Atralin Gel

Name: Atralin Gel

Indications and Usage for Atralin Gel

Atralin Gel is indicated for topical treatment of acne vulgaris.

Contraindications

None.

Warnings and Precautions

Skin Irritation

The skin of certain individuals may become dry, red, or exfoliated while using Atralin Gel. 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. Mild to moderate skin dryness may also be experienced; if so, use of an appropriate moisturizer during the day may be helpful.

Tretinoin has been reported to cause severe irritation on eczematous or sunburned skin and should be used with caution in patients with these conditions.

To help limit skin irritation, patients must:

• wash the treated skin gently, using a mild, non-medicated soap, and pat it dry • avoid washing the treated skin too often and scrubbing the affected skin area • avoid contact with the peels of limes

Ultraviolet Light and Environmental Exposure

Unprotected exposure to sunlight, including sunlamps, should be minimized during the use of Atralin Gel. Patients who normally experience high levels of sun exposure, and those with inherent sensitivity to sun, should be warned to exercise caution. Use of sunscreen products of at least SPF 15 and protective clothing over treated areas is recommended when exposure cannot be avoided.

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

Fish Allergies

Atralin Gel contains soluble fish proteins and should be used with caution in patients with known sensitivity or allergy to fish. Patients who develop pruritus or urticaria should contact their health care provider.

Atralin Gel Description

Atralin (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 C20H28O2 and the following structure:

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

Other components of this formulation are benzyl alcohol, butyl paraben, butylated hydroxytoluene, carbomer 940, ethylparaben, fish collagen hydrolyzates, glycerin, iso-butyl paraben, 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.

Atralin Gel - Clinical Pharmacology

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.

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 Atralin 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 Atralin 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 Atralin 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

Clinical Trials

The safety and efficacy of Atralin 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

Atralin 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

Atralin 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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