Drug Safety-related Labeling Changes (SrLC)

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Drug Safety-related Labeling Changes (SrLC) Database

ANDA	Abbreviated New Drug Application
BLA	Biologics License Application
CDER	Center for Drug Evaluation and Research
MG	Medication Guide
NDA	New Drug Application
PCI	Patient Counseling Information
PI	Patient Information
PLR	Physician Labeling Rule
PLLR	Pregnancy and Lactation Labeling Rule
Italics	For the most part, italics indicate an FDA comment such as: Additions and/or revisions underlined These italics usually appear at the beginning of the section. In some cases, italics may be an inherent part of the label, and will most often appear in the body of the section.
Underlines	Any text that is underlined indicates text that has been added or revised. There are exceptions where underlining occurs in a section subtitle or heading. This is the case when there is just one word underlined in the body of the text.

Sections

BW	Box Warning
WP	Warnings and Precautions all in one section (PLR-format) Warnings as one section (pre-PLR format) Precautions as one section (pre-PLR format)
AR	Adverse Reactions (in pre-PLR format, this may be a subheading under precautions).
DI	Drug Interactions (in pre-PLR format, this may be a subheading under precautions).
USP	Use in Specific Populations (Inclusive on one or more of the following: Pregnancy; Lactation (PLLR- format); Nursing Mothers (pre-PLLR format); Females and Males of Reproductive Potential (PLLR format only); Pediatric Use, Geriatric Use, Renal Impairment, Hepatic Impairment, Sex, Race (these last six may be a subheading of precautions if label in pre-PLLR format.
PCI/PI/MG	Patient Counseling Information (PLR format only) - summarizes the information that a health care provider should convey to a patient (or caregiver when applicable) when a counseling discussion is taking place (e.g., a physician prescribing a drug during an office visit, a nurse providing discharge instructions at a hospital, or a pharmacist conveying information at a pharmacy). Patient Information - FDA approved patient labeling. Medication Guide - paper handouts that come with many prescription medicines. The guides address issues that are specific to particular drugs and drug classes, and they contain FDA-approved information that can help patients avoid serious adverse events.

Only NDAs and CDER regulated BLAs are included in this database. ANDAs are not included.

Applications that remain active, even if the product has been discontinued, undergo safety-related labeling changes.

DIFFERIN (NDA-021753)

(ADAPALENE)

Safety-related Labeling Changes Approved by FDA Center for Drug Evaluation and Research (CDER)

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12/27/2023 (SUPPL-14)

Approved Drug Label (PDF)

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

Patient Information

Extensive changes; please refer to label

08/25/2022 (SUPPL-11)

Approved Drug Label (PDF)

4 Contraindications

Additions and/or revisions underlined

DIFFERIN Gel is contraindicated in patients who have known hypersensitivity to adapalene or any excipient of DIFFERIN Gel [see WARNINGS AND PRECAUTIONS (5.1)].

6 Adverse Reactions

6.2 Postmarketing Experience

Additions and/or revisions underlined

The following adverse reactions have been identified during post approval use of adapalene:

Immune system disorders: angioedema, face edema, lip swelling

Skin disorders: application site pain

Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate the frequency or establish a causal relationship to drug exposure.

8 Use in Specific Populations

8.1 Pregnancy

PLLR conversion

Risk Summary

Available data from clinical trials with DIFFERIN Gel 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 40 and 81 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 8 times the MRHD based on a mg/m² comparison. However, malformations were observed in rats and rabbits when treated with oral doses of greater than or equal to 25 mg/kg/day adapalene (40 and 81 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 (9.7 and 19.5 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

PLLR conversion

Risk Summary

There are no data on the presence of topical adapalene gel 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 Gel and any potential adverse effects on the breastfed child from DIFFERIN Gel, or from the underlying maternal condition.

Clinical Considerations

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

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

PATIENT COUNSELING INFORMATION

Additions and/or revisions underlined

…

1. Apply a thin film of DIFFERIN Gel to the entire face and any other affected areas of the skin once daily in the evening. Apply a thin film of DIFFERIN Gel to the entire face and any other affected areas of the skin once daily in the evening, after washing gently with a non- medicated soap.

…

9.Lactation: Use DIFFERIN Gel on the smallest area of skin and for the shortest duration possible while breastfeeding. Avoid application of DIFFERIN Gel to areas with increased risk for potential ingestion by or ocular exposure to the breastfeeding child. [See Use in Specific Populations, Lactation (8.2)]