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 I.V. RTU IN PLASTIC CONTAINER (NDA-018657)

(METRONIDAZOLE)

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

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06/24/2025 (SUPPL-45)

Approved Drug Label (PDF)

6 Adverse Reactions

Additions and/or revisions underlined:

…

SKIN AND SUBCUTANEOUS DISORDERS: Toxic epidermal necrolysis, Swelling face, Pruritus, Urticaria, Hyperhidrosis, Erythema, Rash; Stevens-Johnson syndrome, Fixed drug eruption, Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), acute generalized exanthematous pustulosis (AGEP) (see WARNINGS)

…

03/14/2025 (SUPPL-43)

Approved Drug Label (PDF)

5 Warnings and Precautions

PRECAUTIONS

Additions and/or revisions underlined:

Pediatric Use

Pediatric Patients Less than 4 Months of Age

The safety and effectiveness of Metronidazole Injection have been established for the treatment of intraabdominal infections in pediatric patients from birth to less than 4 months. Use of Metronidazole Injection in this age group is supported by evidence from data in adults with additional pharmacokinetic and safety data in pediatric patients from birth to less than 4 months of age.

A partially randomized, open-label, phase 2/3 study of intravenous Metronidazole Injection in combination with other intravenous antibacterial drugs was conducted in 62 preterm infants (less than or equal to 33 weeks gestational age at birth, and postnatal age <121 days) and 55 late pre-term and term infants (greater than or equal to 34 weeks gestational age at birth, and postnatal age <121 days), with complicated intra-abdominal infections. The primary objective of this study was to evaluate the safety of metronidazole-containing regimens, which were administered for up to 10 days. The adverse reactions reported in patients receiving metronidazole-containing regimens were comparable to patients receiving other antibacterial regimens in the study and generally similar to adverse reactions described in adults.

The safety and effectiveness of Metronidazole Injection in pediatric patients less than 4 months of age have not been established for (1) the treatment of anaerobic infections other than intra-abdominal infections or for (2) prophylaxis for postoperative infections (see INDICATIONS AND USAGE, CLINICAL PHARMACOLOGY, Pediatric Patients and DOSAGE AND ADMINISTRATION).

Pediatric Patients 4 Months of Age and Older

The safety and effectiveness of Metronidazole Injection in pediatric patients 4 months of age and older have not been established.

07/08/2024 (SUPPL-42)

Approved Drug Label (PDF)

5 Warnings and Precautions

WARNINGS

Additions and/or revisions underlined:

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 Metronidazole injection immediately and institute appropriate therapy.

PRECAUTIONS

Additions and/or revisions underlined:

Severe Cutaneous Adverse Reactions

Advise patients that Metronidazole Injection may increase the risk of serious and sometimes fatal dermatologic reactions, including toxic epidermal necrolysis (TEN), Stevens-Johnson syndrome (SJS), and drug reaction with eosinophilia and systemic symptoms (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 Metronidazole Injection immediately if they develop any type of rash and seek medical attention.

6 Adverse Reactions

Additions and/or revisions underlined:

EAR AND LABYRINTH DISORDERS: Vertigo, tinnitus, hearing impairment, hearing loss

…

SKIN AND SUBCUTANEOUS DISORDERS: Toxic epidermal necrolysis, Swelling face, Pruritus, Urticaria, Hyperhidrosis, Erythema, Rash; Stevens-Johnson syndrome, Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), acute generalized exanthematous pustulosis (AGEP) (see WARNINGS)

12/15/2021 (SUPPL-39)

Approved Drug Label (PDF)

4 Contraindications

Additions and/or revisions underlined

…

Cockayne Syndrome

Metronidazole Injection is 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)

…

03/05/2021 (SUPPL-38)

Approved Drug Label (PDF)

5 Warnings and Precautions

PRECAUTIONS

Additions underlined

…

Drug Interactions

…

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

…

CARDIAC DISORDERS: 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, Tachycardia, Palpitation

…

12/04/2017 (SUPPL-36)

Approved Drug Label (PDF)

5 Warnings and Precautions

PRECAUTIONS

Hepatic Impairment

Additions and/or revisions underlined:

Patients with hepatic impairment metabolize metronidazole slowly, with resultant accumulation of metronidazole and increase the plasma concentrations. Reduce the dose of Metronidazole Injection, USP by 50% in patients with severe hepatic impairment (Child-Pugh C). For patients with mild to moderate hepatic impairment, no dosage adjustment is needed but these patients should be monitored for metronidazole associated adverse events.

