Metronidazole (injection)

Metronidazole (injection)
Adult Indications & Dosage
Pediatric Indications & Dosage
Contraindications
Warnings & Precautions
Adverse Reactions
Drug Interactions
Use in Specific Populations
Administration & Monitoring
Overdosage
Pharmacology
Clinical Studies
How Supplied
Images
Patient Counseling Information
Precautions with Alcohol
Brand Names
Look-Alike Names

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Adeel Jamil, M.D. [2]

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Overview

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Adult Indications and Dosage

FDA-Labeled Indications and Dosage (Adult)

Treatment of Anaerobic Infections

• Metronidazole Injection, USP is indicated in the treatment of serious infections caused by susceptible anaerobic bacteria. Indicated surgical procedures should be performed in conjunction with metronidazole therapy. In a mixed aerobic and anaerobic infection, antibiotics appropriate for the treatment of the aerobic infection should be used in addition to metronidazole.

• Metronidazole is effective in Bacteroides fragilis infections resistant to clindamycin, chloramphenicol and penicillin.

• Intra-abdominal Infections

• including peritonitis, intra-abdominal abscess and liver abscess, caused by Bacteroides species including the B. fragilis group (B. fragilis, B. distasonis, B. ovatus, B. thetaiotaomicron, B. vulgatus). Clostridium species, Eubacterium species, Peptococcus species, and Peptostreptococcus species.

• Skin and Skin Structure Infections

• caused by Bacteroides species including B. fragilis group, Clostridium species, Peptococcus species, Peptostreptococcus species and Fusobacterium species.

• Gynecologic Infections

• including endometritis, endomyometritis, tubo-ovarian abscess, and post-surgical vaginal cuff infection, caused by Bacteroides species including the B. fragilis group, Clostridium species, Peptococcus species, Peptostreptococcus species and Fusobacterium species.

• Bacterial Septicemia

• caused by Bacteroides species including the B. fragilis group and Clostridium species.

• Bone and Joint Infections

• as adjunctive therapy, caused by Bacteroides species including the B. fragilis group.

• Central Nervous System (CNS) Infections

• including meningitis and brain abscess, caused by Bacteroides species including the B. fragilis group.

• Lower Respiratory Tract Infections

• including pneumonia, empyema, and lung abscess, caused by Bacteroides species including the B. fragilis group.

• Endocarditis

• caused by Bacteroides species including the B. fragilis group.

Prophylaxis

• The prophylactic administration of Metronidazole Injection, USP preoperatively, intraoperatively, and postoperatively may reduce the incidence of postoperative infection in patients undergoing elective colorectal surgery which is classified as contaminated or potentially contaminated.

• Prophylactic use of Metronidazole Injection, USP should be discontinued within 12 hours after surgery. If there are signs of infection, specimens for cultures should be obtained for the identification of the causative organism(s) so that appropriate therapy may be given.

• To reduce the development of drug-resistant bacteria and maintain the effectiveness of metronidazole and other antibacterial drugs, metronidazole should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy.

Off-Label Use and Dosage (Adult)

Guideline-Supported Use

There is limited information regarding Off-Label Guideline-Supported Use of Metronidazole (injection) in adult patients.

Non–Guideline-Supported Use

There is limited information regarding Off-Label Non–Guideline-Supported Use of Metronidazole (injection) in adult patients.

Pediatric Indications and Dosage

FDA-Labeled Indications and Dosage (Pediatric)

There is limited information regarding Metronidazole (injection) FDA-Labeled Indications and Dosage (Pediatric) in the drug label.

Off-Label Use and Dosage (Pediatric)

Guideline-Supported Use

There is limited information regarding Off-Label Guideline-Supported Use of Metronidazole (injection) in pediatric patients.

Non–Guideline-Supported Use

There is limited information regarding Off-Label Non–Guideline-Supported Use of Metronidazole (injection) in pediatric patients.

Contraindications

There is limited information regarding Metronidazole (injection) Contraindications in the drug label.

Warnings

There is limited information regarding Metronidazole (injection) Warnings' in the drug label.

Adverse Reactions

Clinical Trials Experience

There is limited information regarding Metronidazole (injection) Clinical Trials Experience in the drug label.

