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.

MULTAQ (NDA-022425)

(DRONEDARONE HYDROCHLORIDE)

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

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10/23/2023 (SUPPL-28)

Approved Drug Label (PDF)

8 Use in Specific Populations

8.1 Pregnancy

Additions and/or revisions underlined:

Risk Summary

MULTAQ may cause fetal harm when administered to a pregnant woman. In animal studies, dronedarone administered to pregnant rats and rabbits during the period of organogenesis caused multiple visceral (rats) and skeletal malformations (rats and rabbits) when administered at doses equivalent to or lower than the maximum recommended human dose (MRHD) (see Data). There are no available data on dronedarone use in pregnant women to evaluate for a drug-associated risk of major birth defects or miscarriage or other adverse maternal or fetal outcomes. Advise pregnant women of the potential risk to a fetus. The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, 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 is 2% to 4% and 15% to 20%, respectively.

Data Animal data

When pregnant rats in embryofetal development studies received dronedarone at oral doses greater than or equal to the MRHD (on a mg/m2 basis) during organogenesis (gestational days 6 to 15) fetuses had increased rates of external, visceral and skeletal malformations (cranioschisis, cleft palate, incomplete evagination of pineal body, brachygnathia, partially fused carotid arteries, truncus arteriosus, abnormal lobation of the liver, partially duplicated inferior vena cava, brachydactyly, ectrodactyly, syndactyly, and anterior and/or posterior club feet). When pregnant rabbits in embryofetal development studies received dronedarone, at a dose approximately half the MRHD (on a mg/m2 basis) during organogenesis (gestational days 6 to 18), fetuses had an increased rate of skeletal abnormalities (anomalous ribcage and vertebrae, pelvic asymmetry) at doses ?20 mg/kg (the lowest dose tested and approximately half the MRHD on a mg/m2 basis).
Actual animal doses: rat (?80 mg/kg/day); rabbit (?20 mg/kg)

8.2 Lactation

Additions and/or revisions underlined:

Risk Summary

There are no available data on the presence of dronaderone in human milk, the effects on the breastfed infant, or the effect on milk production. Dronedarone and its metabolites are present in rat milk. During a prenatal and postnatal study in rats, maternal dronedarone administration was associated with minor reduced body-weight gain in the offspring. When a drug is present in animal milk, it is likely that the drug will be present in human milk. Because of the potential for serious adverse reactions in breastfed infants from Multaq like the adverse effects in adults, (liver injury, and pulmonary toxicity), advise patients not to breastfeed during treatment with Multaq and for 5 days (about 6 half-lives) after the last dose.

8.3 Females and Males of Reproductive Potential

Newly added subsection:
Multaq may cause fetal harm when administered to pregnant women [see Use in Specific Populations (8.1)].
Pregnancy Testing
Verify that females of reproductive potential are not pregnant prior to initiating Multaq.

Contraception
Advise female patients of reproductive potential to use effective contraception during treatment with Multaq and for 5 days after the final dose.

10/23/2023 (SUPPL-30)

Approved Drug Label (PDF)

4 Contraindications

Addition of the following to the bulleted line listing:

Concomitant use of erythromycin [see Clinical Pharmacology (12.3)]

5 Warnings and Precautions

5.8 QT Interval Prolongation

Additions and/or revisions underlined:

MULTAQ is associated with concentration-dependent QTcF interval prolongation (estimated QTcF increase for 400 mg BID with food is 15 ms) [see Clinical Pharmacology (12.2)]. If the QTc interval is >500 ms, discontinue MULTAQ [see Contraindications (4)].

5.10 Embryofetal Toxicity

Subsection title revised

Additions and/or revisions underlined:

Based on animal data, Multaq may cause fetal harm when administered to a pregnant woman. Dronedarone caused multiple visceral and skeletal malformations in animal reproduction studies when pregnant rats and rabbits were administered dronedarone at doses equivalent to recommended human doses. Advise pregnant women of the potential risk to the fetus. Verify that females of reproductive potential are not pregnant prior to initiating Multaq. Advise females of reproductive potential to use effective contraception during treatment with Multaq and for 5 days (about 6 half-lives) after the final dose [see Use in Specific Populations (8.1, 8.3)].

6 Adverse Reactions

6.1 Clinical Trials Experience

Additions and/or revisions underlined:

…

In randomized clinical trials of patients with paroxysmal or persistent atrial fibrillation, one case of torsade de pointes was reported in patients treated with MULTAQ (2301 patients) versus no cases of torsade de pointes in patients treated with placebo (2327) in the ATHENA study. No cases of torsade de pointes were reported in patients treated with MULTAQ (828 patients) or placebo (409 patients) in the EURIDIS and ADONIS studies [see Clinical Studies (14)].

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

MEDICATION GUIDE

Extensive changes; please refer to label for complete information

11/16/2020 (SUPPL-29)

Approved Drug Label (PDF)

7 Drug Interactions

7.3 Effects of Dronedarone on Other Drugs

Additions and/or revisions underlined:

Dabigatran

Dronedarone increases dabigatran plasma exposures by inhibiting the P-gp transporter [see Clinical Pharmacology (12.3)]. In patients with moderate renal impairment (CrCL 30-50 mL/min), reduce the dose of dabigatran to 75 mg twice daily when concomitantly administered with dronedarone. In patients with severe renal impairment (CrCL 15-30 mL/min), concomitant use of dronedarone with dabigatran should be avoided.

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

PATIENT COUNSELING INFORMATION

Subtitles additions are underlined:
Administration Instructions

MULTAQ should be administered with a meal …

New Onset or Worsening Heart Failure

Advise patients to consult a physician if they develop signs or symptoms …

Liver Injury

Advise patients to immediately report any symptoms …

Drug Interactions

Advise patients to inform their physician of any history of heart failure …