35%

19%

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