Postmarketing Experience

There is limited information regarding Metronidazole (injection) Postmarketing Experience in the drug label.

Drug Interactions

There is limited information regarding Metronidazole (injection) Drug Interactions in the drug label.

Use in Specific Populations

Pregnancy

Pregnancy Category (FDA): There is no FDA guidance on usage of Metronidazole (injection) in women who are pregnant.
Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Metronidazole (injection) in women who are pregnant.

Labor and Delivery

There is no FDA guidance on use of Metronidazole (injection) during labor and delivery.

Nursing Mothers

There is no FDA guidance on the use of Metronidazole (injection) in women who are nursing.

Pediatric Use

There is no FDA guidance on the use of Metronidazole (injection) in pediatric settings.

Geriatic Use

There is no FDA guidance on the use of Metronidazole (injection) in geriatric settings.

Gender

There is no FDA guidance on the use of Metronidazole (injection) with respect to specific gender populations.

Race

There is no FDA guidance on the use of Metronidazole (injection) with respect to specific racial populations.

Renal Impairment

There is no FDA guidance on the use of Metronidazole (injection) in patients with renal impairment.

Hepatic Impairment

There is no FDA guidance on the use of Metronidazole (injection) in patients with hepatic impairment.

Females of Reproductive Potential and Males

There is no FDA guidance on the use of Metronidazole (injection) in women of reproductive potentials and males.

Immunocompromised Patients

There is no FDA guidance one the use of Metronidazole (injection) in patients who are immunocompromised.

Administration and Monitoring

Administration

There is limited information regarding Metronidazole (injection) Administration in the drug label.

Monitoring

There is limited information regarding Metronidazole (injection) Monitoring in the drug label.

IV Compatibility

There is limited information regarding the compatibility of Metronidazole (injection) and IV administrations.

Overdosage

There is limited information regarding Metronidazole (injection) overdosage. If you suspect drug poisoning or overdose, please contact the National Poison Help hotline (1-800-222-1222) immediately.

Pharmacology

There is limited information regarding Metronidazole (injection) Pharmacology in the drug label.

Mechanism of Action

• Metronidazole exerts antibacterial effects in an anaerobic environment by the following possible mechanism: Once metronidazole enters the organism, the drug is reduced by intra-cellular electron transport proteins. Because of this alteration to the metronidazole molecule, a concentration gradient is created and maintained which promotes the drug’s intracellular transport. Presumably, free radicals are formed which, in turn, react with cellular components resulting in death of bacteria.

• Metronidazole is active against most obligate anaerobes, but does not possess any clinically relevant activity against facultative anaerobes or obligate aerobes.

Structure

• Metronidazole Injection, USP is a sterile, nonpyrogenic, isotonic, buffered parenteral dosage form of metronidazole in water for injection.

• Each 100 mL contains metronidazole 500 mg (5 mg/mL) and sodium chloride 790 mg in water for injection; with dibasic sodium phosphate (anhydrous) 48 mg and citric acid (anhydrous) 23 mg added as buffers. The osmolarity of this solution is 314 mOsmol/liter (calc.). Each 100 mL contains 14 mEq sodium, pH 5.8 (4.5 ― 7.0).

• Metronidazole is classified as a synthetic antibacterial and antiprotozoal agent and is administered by the intravenous route.

• Metronidazole, USP is chemically designated 2-methyl-5-nitroimidazole-1-ethanol (C6H9N3O3), a crystalline powder sparingly soluble in water. It has the following structural formula:

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• Sodium Chloride, USP is chemically designated NaCl, a white crystalline powder freely soluble in water.

• Water for Injection, USP is chemically designated H2O.

• The flexible plastic container is fabricated from a specially formulated polyvinylchloride. Water can permeate from inside the container into the overwrap but not in amounts sufficient to affect the solution significantly. Solutions inside the plastic container also can leach out certain of its chemical components in very small amounts before the expiration period is attained. However, the safety of the plastic has been confirmed by tests in animals according to USP biological standards for plastic containers.

Pharmacodynamics

Microbiology

Activity In Vitro and In Vivo

• Metronidazole has been shown to be active against most isolates of the following bacteria both in vitro and in clinical infections as described in the INDICATIONS AND USAGE section.

