Adapalene (Page 2 of 4)

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Teratogenic effects: Pregnancy Category C.

Retinoids may cause fetal harm, when administered to pregnant women. Adapalene has been shown to be teratogenic in rats and rabbits when administered orally (see Animal Data below). There are no adequate and well-controlled studies in pregnant women. Adapalene gel, 0.3% should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. The safety and efficacy of adapalene gel, 0.3% in pregnancy has not been established.

Human Data

In clinical trials involving adapalene gel, 0.3% in the treatment of acne vulgaris, women of child-bearing potential initiated treatment only after having had a negative pregnancy test and used effective birth control measures during therapy. However, 6 women treated with adapalene gel, 0.3% became pregnant. One patient elected to terminate the pregnancy, two patients delivered healthy babies by normal delivery, two patients delivered prematurely and the babies remained in intensive care until reaching a healthy state and one patient was lost to follow-up.

Animal Data

  • No teratogenic effects were seen in rats at oral doses of 0.15 mg/kg/day to 5.0 mg/kg/day adapalene representing up to 6 times the maximum recommended human dose (MRHD) based on mg/m2 comparisons. Adapalene has been shown to be teratogenic in rats and rabbits when administered orally at doses greater than or equal to 25 mg/kg representing 32 and 65 times, respectively, the MRHD based on mg/m2 comparisons. Findings included cleft palate, microphthalmia, encephalocele and skeletal abnormalities in the rat and umbilical hernia, exophthalmos and kidney and skeletal abnormalities in the rabbit.
  • Cutaneous teratology studies in rats and rabbits at doses of 0.6 mg/kg/day, 2.0 mg/kg/day, and 6.0 mg/kg/day exhibited no fetotoxicity and only minimal increases in supernumerary ribs in both species and delayed ossification in rabbits. Systemic exposure (AUC0-24h ) to adapalene 0.3% gel at topical doses of 6.0 mg/kg/day in rats and rabbits represented 5.7 and 28.7 times, respectively, the exposure in acne patients treated with adapalene 0.3% gel applied to the face, chest and back (2 grams applied to 1000 cm2 of acne involved skin).

8.3 Nursing Mothers

It is not known whether adapalene is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when adapalene gel, 0.3% is administered to a nursing woman.

8.4 Pediatric Use

Safety and effectiveness have not been established in pediatric patients below the age of 12.

8.5 Geriatric Use

Clinical studies of adapalene gel, 0.3% did not include subjects 65 years of age and older to determine whether they respond differently than younger subjects. Safety and effectiveness in geriatric patients age 65 and above have not been established.

10 OVERDOSAGE

Adapalene gel, 0.3% is intended for topical 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. Chronic ingestion of the drug may lead to the same side effects as those associated with excessive oral intake of vitamin A.

11 DESCRIPTION

Adapalene gel, 0.3% contains adapalene 0.3% (3 mg/g) in a topical aqueous gel for use in the treatment of acne vulgaris, consisting of carbomer 940, edetate disodium, methylparaben, poloxamer 182, propylene glycol, purified water and sodium hydroxide. May contain hydrochloric acid for pH adjustment.

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, very slightly soluble in ethanol, and practically insoluble in water. The molecular formula is C28 H28 O3 and molecular weight is 412.53. Adapalene is represented by the following structural formula.

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(click image for full-size original)

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Adapalene binds to specific retinoic acid nuclear receptors but does not bind to cytosolic receptor protein. Biochemical and pharmacological profile studies have demonstrated that adapalene is a modulator of cellular differentiation, keratinization, and inflammatory processes. However, the significance of these findings with regard to the mechanism of action of adapalene for the treatment of acne is unknown.

12.2 Pharmacodynamics

Clinical pharmacodynamic studies have not been conducted for adapalene gel, 0.3%.

12.3 Pharmacokinetics

Systemic exposure of adapalene following topical application of adapalene gel, 0.3% was evaluated in a clinical study. Sixteen acne patients were treated once daily for 10 days with 2 grams of adapalene gel, 0.3% applied to the face, chest and back, corresponding to approximately 2 mg/cm2. Fifteen patients had quantifiable (LOQ = 0.1 ng/mL) adapalene levels resulting in a mean Cmax of 0.553 ± 0.466 ng/mL on Day 10 of treatment. The mean AUC0-24hr was 8.37 ± 8.46 ng.h/mL as determined in 15 of the 16 patients on Day 10. The terminal apparent half-life, determined in 15 of 16 patients, ranged from 7 to 51 hours, with a mean of 17.2 ± 10.2 hours. Adapalene was rapidly cleared from plasma and was not detected 72 hours after the last application for all but one subject. Exposure of potential circulating metabolites of adapalene was not measured. Excretion of adapalene appears to be primarily by the biliary route.

In another clinical study in patients with moderate to moderately severe acne, adapalene gel, 0.3% or Adapalene Gel, 0.1% was applied to the face and optionally to the trunk, once daily for 12 weeks. Seventy-eight (78) patients had plasma adapalene levels evaluated at Weeks 2, 8, and 12. Of the 209 plasma samples analyzed, adapalene concentrations were below the limit of detection (LOD = 0.15 ng/mL) of the method in all samples but three. For the three samples, traces of adapalene below the limit of quantification (LOQ = 0.25 ng/mL) of the method were found. One of these samples was taken at Week 12 from a male patient treated with adapalene gel, 0.3% who treated the face and the trunk for eight weeks (thereafter, only the face was treated). The second and third samples were from the Week 2 and 12 visits of a female patient treated with Adapalene Gel, 0.1% who treated only the face for 12 weeks. In this study, the average daily usage of product was 1 g/day.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenicity studies with adapalene have been conducted in mice at topical doses of 0.4 mg/kg/day, 1.3 mg/kg/day, and 4.0 mg/kg/day, and in rats at oral doses of 0.15 mg/kg/day, 0.5 mg/kg/day, and 1.5 mg/kg/day. These doses are up to 3 times (mice) and 2 times (rats) in terms of mg/m2 /day the potential exposure at the maximum recommended human dose (MRHD), assumed to be 2.5 grams adapalene gel, 0.3%. 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 vitro (Ames test, Chinese hamster ovary cell assay, mouse lymphoma TK assay) and in vivo (mouse micronucleus test).

Reproductive function and fertility studies were conducted in rats administered oral doses of adapalene in amounts up to 20 mg/kg/day (up to 26 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 offspring.

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