Adapalene (3292)
[ a-dap'-a-leen ]
| Ingredients: |
Adapalene |
| Indications: |
Acne vulgaris |
| Pregnancy Category: |
C |
| FDA Approved: |
1996- 05- 01 |
| Classes: |
Dermatologics; Retinoids |
| Brand Names: |
Adaferin
-
India, Mexico
;
Adaferin Gel
-
Israel
;
Differin
-
US
;
Differine
-
France
;
Differin Gel
-
Austria, Germany, Ireland, Italy, Spain, Sweden, Switzerland
;
|
| DEA schedules: |
(none)
|
| Cost of therapy: |
$113.31
(
Acne Vulgaris ;
Differin Topical Cream ;
0.1%; 45 g ;
1 application/day ;
60 day supply
)
$113.31
(
Acne Vulgaris ;
Differin Topical Gel ;
0.1%; 45 g ;
1 application/day ;
60 day supply
)
|
DESCRIPTION
|
| |
For topical use only. Not for ophthalmic, oral, or intravaginal use.
Differin (adapalene) cream, 0.1%, contains adapalene 0.1% in an aqueous cream emulsion consisting of carbomer 934P, cyclomethicone,
edetate disodium, glycerin, methyl glucose sesquistearate, methylparaben, PEG- 20 methyl glucose sesquistearate, phenoxyethanol,
propylparaben, purified water, squalane, and trolamine.
Differin (adapalene) gel is used for the topical treatment of acne vulgaris. Each gram of adapalene gel contains adapalene
0.1% (1 mg) in a vehicle consisting of propylene glycol, carbomer 940, poloxamer 182, edelate disodium, methylparaben, sodium
hydroxide, and purified water. May contain hydrochloric acid to adjust pH.
The chemical name of adapalene is 6–[3–(1–adamantyl)- 4–methoxyphenyl]- 2–naphthoic acid. It is a white to off- white powder
which is soluble in tetrahydrofuran, sparingly soluble in ethanol, and practically insoluble in water. The molecular formula
is C28 H28 O3 and the molecular weight is 412.52.
|
CLINICAL PHARMACOLOGY
|
| |
Mechanism of Action
|
| |
Adapalene acts on retinoid receptors. Biochemical and pharmacological profile studies have demonstrated that adapalene is
a modulator of cellular differentiation, keratinization, and inflammatory processes — all of which represent important features
in the pathology of acne vulgaris.
Mechanistically, adapalene binds to specific retinoic acid nuclear receptors but does not bind to the cytosolic receptor protein.
Although the exact mode of action of adapalene is unknown, it is suggested that topical adapalene may normalize the differentiation
of follicular epithelial cells resulting in decreased microcomedone formation.
|
Pharmacokinetics
|
| |
Absorption of adapalene through human skin is low. In a pharmacokinetic study with 6 acne patients treated once daily for
5 days with 2 g of adapalene cream applied to 1000 cm2of acne involved skin, there were no quantifiable amounts (limit of quantification = 0.35 ng/ ml) of adapalene in the plasma
samples from any patient. Excretion appears to be primarily by the biliary route.
|
|
CLINICAL STUDIES
|
| |
Two vehicle- controlled clinical studies were conducted in patients 12- 30 years of age with mild to moderate acne vulgaris,
in which adapalene cream was compared with its vehicle. Patients were instructed to apply their treatment medication once
daily at bedtime for 12 weeks. In one study patients were provided with a soapless cleanser and were encouraged to refrain
from using moisturizers. No other topical medications, other than adapalene cream, were to be applied to the face during the
studies. Adapalene cream was significantly more effective than its vehicle in the reduction of acne lesion counts. The mean
percent reduction in lesion counts from baseline after treatment for 12 weeks are presented in TABLE 1 .