Gram-positive anaerobes

• Clostridium species
• Eubacterium species
• Peptococcus species
• Peptostreptococcus species

Gram-negative anaerobes

• Bacteroides fragilis group (B. fragilis, B. distasonis, B. ovatus, B. thetaiotaomicron,

B. vulgatus)

• Fusobacterium species

• The following in vitro data are available, but their clinical significance is unknown.

• Metronidazole exhibits in vitro minimal inhibitory concentrations (MIC’s) of 8 mcg/mL or less against most (≥ 90%) isolates of the following bacteria; however, the safety and effectiveness of metronidazole in treating clinical infections due to these bacteria have not been established in adequate and well-controlled clinical trials.

Gram-negative anaerobes

• Bacteroides fragilis group (B. caccae, B. uniformis)
• Prevotella species (P. bivia, P. buccae, P. disiens)

Susceptibility Test Methods

• When available, the clinical microbiology laboratory should provide results of in vitro susceptibility test results for antimicrobial drug products used in resident hospitals to the physician as periodic reports that describe the susceptibility profile of nosocomial or community-acquired pathogens. These reports should aid the physician in selecting an antibacterial drug product for treatment.

Anaerobic Techniques

• Quantitative methods are used to determine antimicrobial inhibitory concentrations (MICs). These MICs provide estimates of the susceptibility of bacteria to antimicrobial compounds. For anaerobic bacteria, the susceptibility to metronidazole can be determined by the reference broth and/or agar method.1,2

• The MIC values should be interpreted according to the criteria provided in the following table.

tab

• A report of “Susceptible” indicates that the antimicrobial is likely to inhibit growth of the pathogen if the antimicrobial compound reaches the concentrations at the infection site necessary to inhibit growth of the pathogen. A report of “Intermediate” indicates that the result should be considered equivocal, and, if the microorganism is not fully susceptible to alternative, clinically feasible drugs, the test should be repeated. This category implies possible clinical applicability in body sites where the drug is physiologically concentrated or in situations where a high dosage of the drug product can be used. This category also provides a buffer zone that prevents small uncontrolled technical factors from causing major discrepancies in interpretation. A report of “Resistant” indicates that the antimicrobial is not likely to inhibit growth of the pathogen if the antimicrobial compound reaches the concentrations usually achievable at the infection site; other therapy should be selected.

Quality Control

• Standardized susceptibility test procedures require the use of laboratory controls to monitor and ensure the accuracy and precision of supplies and reagents used in the assay, and the techniques of the individuals performing the test.1,2 Standard metronidazole powder should provide a value within the MIC ranges noted in the following table:

tab

Pharmacokinetics

• In patients treated with metronidazole injection using a dosage regimen of 15 mg/kg loading dose followed six hours later by 7.5 mg/kg every six hours, the average peak steady-state concentrations (Cmax) and trough (Cmin) were 25 mcg/mL and 18 mcg/mL, respectively. Plasma concentrations of metronidazole are proportional to the administered dose. An eight-hour intravenous infusion of 100 mg to 4,000 mg of metronidazole in normal subjects showed a linear relationship between dose and peak plasma concentration. The average elimination half-life of metronidazole in healthy subjects is eight hours.

Distribution

• Metronidazole is the major component appearing in the plasma, with lesser quantities of metabolites also being present. Less than 20% of the circulating metronidazole is bound to plasma proteins. Metronidazole appears in cerebrospinal fluid, saliva and breast milk in concentrations similar to those found in plasma. Bactericidal concentrations of metronidazole have also been detected in pus from hepatic abscesses.

• Following a single intravenous dose of metronidazole 500 mg, 4 healthy subjects who underwent gastrointestinal endoscopy had peak gastric juice metronidazole concentrations of 5 to 6 mcg/mL at one hour post-dose. In patients receiving intravenous metronidazole in whom gastric secretions are continuously removed by nasogastric aspiration, sufficient metronidazole may be removed in the aspirate to cause a reduction in serum levels.

Metabolism

• The metabolites of metronidazole result primarily from side-chain oxidation [1-(βhydroxyethyl)-2-hydroxymethyl-5-nitroimidazole and 2-methyl-5-nitroimidazole-1-ylacetic acid] and glucuronide conjugation. Both the parent compound and the hydroxyl metabolite possess in vitro antimicrobial activity.

