Tretinoin 0.001 MG/MG Topical Gel
Generic Name: TRETINOIN
Brand Name: Retin-A MICRO
- Substance Name(s):
- TRETINOIN
OVERDOSAGE
10 Oral ingestion of large amounts of the drug may lead to the same side effects as those associated with excessive oral intake of Vitamin A.
DESCRIPTION
11 Retin-A Micro (tretinoin) Gel microsphere, 0.1%, 0.08%, 0.06% and 0.04% is a white to very pale yellow opaque gel for topical treatment of acne vulgaris.
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 naturally occurring Vitamin A.
Tretinoin has a molecular weight of 300.44, a molecular formula of C 20 H 28 O 2 and the following chemical structure: Each gram of Retin-A Micro Gel, 0.1%, contains 1 mg of tretinoin.
Each gram of Retin-A Micro Gel, 0.08%, contains 0.8 mg of tretinoin.
Each gram of Retin-A Micro Gel, 0.06%, contains 0.6 mg of tretinoin.
Each gram of Retin-A Micro Gel, 0.04%, contains 0.4 mg of tretinoin.
The formulation uses methyl methacrylate/glycol dimethacrylate crosspolymer porous microspheres (MICROSPONGE ® System) to enable inclusion of the active ingredient, tretinoin, in an aqueous gel.
Other components consist of benzyl alcohol, butylated hydroxytoluene, carbomer 974P, cyclomethicone and dimethicone copolyol, disodium EDTA, glycerin, PPG-20 methyl glucose ether distearate, propylene glycol, purified water, sorbic acid, and trolamine.
Tretinoin Chemical Structure
CLINICAL STUDIES
14 14.1 Retin-A Micro (tretinoin) Gel microsphere, 0.1% In two vehicle-controlled trials, Retin-A Micro (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: Table 1: Mean Percent Reduction in Lesion Counts Retin-A Micro (tretinoin) Gel microsphere, 0.1% Retin-A Micro (tretinoin) Gel microsphere, 0.1% Vehicle Gel Study #1 72 pts Study #2 71 pts Study #1 72 pts Study #2 67 pts Non-inflammatory lesion counts 49% 32% 22% 3% Inflammatory lesion counts 37% 29% 18% 24% Total lesion counts 45% 32% 23% 16% Retin-A Micro (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 Retin-A Micro (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 Retin-A Micro (tretinoin) Gel microsphere, 0.1%, achieved an excellent result, as compared to nine percent (9%) of the subjects on the vehicle control.
14.2 Retin-A Micro (tretinoin) Gel microsphere, 0.04% In two vehicle-controlled clinical trials, Retin-A Micro (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: Table 2: Mean Percent Reduction in Lesion Counts Retin-A Micro (tretinoin) Gel microsphere, 0.04% Retin-A Micro (tretinoin) Gel microsphere, 0.04% Vehicle Gel Study #3 108 pts Study #4 111 pts Study #3 110 pts Study #4 103 pts Non-inflammatory lesion counts 37% 29% −2% – That is, a mean percent increase of 2% 14% Inflammatory lesion counts 44% 41% 13% 30% Total lesion counts 40% 35% 8% 20% Retin-A Micro (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 Retin-A Micro (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 Retin-A Micro (tretinoin) Gel microsphere, 0.04%, achieved an excellent result compared to nine percent (9%) of subjects on vehicle control.
HOW SUPPLIED
16 /STORAGE AND HANDLING 16.1 How Supplied Retin-A Micro Gel is opaque and white to very pale yellow in color.
Retin-A Micro Gel, 0.1%, is supplied in 20 gram tube (NDC 0187-5140-20), 45 gram tube (NDC 0187-5140-45) and 50 gram pump (NDC 0187-5140-50).
Retin-A Micro Gel, 0.08%, is supplied in 50 gram pump (NDC 0187-5148-50).