| TABLE 1
Mean Percent Reduction in Lesion Counts From Baseline to Week 12
|
| |
Study No. 1 |
Study No. 2 |
| Efficacy |
Adapalene Cream, 0.1% |
Cream Vehicle |
Adapalene Cream, 0.1% |
Cream Vehicle |
| Variable |
n=119 |
n=118 |
n=175 |
n=175 |
| Noninflammatory lesions |
34% |
18% |
35% |
15% |
| Inflammatory lesions |
32% |
17% |
14% |
6% |
| Total lesions |
34% |
18% |
30% |
15% |
|
The trend in the investigator's global assessment of severity supported the efficacy of adapalene cream when compared to the
cream vehicle.
|
INDICATIONS AND USAGE
|
| |
Adapalene cream and gel are indicated for the topical treatment of acne vulgaris.
|
CONTRAINDICATIONS
|
| |
Adapalene cream and gel should not be administered to individuals who are hypersensitive to adapalene or any of the components
in the cream vehicle or gel.
|
WARNINGS
|
| |
Use of adapalene gel should be discontinued if hypersensitivity to any of the ingredients is noted. Patients with sunburn
should be advised not to use this product until fully recovered.
|
PRECAUTIONS
|
| |
General
|
| |
Certain cutaneous signs and symptoms such as erythema, dryness, scaling, burning, or pruritus may be experienced during treatment.
These are most likely to occur during the first 2- 4 weeks of treatment, are mostly mild to moderate in intensity, and will
usually lessen with continued use of the medication. Depending upon the severity of adverse events, patients should be instructed
to reduce the frequency of application or discontinue use.
If a reaction suggesting sensitivity or chemical irritation occurs, use of the medication should be discontinued. Exposure
to sunlight, including sunlamps, should be minimized during the use of adapalene. Patients who normally experience high levels
of sun exposure, and those with inherent sensitivity to the sun should be warned to exercise caution. Use of sunscreen products
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 patients under treatment with adapalene.
Avoid contact with eyes, lips, angles of the nose, and mucous membranes. The product should not be applied to cuts, abrasions,
eczematous skin, or sunburned skin. As with other retinoids, use of "waxing" as a depilatory method should be avoided on skin
treated with adapalene.
|
Information for the Patient
|
| |
Patients using adapalene cream should receive the following information and instructions:
- 1. This medication is to be used only as directed by the physician.
- 2. It is for external use only.
- 3. Avoid contact with the eyes, lips, angles of the nose, and mucous membranes.
- 4. Cleanse area with a mild or soapless cleanser before applying this medication.
- 5. Moisturizers may be used if necessary; however, products containing alpha hydroxy or glycolic acids should be avoided.
- 6. Exposure of the eye to this medication may result in reactions such as swelling, conjunctivitis, and eye irritation.
- 7. This medication should not be applied to cuts, abrasions, eczematous or sunburned skin.
- 8. Wax epilation should not be performed on treated skin due to the potential for skin erosions.
- 9. During the early weeks of therapy, an apparent exacerbation of acne may occur. This is due to the action of this medication
on previously unseen lesions and should not be considered a reason to discontinue therapy. Overall clinical benefit may be
noticed after 2 weeks of therapy, but at least 8 weeks are required to obtain consistent beneficial effects.
|
Carcinogenesis, Mutagenesis, and Impairment of Fertility
|
| |
No photocarcinogenicity studies were conducted. Animal studies have shown an increased risk of skin neoplasms with the use
of pharmacologically similar drugs ( e.g., retinoids) when exposed to UV irridation in the laboratory or to sunlight. Although the significance of these studies to human
use is not clear, patients should be advised to avoid or minimize exposure to either sunlight or artificial UV irridation
sources.
Adapalene did not exhibit mutagenic or genotoxic effects in vivo (mouse micronucleous test) and in vitro (Ames test, Chinese hamster ovary cell assay, mouse lymphoma TK assay) studies.