Patients with severe hepatic encephalopathy metabolize metronidazole slowly, with resultant accumulation of metronidazole. This may cause exacerbation of CNS adverse effects. Reduce the dose of Metronidazole Injection, USP as necessary.

Renal Impairment

Additions and/or revisions underlined:

For patients with mild to moderate renal impairment dose adjustment is not considered necessary as elimination half-life is not significantly altered. In patients with severe renal impairment or end stage of renal disease, metronidazole and metronidazole metabolites may accumulate significantly because of reduced urinary excretion in those patients. Monitoring for metronidazole associated adverse events is recommended when metronidazole is administered in patients with severe renal impairment or end stage of renal disease who are not undergoing hemodialysis.

Hemodialysis removes significant amounts of metronidazole and its metabolites from systemic circulation. Therefore, supplementation of metronidazole following a hemodialysis session may be necessary.

Patients receiving peritoneal dialysis should be monitored for signs of toxicity due to the potential accumulation of metronidazole metabolites.

Use in Patients with Blood Dyscrasias

Additions and/or revisions underlined:

Metronidazole is a nitroimidazole, and should be used with care in patients with evidence of or history of blood dyscrasia. Agranulocytosis, leukopenia and neutropenia have been associated with metronidazole administration. Monitor complete blood count in these patients.

Monitoring for Leukopenia

Additions and/or revisions underlined:

Monitoring of complete blood count (CBC) is recommended before, during …

Sodium Retention

Additions and/or revisions underlined:

Metronidazole Injection, USP contains 790 mg of sodium per 100 mL. Care should be taken when administering Metronidazole Injection, USP to patients receiving a controlled sodium diet or corticosteroids or to patients predisposed to edema.

Drug Interactions Disulfiram

Additions and/or revisions underlined:

Psychotic reactions and confusion have been reported in alcoholic patients who are using metronidazole and disulfiram concurrently. Do not administer Metronidazole Injection, USP to patients who have taken disulfiram within the last two weeks.

Alcoholic Beverages

Additions and/or revisions underlined:

Abdominal cramps, nausea, vomiting, headaches, tachycardia and flushing may occur if alcoholic beverages or products containing propylene glycol are consumed during or following metronidazole therapy. Discontinue consumption of alcohol or products containing propylene glycol before, during and up to 72 hours after therapy with Metronidazole Injection, USP.

Warfarin and other Oral Anticoagulants

Additions and/or revisions underlined:

Metronidazole has been reported to potentiate the anticoagulant effect of warfarin and other oral coumarin anticoagulants, resulting in a prolongation of prothrombin time and increased risk of hemorrhages. When Metronidazole Injection, USP is prescribed for patients on this type of anticoagulant therapy, prothrombin time and international normalized ratio (INR) should be carefully monitored and their anticoagulant dose adjusted accordingly. Monitor patients for signs and symptoms of bleeding.

Lithium

Additions and/or revisions underlined:

In patients stabilized on relatively high doses of lithium, short-term metronidazole therapy has been associated with elevation of serum lithium and, in a few cases, signs of lithium toxicity. Lithium toxicity may lead to renal damage. Frequent monitoring of serum lithium and serum creatinine levels is necessary.

Busulfan

Additions and/or revisions underlined:

Metronidazole has been reported to increase plasma concentrations of busulfan, which can result in an increased risk for serious busulfan toxicity such as sinusoidal obstruction syndrome, gastrointestinal mucositis, and hepatic veno-occlusive disease. Metronidazole Injection, USP should not be administered concomitantly with busulfan unless the benefit outweighs the risk …

Drugs that Inhibit CYP450 Enzymes

Additions and/or revisions underlined:

The simultaneous administration of drugs that decrease microsomal liver enzyme activity, such as cimetidine, may decrease metabolism and reduce plasma clearance of metronidazole which may result in metronidazole toxicity.

Drugs that Induce CYP450 Enzymes

Additions and/or revisions underlined:

he simultaneous administration of drugs that induce microsomal liver enzyme activity, such as phenytoin or phenobarbital, may accelerate the elimination of metronidazole and therefore decrease its efficacy.

Cytochrome P450 3A4 (CYP3A4) substrates

Additions and/or revisions underlined:

Concomitant use of Metronidazole Injection, USP and CYP3A4 substrates (e.g., amiodarone, tacrolimus, cyclosporine, carbamazepine, phenytoin, and quinidine) may increase respective CYP3A4-substrate plasma levels. Monitoring of plasma concentrations of CYP3A4 substrates may be necessary.

