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Drug Safety-related Labeling Changes (SrLC)

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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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07/08/2024 (SUPPL-42)

Approved Drug Label (PDF)

5 Warnings and Precautions

WARNINGS

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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

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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

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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

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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

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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

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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

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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

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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

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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

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

Sodium Retention

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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

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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

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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

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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

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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

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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

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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

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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

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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

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

Vecuronium

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Metronidazole Injection, USP may potentiate the effects of vecuronium.

Drug/Laboratory Test Interactions

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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

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… 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

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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

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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

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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

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)

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 …