Retin-A Micro Gel, 0.06%, is supplied in 50 gram pump (NDC 0187-5146-50).
Retin-A Micro Gel, 0.04%, is supplied in 20 gram tube (NDC 0187-5144-20), 45 gram tube (NDC 0187-5144-45) and 50 gram pump (NDC 0187-5144-50).
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.
GERIATRIC USE
8.5 Geriatric Use Safety and effectiveness in a geriatric population have not been established.
Clinical trials of Retin-A Micro (tretinoin) Gel microsphere, 0.1% and 0.04%, did not include sufficient numbers of subjects aged 65 and over to determine whether they responded differently from younger subjects.
DOSAGE FORMS AND STRENGTHS
3 Retin-A Micro is a white to very pale yellow opaque gel.
Retin-A Micro is available in four strengths: 0.1%, 0.08%, 0.06% and 0.04%.
Each gram of Retin-A Micro Gel, 0.1%, contains 1 mg of tretinoin.
Each gram of Retin-A Micro Gel, 0.08%, contains 0.8 mg of tretinoin.
Each gram of Retin-A Micro Gel, 0.06%, contains 0.6 mg of tretinoin.
Each gram of Retin-A Micro Gel, 0.04%, contains 0.4 mg of tretinoin.
Gel, 0.1%, 0.08%, 0.06%, and 0.04% ( 3 )
MECHANISM OF ACTION
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.
INDICATIONS AND USAGE
1 Retin-A Micro ® is a retinoid indicated for topical application in the treatment of acne vulgaris.
Retin-A Micro is a retinoid, indicated for topical treatment of acne vulgaris.
( 1 )
PEDIATRIC USE
8.4 Pediatric Use Safety and effectiveness in children below the age of 12 have not been established.
PREGNANCY
8.1 Pregnancy Pregnancy Category C There are no adequate and well-controlled studies in pregnant women.
Retin-A Micro 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 Retin-A Micro (tretinoin) Gel microsphere, 0.1%, applied daily to a 60 kg person (0.017 mg tretinoin/kg body weight).
Pregnant rats were treated with Retin-A Micro (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 Retin-A Micro (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.
NUSRING MOTHERS
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 Retin-A Micro is administered to a nursing woman.
WARNING AND CAUTIONS
5 WARNINGS AND PRECAUTIONS • Retin-A Micro should not be used on eczematous or sunburned skin due to potential for severe irritation.
( 5.1 , 5.2 ) • Avoid unprotected exposure to sunlight including sunlamps (UV light), when using Retin-A Micro due to potential for increased photosensitization.
Use sunscreen of at least SPF 15 and protective clothing during exposure.
( 5.2 ) • Avoid use of Retin-A Micro with weather extremes, such as wind or cold due to potential for increased irritation.
( 5.2 ) 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 Retin-A Micro 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.
INFORMATION FOR PATIENTS
17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Patient Information).
The patient should be instructed to: Cleanse the treatment area thoroughly, before treatment, with a mild, non-medicated cleanser.
Do not use more than the recommended amount and do not apply Retin-A Micro more than once daily as this will not produce faster or better results, but may increase irritation.
Minimize exposure to sunlight, including sunlamps.
Recommend the use of sunscreen products and protective apparel (e.g., hat) when exposure cannot be avoided.
DOSAGE AND ADMINISTRATION
2 For topical use only.
Not for ophthalmic, oral, or intravaginal use.
Retin-A Micro 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.
Retin-A Micro should be kept away from the eyes, the mouth, paranasal creases of the nose, and mucous membranes.
Patients treated with Retin-A Micro 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 Retin-A Micro.
It also is advisable to allow the effects of such preparations to subside before use of Retin-A Micro is begun.
• Apply a thin layer of Retin-A Micro once daily, before bedtime, to skin where lesions occur.
Keep away from eyes, mouth, nasal creases, and mucous membranes.
( 2 ) • Not for oral, ophthalmic, or intravaginal use.
( 2 )