Excretion

• The major route of elimination of metronidazole and its metabolites is via the urine (60 to 80% of the dose), with approximately 20% of the amount excreted appearing as unchanged metronidazole. Renal clearance of metronidazole is approximately 10 mL/min/1.73 m2. Fecal excretion accounts for 6 to 15% of the dose.

Renal Impairment

• Decreased renal function does not alter the single-dose pharmacokinetics of metronidazole.

• Subjects with end-stage renal disease (ESRD; CLCR= 8.1±9.1 mL/min) and who received a single intravenous infusion of metronidazole 500 mg had no significant change in metronidazole pharmacokinetics but had 2-fold higher Cmax of hydroxy-metronidazole and 5-fold higher Cmax of metronidazole acetate, compared to healthy subjects with normal renal function (CLCR= 126 ± 16 mL/min). Thus, on account of the potential accumulation of metronidazole metabolites in ESRD patients, monitoring for metronidazole associated adverse events is recommended.

Effect of Dialysis

• Following a single intravenous infusion or oral dose of metronidazole 500 mg, the clearance of metronidazole was investigated in ESRD subjects undergoing hemodialysis or continuous ambulatory peritoneal dialysis (CAPD). A hemodialysis session lasting for 4 to 8 hours removed 40% to 65% of the administered metronidazole dose, depending on the type of the dialyzer membrane used and the duration of the dialysis session. If the administration of metronidazole cannot be separated from the dialysis session, supplementation of metronidazole dose following hemodialysis should be considered (see DOSAGE AND ADMINISTRATION). A peritoneal dialysis session lasting for 7.5 hours removed approximately 10% of the administered metronidazole dose. No adjustment in metronidazole dose is needed in ESRD patients undergoing CAPD.

Hepatic Impairment

• Following a single intravenous infusion of 500 mg metronidazole, the mean AUC24 of metronidazole was higher by 114% in patients with severe (Child-Pugh C) hepatic impairment, and by 54% and 53% in patients with a mild (Child-Pugh A) and moderate (Child-Pugh B) hepatic impairment, respectively, compared to healthy control subjects. There were no significant changes in the AUC24 of hydroxy-metronidazole in these hepatically impaired patients. A reduction in metronidazole dosage by 50% is recommended in patients with severe (Child-Pugh C) hepatic impairment (see DOSAGE AND ADMINISTRATION). No dosage adjustment is needed for patients with mild to moderate hepatic impairment. Patients with mild to moderate hepatic impairment should be monitored for metronidazole associated adverse events.

Geriatric Patients

• Following a single 500 mg oral or IV dose of metronidazole, subjects >70 years old with no apparent renal or hepatic dysfunction had a 40% to 80% higher mean AUC of hydroxy-metronidazole (active metabolite), with no apparent increase in the mean AUC of metronidazole (parent compound), compared to young healthy controls < 40 years old. In geriatric patients, monitoring for metronidazole associated adverse events is recommended.

Pediatric Patients

• In one study newborn infants appeared to demonstrate diminished capacity to eliminate metronidazole. The elimination half-life, measured during the first three days of life, was inversely related to gestational age. In infants whose gestational ages were between 28 and 40 weeks, the corresponding elimination half-lives ranged from 109 to 22.5 hours.

Nonclinical Toxicology

There is limited information regarding Metronidazole (injection) Nonclinical Toxicology in the drug label.

Clinical Studies

There is limited information regarding Metronidazole (injection) Clinical Studies in the drug label.

How Supplied

There is limited information regarding Metronidazole (injection) How Supplied in the drug label.

Storage

There is limited information regarding Metronidazole (injection) Storage in the drug label.

Images

Drug Images

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Patient Counseling Information

There is limited information regarding Metronidazole (injection) Patient Counseling Information in the drug label.

Precautions with Alcohol

Alcohol-Metronidazole (injection) interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.

Brand Names

There is limited information regarding Metronidazole (injection) Brand Names in the drug label.

Look-Alike Drug Names

There is limited information regarding Metronidazole (injection) Look-Alike Drug Names in the drug label.

Drug Shortage Status

Price

References

The contents of this FDA label are provided by the National Library of Medicine.