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.

FLAGYL (NDA-020334)

(METRONIDAZOLE)

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

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07/08/2024 (SUPPL-15)

Approved Drug Label (PDF)

5 Warnings and Precautions

WARNINGS

Additions and/or revisions underlined:

Hypersensitivity Reactions

Hypersensitivity reactions including severe cutaneous adverse reactions (SCARs) can be serious and potentially life threatening (see ADVERSE REACTIONS).

Severe Cutaneous Adverse Reactions

Severe cutaneous adverse reactions (SCARs) including toxic epidermal necrolysis (TEN), Stevens-Johnson syndrome (SJS), drug reaction with eosinophilia and systemic symptoms (DRESS), and acute generalized exanthematous pustulosis (AGEP) have been reported with the use of metronidazole. Symptoms can be serious and potentially life threatening. If symptoms or signs of SCARs develop, discontinue FLAGYL capsules immediately and institute appropriate therapy.

PRECAUTIONS

Additions and/or revisions underlined:

Severe Cutaneous Adverse Reactions

Advise patients that FLAGYL capsules may increase the risk of serious and sometimes fatal dermatologic reactions, including TEN, SJS, and DRESS. Instruct the patient to be alert for skin rash, blisters, fever or other signs and symptoms of these hypersensitivity reactions. Advise patients to stop FLAGYL capsules immediately if they develop any type of rash and seek medical attention.

6 Adverse Reactions

Additions and/or revisions underlined:

Central Nervous System: The most serious adverse reactions reported in patients treated with metronidazole have been convulsive seizures, encephalopathy, aseptic meningitis, optic and peripheral neuropathy, the latter characterized mainly by numbness or paresthesia of an extremity. Since persistent peripheral neuropathy has been reported in some patients receiving prolonged administration of metronidazole, patients should be specifically warned about these reactions and should be told to stop the drug and report immediately to their physicians if any neurologic symptoms occur. In addition, patients have reported headache, syncope, dizziness, vertigo, incoordination, ataxia, tinnitus, hearing impairment, hearing loss, confusion, dysarthria, irritability, depression, weakness, and insomnia (see WARNINGS).

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Dermatologic: Dermatitis bullous, fixed drug eruption, erythematous rash and pruritus.

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Hypersensitivity: Toxic epidermal necrolysis (TEN), Stevens-Johnson Syndrome (SJS), drug reaction with eosinophilia and systemic symptoms (DRESS), acute generalized exanthematous pustulosis (AGEP) (see WARNINGS), urticaria, erythematous rash, flushing, nasal congestion, dryness of the mouth (or vagina or vulva), and fever.

10/06/2023 (SUPPL-13)

Approved Drug Label (PDF)

5 Warnings and Precautions

PRECAUTIONS

…

Nursing mothers

Additions and/or revisions underlined:

Metronidazole is present in human milk at concentrations similar to maternal serum levels, and infant serum levels can be close to or comparable to infant therapeutic levels. There are no data on the effects of metronidazole on milk production. Animal studies have shown the potential for tumorigenicity after oral metronidazole was administered chronically to rats and mice (see PRECAUTIONS, Carcinogenesis, Mutagenesis, Impairment of Fertility). This drug is not intended to be administered chronically; therefore, the clinical relevance of the findings of the animal studies is unclear. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for FLAGYL and any potential adverse effects on the breastfed infant from FLAGYL or from the underlying maternal condition. Alternatively, a nursing mother may choose to pump and discard human milk for the duration of FLAGYL therapy, and for 48 hours after the last dose and feed her infant stored human milk or formula.

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12/15/2021 (SUPPL-12)

Approved Drug Label (PDF)

4 Contraindications

Additions and/or revisions underlined

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Cockayne Syndrome

FLAGYL 375 capsules are contraindicated in patients with Cockayne syndrome. Severe irreversible hepatotoxicity/acute liver failure with fatal outcomes have been reported after initiation of metronidazole in patients with Cockayne syndrome (see ADVERSE REACTIONS).

6 Adverse Reactions

Additions underlined

…

Hepatic: Cases of severe irreversible hepatotoxicity/acute liver failure, including cases with fatal outcomes with very rapid onset after initiation of systemic use of metronidazole, have been reported in patients with Cockayne syndrome (latency from drug start to signs of liver failure as short as 2 days) (see CONTRAINDICATIONS).

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03/05/2021 (SUPPL-11)

Approved Drug Label (PDF)

5 Warnings and Precautions

PRECAUTIONS

Additions underlined

General

Hepatic Impairment

Patients with hepatic impairment metabolize metronidazole slowly, with resultant accumulation of metronidazole in the plasma. The FLAGYL 375 capsules dosage or the frequency of administration should be reduced in patients with severe (Child-Pugh C) hepatic impairment. For patients with mild to moderate hepatic impairment, no dosage adjustment is needed. Patients with hepatic impairment should be monitored for metronidazole associated adverse events (see CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION).

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Drug Interactions

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Drugs that Prolong the QT interval

QT prolongation has been reported, particularly when metronidazole was administered with drugs with the potential for prolonging the QT interval.

6 Adverse Reactions

Additions underlined

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Cardiovascular: QT prolongation has been reported, particularly when metronidazole was administered with drugs with the potential for prolonging the QT interval. Flattening of the T-wave may be seen in electrocardiographic tracings.

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8 Use in Specific Populations

Hepatic Impairment

Additions underlined

… Pharmacokinetic modeling and simulation indicate the metronidazole dosage in amebiasis should be reduced by 50% and the dosage interval for trichomoniasis should be increased from every 12 hours to every 24 hours in patients with severe (Child-Pugh C) hepatic impairment.

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04/03/2018 (SUPPL-10)

Approved Drug Label (PDF)

5 Warnings and Precautions

WARNINGS

(Newly added subsection)

…

Risk of Hepatotoxicity and Death in Patients with Cockayne Syndrome

Cases of severe hepatotoxicity/acute hepatic failure, including cases with a fatal outcome with very rapid onset after treatment initiation in patients with Cockayne syndrome have been reported with products containing metronidazole for systemic use. In this population, metronidazole should therefore be used after careful benefit-risk assessment and only if no alternative treatment is available. Obtain liver function tests prior to the start of therapy, within the first 2-3 days after initiation of therapy, frequently during therapy and after end of treatment. Discontinue metronidazole if elevation of liver function tests occurs, and monitor liver function tests until the baseline values are reached.

Advise patients with Cockayne syndrome to stop taking metronidazole immediately if they experience any symptoms of potential liver injury, such as abdominal pain, nausea, change in stool color or jaundice, and to contact their healthcare provider.