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.

ENABLEX (NDA-021513)

(DARIFENACIN HYDROBROMIDE)

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

Download Data

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07/14/2021 (SUPPL-17)

Approved Drug Label (PDF)

8 Use in Specific Populations

8.1 Pregnancy

(PLLR conversion)

Risk Summary

There are no available data on Enablex use in pregnant women to evaluate for a drug-associated risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes. In animal studies, darifenacin was not teratogenic in rats and rabbits at plasma exposures of free drug (via AUC) up to 59 and 28 times the maximum recommended human dose (MRHD) of 15 mg, respectively. Effects on embryofetal development were observed following administration of darifenacin during pregnancy (dilated ureter and/or kidney pelvis in rabbits at about 9 times the MRHD, post-implantation loss in rabbits at about 28 times, and delayed ossification in rats at about 59 times) and during pregnancy and lactation (developmental delays in rats at about 17 times the MRHD), which was associated with maternal toxicity (see Data). Dystocia was observed in rat dams at about 17 times the MRHD.

In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

Data

Animal Data

Embryofetal development studies were conducted with oral darifenacin in female rats (0, 3, 10, and 50 mg/kg/day) and rabbits (0, 3, 10, and 30 mg/kg/day) during the period of organogenesis (gestation days 6 to 17 in the rat and gestation days 6 to 18 in the rabbit).

Darifenacin was not teratogenic in rats and rabbits at plasma exposures of free drug (via AUC) up to 59 times and 28 times, respectively (doses up to 50 and 30 mg/kg/day, respectively) the maximum recommended human dose [MRHD] of 15 mg.

At approximately 59 times the MRHD in pregnant rats, there was a delay in the ossification of the sacral and caudal vertebrae (associated with a decrease in maternal and pup body weight gains) which was not observed at an exposure approximately 13 times the AUC at the MRHD. At five times the AUC (3 mg/kg/day), there were no effects on dams or pups.

In pregnant rabbits, an exposure of darifenacin approximately 28 times the AUC at the MRHD of 15 mg (30 mg/kg/day) was shown to increase post-implantation loss (associated with decreased maternal body weight gain), with a no effect level at 10 mg/kg/day (9 times the AUC at the MRHD). Dilated ureter and/or kidney pelvis was also observed in offspring at this highest dose along with urinary bladder dilation consistent with the pharmacological action of darifenacin, with one case observed at the mid dose of 10 mg/kg/day (9 times the MRHD ). No effect was observed at the lowest dose of 3 mg/kg/day ((approximately 2.8 times the AUC at the MRHD).

A pre- and post-natal development study was conducted with oral darifenacin in female rats (0, 3, 10, and 50 mg/kg/day) throughout gestation and lactation. Decreased body weight gain and dystocia were observed in dams at 10 mg/kg/day (approximately 17 times the MRHD) and above. Slight developmental delays (surface righting reflex, incisor eruption, eyelid opening, vaginal opening, preputial separation) were observed in pups at these doses. At 5 times the AUC at the MRHD (3 mg/kg/day), there were no effects on dams or pups.

8.2 Lactation

(PLLR conversion)

Risk Summary

There are no data on the presence of darifenacin in human milk, the effects on the breastfed infant, or the effects of Enablex on milk production. Darifenacin is present in rat milk [see Data]. When a drug is present in animal milk, it is likely that the drug will be present in human milk.

The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for darifenacin and any potential adverse effects on the breastfed child from darifenacin or from the underlying maternal conditions.

Data

After a single oral dose of 14C radiolabeled darifenacin to lactating rats, darifenacin was detected in maternal milk.