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.

CARDIZEM LA (NDA-021392)

(DILTIAZEM HYDROCHLORIDE)

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

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04/16/2025 (SUPPL-25)

Approved Drug Label (PDF)

8 Use in Specific Populations

8.1 Pregnancy

PLLR conversion:

Risk Summary

The available data from the published literature over decades of use with diltiazem during pregnancy have not identified a drug associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. In animal reproduction studies in rats and rabbits, administration of diltiazem to pregnant animals during organogenesis at oral doses approximately 1 and 4 times the Maximum Recommended Human Dose (MRHD) of CARDIZEM LA produced embryofetal deaths and increased incidence of skeletal abnormalities. An increased incidence of stillbirths was noted at diltiazem doses approximately 2 times the MRHD of CARDIZEM LA.

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of major birth defects, loss, and other adverse outcomes. 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 have been conducted with diltiazem in rats and rabbits. Daily oral administration of diltiazem at 0, 17.5, 35 or 70 mg/kg to pregnant rabbits during organogenesis (gestational day 6 to 18) resulted in embryo- fetal lethality at 35 mg/kg/day (approximately 1 time the MRHD of CARDIZEM LA, on a mg/m2 basis) and higher, concurrent with maternal toxicity (reduced body weight gain). Daily oral administration of diltiazem at 0, 100, 200 and 400 mg/kg to pregnant rats during organogenesis (gestation day 9 to 14) resulted in embryo-fetal lethality at 200 mg/kg/day (approximately 4 times the MRHD of CARDIZEM LA, on a mg/m2 basis) and higher. These doses, in some studies, were reported to cause increased incidence of skeletal malformations (e.g. malformations of vertebral column) or variations. In an oral perinatal/postnatal study in rats with diltiazem at 0, 50, 100, 200 and 400 mg/kg/day from gestation day 15 to lactation/post-partum day 20, there was an increased incidence of stillbirths at 100 mg/kg/day, approximately 2 times (on a mg/m2 basis) the MRHD of CARDIZEM LA.

8.2 Lactation

PLLR conversion:

Risk Summary

Diltiazem is excreted in human milk. One report suggests that concentrations in breast milk may approximate serum levels. Because of the potential for serious adverse reactions in nursing infants from diltiazem, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

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

04/16/2025 (SUPPL-28)

Approved Drug Label (PDF)

7 Drug Interactions

7.2 P-glycoprotein (P-gp) and Cytochrome P450 3A4 Mediated Drug Interactions

Additions and/or revisions underlined:

Diltiazem is both a substrate and an inhibitor of the Pg-p and cytochrome P450 3A4 enzyme system which may affect exposure to diltiazem and concomitant drugs metabolized by those pathways. Patients with renal and/or hepatic impairment may be particularly at risk of exposure changes [see Clinical Pharmacology (12.3)].

11/18/2016 (SUPPL-20)

Approved Drug Label (PDF)

7 Drug Interactions

7.1 Agents Known to Impair Cardiac Contractility and Conduction (Addition underlined)

Ivabradine

Concurrent use of diltiazem increases exposure to ivabradine and may exacerbate bradycardia and conduction disturbances. Avoid concomitant use of ivabradine and diltiazem.