Cream
|
| |
Carcinogenicity studies with adapalene have been conducted in mice at topical doses of 0.4, 1.3, and 4.0 mg/ kg/ day, and
in rats at oral doses of 0.15, 0.5, and 1.5 mg/ kg/ day. These doses are up to 8 times (mice) and 6 times (rats) in terms
of mg/ m2/ day the maximum potential exposure at the recommended topical human dose (MRHD), assumed to be 2.5 g adapalene cream, which
is approximately 1.5 mg/ m2adapalene. In the oral study, increased incidence of benign and malignant pheochromocytomas in the adrenal medullas of male
rats was observed.
Reproductive function and fertility studies were conducted in rats administered oral doses of adapalene in amounts up to 20
mg/ kg/ day (up to 80 times the MRHD based on mg/ m2comparisons). No effects of adapalene were found on the reproductive performance or fertility of the F0 males or females. There were also no detectable effects on the growth, development and subsequent reproductive function of
the F1 generation.
|
Gel
|
| |
Carcinogenicity studies have been conducted in mice at topical doses of 0.3, 0.9, and 2.6 mg/ kg/ day and in rats at oral
doses of 0.15, 0.5, and 1.5 mg/ kg/ day, approximately 4- 75 times the maximal daily human topical dose. In the oral study,
positive linear trends were observed in the incidence of follicular cell adenomas and carcinomas in the thyroid glands of
female rats, and in the incidence of benign and malignant pheochromocytomas in the adrenal medullas of male rats.
|
|
Pregnancy, Teratogenic Effects, Pregnancy Category C
|
| |
No teratogenic effects were seen in rats at oral doses of 0.15- 5.0 mg/ kg/ day adapalene (up to 20 times the MRHD based on
mg/ m2comparisons). However, adapalene administered orally at doses of ≥25 mg/ kg, (100 times the MRHD for rats or 200 times MRHD
for rabbits) has been shown to be teratogenic. Cutaneous teratology studies in rats and rabbits at doses of 0.6, 2.0, and
6.0 mg/ kg/ day (24 times the MRHD for rats or 48 times the MRHD for rabbits) exhibited no fetotoxicity and only minimal increases
in supernumerary ribs in rats. There are no adequate and well- controlled studies in pregnant women. Adapalene should be used
during pregnancy only if the potential benefit justifies the potential risk to the fetus.
|
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 adapalene is administered to a nursing woman.
|
Pediatric Use
|
| |
Safety and effectiveness in pediatric patients below the age of 12 have not been established.
|
Geriatric Use
|
| |
Clinical studies of adapalene cream were conducted in patients 12- 30 years of age with acne vulgaris and therefore did not
include subjects 65 years and older to determine whether they respond differently than younger subjects. Other reported clinical
experience has not identified differences in responses between the elderly and younger patients.
|
|
DRUG INTERACTIONS
|
| |
As adapalene has the potential to produce local irritation in some patients, concomitant use of other potentially irritating
topical products (medicated or abrasive soaps and cleansers, soaps and cosmetics that have a strong drying effect, and products
with high concentrations of alcohol, astringents, spices, or lime rind) should be approached with caution. Particular caution
should be exercised in using preparations containing sulfur, resorcinol, or salicylic acid in combination with adapalene.
If these preparations have been used, it is advisable not to start therapy with adapalene until the effects of such preparations
in the skin have subsided.
|
ADVERSE REACTIONS
|
| |
Cream
|
| |
In controlled clinical trials, local cutaneous irritation was monitored in 285 acne patients who used adapalene cream once
daily for 12 weeks. The frequency and severity of erythema, scaling, dryness, pruritus and burning were assessed during these
studies. The incidence of local cutaneous irritation with adapalene cream from the controlled clinical studies is provided
in TABLE 2 .
