Adapalene (Page 2 of 3)

Carcinogenesis, Mutagenesis, Impairment of Fertility

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 grams Adapalene Cream, 0.1%, which is approximately 1.5 mg/m2 adapalene. In the oral study, increased incidence of benign and malignant pheochromocytomas in the adrenal medullas of male rats was observed.

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 irradiation 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 irradiation sources.

Adapalene did not exhibit mutagenic or genotoxic effects in vivo (mouse micronucleus test) and in vitro (Ames test, Chinese hamster ovary cell assay, mouse lymphoma TK assay) studies.

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/m2 comparisons). 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.

Pregnancy

Teratogenic effects

Pregnancy category C

No teratogenic effects were seen in rats at oral doses of 0.15 to 5.0 mg/kg/day adapalene (up to 20 times the MRHD based on mg/m2 comparisons). 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 as doses of 0.6, 2.0, and 6.0 mg/kg/day (24 times MRHD for rats or 48 times the MRHD for rabbits) exhibited on 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 Cream, 0.1% 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, 0.1% were conducted in patients 12 to 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.

ADVERSE REACTIONS

In controlled clinical trials, local cutaneous irritation was monitored in 285 acne patients who used Adapalene Cream, 0.1% 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, 0.1% from the controlled clinical studies is provided in the following table:

Incidence of Local Cutaneous Irritation with Adapalene Cream, 0.1% 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, 0.1% 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, 0.1% included: acne flare, dermatitis and contact dermatitis, eyelid edema, conjunctivitis, erythema, pruritus, skin discoloration, rash, and eczema.

OVERDOSAGE

Adapalene Cream, 0.1% 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, or skin discomfort may occur. The acute oral toxicity of Adapalene Cream, 0.1% 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

Adapalene Cream, 0.1% 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 areas lightly. A mild transitory sensation of warmth or slight stinging may occur shortly after the application of Adapalene Cream, 0.1%.

HOW SUPPLIED

Adapalene Cream, 0.1% is available as follows:

45 g tube (NDC 45802-453 -84)

STORAGE

Store at controlled room temperatures 68˚ to 77˚F (20˚ — 25˚C) with excursions permitted between 59˚ and 86˚F (15˚ — 30˚C).

Protect from freezing.

Made in Canada

Manufactured by:

G Production Inc.

Baie d’Urfé QC, H9X 3S4 Canada

Distributed By

PERRIGO®

Allegan, MI 49010 • www.perrigo.com

P51447-0

9A100 RC J3


Rev. 06-13

PACKAGE/LABEL PRINCIPAL DISPLAY PANEL — CARTON

adapalene_cream_carton_image
(click image for full-size original)

For topical use only. Not for ophthalmic, oral, or intravaginal use.

Usual Dosage: Apply a thin film once a day at nighttime to affected areas. See package insert for complete prescribing information.

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.

Store at controlled room temperature 68-77°F (20-25°C) excursions permitted between 59 and 86°F (15-30°C). Protect from freezing.

Rx Only

NDC 45802-453 -84

Adapalene Cream, 0.1%

NET WT 45 g
Perrigo

Made in Canada

Manufactured by:

G Production Inc

Baie d’Urfé, QC, H9X 3S4 Canada

Distributed By

PERRIGO®

Allegan, MI 49010 • www.perrigo.com

P51446-1 9A184 RC C4 Rev. 01-17

adapalene_cream_tube_image
(click image for full-size original)

Rx Only

NDC 45802-453 -84

Adapalene Cream, 0.1%

NET WT 45 g Perrigo

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