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Differin

These highlights do not include all the information needed to use DIFFERIN Lotion safely and effectively. See full prescribing information for DIFFERIN Lotion. DIFFERIN (adapalene) lotion, for topical use Initial U.S. Approval: 1996

Approved
Approval ID

78b3c1f9-0fc2-4075-6cf0-454a492e6ae3

Product Type

HUMAN PRESCRIPTION DRUG LABEL

Effective Date

Apr 19, 2023

Manufacturers
FDA

Galderma Laboratories, L.P.

DUNS: 047350186

Products 1

Detailed information about drug products covered under this FDA approval, including NDC codes, dosage forms, ingredients, and administration routes.

adapalene

PRODUCT DETAILS

NDC Product Code0299-5912
Application NumberNDA022502
Marketing CategoryC73594
Route of AdministrationTOPICAL
Effective DateApril 20, 2023
Generic Nameadapalene

INGREDIENTS (14)

AdapaleneActive
Quantity: 0.1 g in 100 mL
Code: 1L4806J2QF
Classification: ACTIB
Carbomer Homopolymer Type AInactive
Code: F68VH75CJC
Classification: IACT
Edetate DisodiumInactive
Code: 7FLD91C86K
Classification: IACT
Medium-chain TriglyceridesInactive
Code: C9H2L21V7U
Classification: IACT
MethylparabenInactive
Code: A2I8C7HI9T
Classification: IACT
PhenoxyethanolInactive
Code: HIE492ZZ3T
Classification: IACT
Poloxamer 124Inactive
Code: 1S66E28KXA
Classification: IACT
POLYETHYLENE GLYCOL 300Inactive
Code: 5655G9Y8AQ
Classification: IACT
POLYETHYLENE GLYCOL 1500Inactive
Code: 1212Z7S33A
Classification: IACT
Propylene GlycolInactive
Code: 6DC9Q167V3
Classification: IACT
PropylparabenInactive
Code: Z8IX2SC1OH
Classification: IACT
WaterInactive
Code: 059QF0KO0R
Classification: IACT
Sodium HydroxideInactive
Code: 55X04QC32I
Classification: IACT
Stearyl AlcoholInactive
Code: 2KR89I4H1Y
Classification: IACT

Drug Labeling Information

USE IN SPECIFIC POPULATIONS SECTION

LOINC: 43684-0Updated: 8/26/2022

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary
Available data from clinical trials with DIFFERIN Lotion use in pregnant women are insufficient to establish a drug-associated risk of major birth defects, miscarriage or other adverse maternal or fetal outcomes. In animal reproduction studies, oral administration of adapalene to pregnant rats and rabbits during organogenesis at dose exposures 122 and 243 times, respectively, the human exposure at the maximum recommended human dose (MRHD) of 2 g resulted in fetal skeletal and visceral malformations (see Data).

The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defects, loss, or other adverse outcomes. In the U.S. general population the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies are 2 to 4% and 15 to 20%, respectively.

Data
Animal Data
No malformations were observed in rats treated with oral adapalene doses of 0.15 to 5.0 mg/kg/day, up to 24 times the MRHD based on a mg/m2 comparison. However, malformations were observed in rats and rabbits when treated with oral doses of ≥ 25 mg/kg/day adapalene (122 and 243 times the MRHD, respectively, based on a mg/m2 comparison). Findings included cleft palate, microphthalmia, encephalocele, and skeletal abnormalities in rats and umbilical hernia, exophthalmos, and kidney and skeletal abnormalities in rabbits.

Dermal adapalene embryofetal development studies in rats and rabbits at doses up to 6.0 mg/kg/day (29 and 58 times the MRHD, respectively, based on a mg/m2 comparison) exhibited no fetotoxicity and only minimal increases in skeletal variations (supernumerary ribs in both species and delayed ossification in rabbits).

8.2 Lactation

Risk Summary
There are no data on the presence of topical adapalene lotion or its metabolite in human milk, the effects on the breastfed infant, or the effects on milk production. In animal studies, adapalene is present in rat milk with oral administration of the drug. When a drug is present in animal milk, it is likely that the drug will be present in human milk. It is possible that topical administration of large amounts of adapalene could result in sufficient systemic absorption to produce detectable quantities in human milk (see Clinical Considerations). The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for DIFFERIN Lotion and any potential adverse effects on the breastfed child from DIFFERIN Lotion or from the underlying maternal condition.

Clinical Considerations
To minimize potential exposure to the breastfed infant via breastmilk, use DIFFERIN Lotion on the smallest area of skin and for the shortest duration possible while breastfeeding. Avoid application of DIFFERIN Lotion to areas with increased risk for potential ingestion by or ocular exposure to the breastfeeding child.

8.4 Pediatric Use

Safety and effectiveness of DIFFERIN Lotion in pediatric patients under the age of 12 have not been established.

8.5 Geriatric Use

Clinical studies of DIFFERIN Lotion did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.

DESCRIPTION SECTION

LOINC: 34089-3Updated: 8/26/2022

11 DESCRIPTION

DIFFERIN (adapalene) Lotion, for topical use, contains adapalene in a white to off-white oil-in-water emulsion.

Adapalene is a naphthoic acid derivative with retinoid-like properties. The chemical name for adapalene is (6-[3-(1-adamantyl)-4methoxyphenyl]- 2-naphthoic acid). Adapalene has the following structural formula:

differin structural Formula

Adapalene:

Molecular formula: C28H28O3 Molecular weight: 412.5
Each gram of DIFFERIN Lotion contains 1 mg of adapalene. The lotion also contains the following inactive ingredients: carbomer 941, disodium edetate, medium chain triglycerides, methylparaben, phenoxyethanol, poloxamer 124, polyoxyl-6-polyoxyl-32 palmitostearate, PPG12/SMDI copolymer, propylene glycol, propylparaben, purified water, sodium hydroxide, and stearyl alcohol.

CLINICAL PHARMACOLOGY SECTION

LOINC: 34090-1Updated: 8/26/2022

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

Pharmacodynamics of DIFFERIN Lotion is unknown.

12.3 Pharmacokinetics

Systemic exposure of adapalene following a topical application of DIFFERIN Lotion was studied in two pharmacokinetic (PK) clinical trials. The first trial was conducted in 14 adult subjects 18 to 29 years of age with severe acne and the second trial was conducted in 13 adolescent subjects 12 to 17 years of age with moderate to severe acne.

In each trial, subjects were treated with 2 g of DIFFERIN Lotion applied once daily to approximately 1000 cm² of acne involved skin for 28 days (adolescent subjects) or 30 days (adult subjects). Serial plasma samples were collected at 24 or 72 hours following application on days 1, 15 and 28/30.

Daily topical application of DIFFERIN Lotion resulted in low systemic exposure to adapalene in the two populations (adult and adolescent subjects). In the adult population, all plasma concentrations in 12 out of 14 subjects were below the limit of quantification (LOQ=0.1 ng/mL). One subject had one sample above LOQ at day 30 and the other subject had four plasma samples above LOQ on both days 1 and 15, which ranged from 0.102 and 0.131 ng/mL.

In the adolescent population, plasma concentrations were quantifiable (>0.1 ng/mL) in five subjects. On Day 28, the mean Cmax was 0.128 ± 0.049 ng/mL (range: <0.100 to 0.244 ng/mL) and the mean of AUC0-24hr was 3.07 ± 1.21 ng.hr/mL (range: 1.86 to 4.93 ng.hr/mL). Adapalene plasma concentrations in all subjects were below the limit of quantification (<0.1 ng/mL) 48 hours after the last application on Day 28.

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