| TABLE 2
Incidence of Local Cutaneous Irritation With Adapalene Cream From Controlled Clinical Studies (n=285)
|
| |
None |
Mild |
Moderate |
Severe |
| Erythema |
52% (148) |
38% (108) |
10% (28) |
<1% (1) |
| Scaling |
58% (166) |
35% (100) |
6% (18) |
<1% (1) |
| Dryness |
48% (136) |
42% (121) |
9% (26) |
<1% (2) |
| Pruritus (persistent) |
74% (211) |
21% (61) |
4% (12) |
<1% (1) |
| Burning/ stinging (persistent) |
71% (202) |
24% (69) |
4% (12) |
<1% (2) |
|
Other reported local cutaneous adverse events in patients who used adapalene cream once daily included: Sunburn (2%), skin discomfort, burning and stinging (1%), and skin irritation (1%).
Events occurring in less than 1% of patients treated with adapalene cream included: Acne flare, dermatitis and contact dermatitis, eyelid edema, conjunctivitis, erythema, pruritus, skin discoloration, rash,
and eczema.
|
Gel
|
| |
Some adverse effects such as erythema, scaling, dryness, pruritus, and burning will occur in 10- 40% of patients. Pruritus
or burning immediately after application also occurs in approximately 20% of patients.
The following adverse experiences were reported in approximately 1% or less of patients: Skin irritation, burning/ stinging, erythema, sunburn, and acne flares. These are most commonly seen during the first month
of therapy and decrease in frequency and severity thereafter. All adverse effects with use of adapalene gel during clinical
trials were reversible upon discontinuation of therapy.
|
|
OVERDOSAGE
|
| |
Adapalene is intended for cutaneous use only. If the medication is applied excessively, no more rapid or better results will
be obtained and marked redness, scaling, peeling, or skin discomfort may occur. The acute oral toxicity of adapalene in mice
and rats is greater than 10 ml/ kg. Chronic ingestion of the drug may lead to the same side effects as those associated with
excessive oral intake of vitamin A.
|
DOSAGE AND ADMINISTRATION
|
| |
Cream
|
| |
Adapalene cream should be applied to affected areas of the skin once daily at nighttime. A thin film of the cream should be
applied to the skin areas where acne lesions appear, using enough to cover the entire affected area lightly. A mild transitory
sensation of warmth or slight stinging may occur shortly after the application of adapalene cream.
|
Gel
|
| |
Adapalene gel should be applied once a day to affected areas after washing in the evening before retiring. A thin film of
the gel should be applied, avoiding eyes, lips, and mucous membranes.
During the early weeks of therapy, an apparent exacerbation of acne may occur. This is due to the action of the medication
on previously unseen lesions and should not be considered a reason to discontinue therapy. Therapeutic results should be noticed
after 8- 12 weeks of treatment.
|
|
HOW SUPPLIED
|
| |
Storage: Store at controlled room temperature 20- 25°C (68- 77°F). Protect from freezing.
|
PRODUCT IDENTIFICATION
|
| |
None Available |
PRODUCT LISTING - EQUIVALENTS NOT AVAILABLE
|
| |
| cream - topical - 0.1% -
|
| 15.0 gm |
$42.19 |
Differin
Galderma Laboratories Inc
|
00299591515 |
| 45.0 gm |
$98.69 |
Differin
Galderma Laboratories Inc
|
00299591545 |
| gel - topical - 0.1% -
|
| 15.0 gm |
$27.31 |
Differin
Allscripts Healthcare Solutions
|
54569464000 |
| 15.0 gm |
$42.19 |
Differin
Galderma Laboratories Inc
|
00299591015 |
| 45.0 gm |
$98.69 |
Differin
Galderma Laboratories Inc
|
00299591045 |
| solution - topical - 0.1% -
|
| 1.0 ml x 60.0 |
$86.19 |
Differin
Galderma Laboratories Inc
|
00299590516 |
| 30.0 ml |
$86.19 |
Differin
Galderma Laboratories Inc
|
00299590530 |
|
|