5-Fluorouracil

Additions and/or revisions underlined:

Metronidazole Injection, USP decreases the clearance of 5-fluorouracil and may therefore cause 5-fluorouracil toxicity.

Vecuronium

Additions and/or revisions underlined:

Metronidazole Injection, USP may potentiate the effects of vecuronium.

Drug/Laboratory Test Interactions

Additions and/or revisions underlined:

Metronidazole may interfere with certain types of determinations of serum chemistry values, such as aspartate aminotransferase (AST, SGOT), alanine aminotransferase (ALT, SGPT), lactate dehydrogenase (LDH), triglycerides and glucose hexokinase.

Metronidazole causes an increase in ultraviolet absorbance at 340 nm resulting in falsely decreased values.

Pregnancy Teratogenic Effects

Additions and/or revisions underlined:

… Metronidazole crosses the placental barrier and its effects on the human fetal organogenesis are not known. Reproduction studies have been performed in rats, rabbits and mice at doses similar to the maximum recommended daily dose based on body surface area comparisons. There was no evidence of harm to the fetus due to metronidazole.

Healthcare provider should carefully consider the potential risks and benefits for each specific patient before prescribing Metronidazole Injection, USP.

Geriatric Use

Additions and/or revisions underlined:

In general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

WARNINGS

Additions and/or revisions underlined:

Central and Peripheral Nervous System Effects

Severe neurological disturbances, including encephalopathy, cerebellar symptoms, convulsive seizures, peripheral neuropathy, optic neuropathy, and aseptic meningitis, have been reported in patients treated with metronidazole.

Encephalopathy associated with metronidazole may manifest as confusion or decreased level of consciousness, and is associated with widespread lesions on magnetic resonance imaging (MRI) of the brain. Cerebellar toxicity associated with metronidazole may manifest as ataxia, dizziness, dysarthria, nystagmus and saccadic pursuit and is accompanied by T2 flair lesions within the dentate nuclei seen on MRI. Cerebellar toxicity may concurrently occur with encephalopathy, peripheral neuropathy or seizures. CNS symptoms and CNS lesions are generally reversible within days to weeks upon discontinuation of Metronidazole Injection, USP. Peripheral neuropathy, usually symmetric and mainly of sensory type is characterized by numbness or paresthesia of an extremity. Symptoms may be prolonged after drug discontinuation. Aseptic meningitis may occur within hours of dose administration and generally resolve after metronidazole therapy is discontinued.

Advise patients to report neurologic symptoms that occur during metronidazole administration. Discontinue metronidazole treatment if any abnormal neurologic symptoms occur such as ataxia, dizziness, confusion or any other CNS adverse reaction.

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 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.

6 Adverse Reactions

Additions and/or revisions underlined:

The following reactions have been reported during treatment with metronidazole formulations:

INFECTIONS AND INFESTATIONS: Vaginal candidiasis

BLOOD AND LYMPHATIC SYSTEM DISORDERS: Agranulocytosis, Leukopenia, Neutropenia, Thrombocytopenia, Eosinophilia

IMMUNE SYSTEM DISORDERS: Anaphylactic reaction, Hypersensitivity

METABOLISM AND NUTRITION DISORDERS: Decreased appetite

PSYCHIATRIC DISORDERS: Confusional state, Depression, Insomnia, Decreased libido

NERVOUS SYSTEM DISORDERS: Encephalopathy, Seizure, Neuropathy peripheral, Ataxia, Dizziness, Hypoesthesia, Paresthesia, Dysgeusia, Headache, Nystagmus, Aseptic meningitis, Somnolence, Dysarthria, Numbness, Syncope

EYE DISORDERS: Optic neuropathy, Saccadic eye movement

EAR AND LABYRINTH DISORDERS: Vertigo

CARDIAC DISORDERS: Tachycardia, Palpitation

RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS: Dyspnea

GASTROINTESTINAL DISORDERS: Pancreatitis, Abdominal pain, Diarrhea, Nausea, Vomiting, Asthenia, Proctitis

HEPATOBILIARY DISORDERS: Hepatotoxicity/Liver Failure in patients with Cockayne syndrome (See WARNINGS), Jaundice

MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS: Muscle spasms, Arthralgia, Myalgia

RENAL AND URINARY DISORDERS: Chromaturia, Dysuria

REPRODUCTIVE: Dyspareunia

GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS: Injection site reaction, Malaise, Face edema, Edema peripheral, Chest pain, Chills

INVESTIGATIONS: Hepatic enzyme increased

Patients with Crohn's disease are known to have an increased incidence of gastrointestinal and certain extraintestinal cancers …