metronidazole injection, USP NDC 0409-7811-XX

INDICATIONS AND USAGE

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 (see DOSAGE AND ADMINISTRATION).

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.

DOSAGE AND ADMINISTRATION

In elderly patients the pharmacokinetics of metronidazole may be altered and, therefore, monitoring of serum levels may be necessary to adjust the metronidazole dosage accordingly.

Treatment of Anaerobic Bacterial Infections:

The recommended dosage schedule for Adults is:

Parenteral therapy may be changed to oral metronidazole when conditions warrant, based upon the severity of the disease and the response of the patient to treatment with Metronidazole Injection, USP treatment. The usual adult oral dosage is 7.5 mg/kg every six hours (approximately 500 mg for a 70-kg adult).

A maximum of 4 g should not be exceeded during a 24-hour period.

The usual duration of therapy is 7 to 10 days; however, infections of the bone and joint, lower respiratory tract, and endocardium may require longer treatment.

Dosage Adjustments

Patients with Severe Hepatic Impairment

For patients with severe hepatic impairment (Child-Pugh C), the metronidazole dose should be reduced by 50% (see CLINICAL PHARMACOLOGY and PRECAUTIONS).

Patients Undergoing Hemodialysis

Hemodialysis removes significant amounts of metronidazole and its metabolites from systemic circulation. The clearance of metronidazole will depend on the type of dialysis membrane used, the duration of the dialysis session, and other factors. If the administration of metronidazole cannot be separated from a hemodialysis session, supplementation of metronidazole dosage following a hemodialysis session should be considered, depending on the patient's clinical situation (see CLINICAL PHARMACOLOGY).

Prophylaxis

For surgical prophylactic use, to prevent postoperative infection in contaminated or potentially contaminated colorectal surgery, the recommended dosage schedule for adults is:

a.

15 mg/kg infused over 30 to 60 minutes and completed approximately one hour before surgery; followed by

b.

7.5 mg/kg infused over 30 to 60 minutes at 6 and 12 hours after the initial dose.

It is important that (1) administration of the initial preoperative dose be completed approximately one hour before surgery so that adequate drug levels are present in the serum and tissues at the time of initial incision, and (2) Metronidazole Injection, USP be administered, if necessary, at 6-hour intervals to maintain effective drug levels. Prophylactic use of Metronidazole Injection, USP should be limited to the day of surgery only, following the above guidelines.

CAUTION: Metronidazole Injection, USP is to be administered by slow intravenous drip infusion only, either as a continuous or intermittent infusion. I.V. admixtures containing metronidazole and other drugs should be avoided. Additives should not be introduced into this solution. If used with a primary intravenous fluid system, the primary solution should be discontinued during metronidazole infusion. DO NOT USE EQUIPMENT CONTAINING ALUMINUM (e.g., NEEDLES, CANNULAE) THAT WOULD COME IN CONTACT WITH THE DRUG SOLUTION.

Metronidazole Injection, USP is a ready-to-use isotonic solution. NO DILUTION OR BUFFERING IS REQUIRED. Do not refrigerate. Each container of Metronidazole Injection contains 14 mEq of sodium.

Do not use if cloudy or precipitated or if the seal is not intact.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

Use sterile equipment. It is recommended that the intravenous administration apparatus be replaced at least once every 24 hours.

CONTRAINDICATIONS

Hypersensitivity

Metronidazole Injection, USP is contraindicated in patients with a prior history of hypersensitivity to metronidazole or other nitroimidazole derivatives.

Psychotic Reaction with Disulfiram

Use of oral metronidazole is associated with psychotic reactions in alcoholic patients who were using disulfiram concurrently. Do not administer metronidazole to patients who have taken disulfiram within the last two weeks (see PRECAUTIONS-Drug Interactions).

Interaction with Alcohol

Use of oral metronidazole is associated with a disulfiram-like reaction to alcohol, including abdominal cramps, nausea, vomiting, headaches, and flushing. Discontinue consumption of alcohol or products containing propylene glycol during and for at least three days after therapy with metronidazole (see PRECAUTIONS-Drug Interactions).

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).

WARNINGS

PRECAUTIONS

ADVERSE REACTIONS

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

Central Nervous System

The most serious adverse reactions reported in patients treated with metronidazole injection 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).

The following reactions have also been reported during treatment with metronidazole injection:

Gastrointestinal

The most common adverse reactions reported have been referable to the gastrointestinal tract, particularly nausea, sometimes accompanied by headache, anorexia and occasionally vomiting, diarrhea; epigastric distress; abdominal cramping; and constipation.

Mouth

A sharp, unpleasant metallic taste is not unusual. Furry tongue, glossitis, and stomatitis have occurred; these may be associated with a sudden overgrowth of Candida which may occur during effective therapy.

Dermatologic

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

Hematopoietic

Reversible neutropenia (leukopenia); rarely, reversible thrombocytopenia.

Local Reactions

Thrombophlebitis after intravenous infusion. This reaction can be minimized or avoided by avoiding prolonged use of indwelling intravenous catheters.

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.

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.

Renal

Dysuria, cystitis, polyuria, incontinence, and a sense of pelvic pressure. Instances of darkened urine have been reported by approximately one patient in 100,000. Although the pigment which is probably responsible for this phenomenon has not been positively identified, it is almost certainly a metabolite of metronidazole and seems to have no clinical significance.

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).

Other

Proliferation of Candida in the vagina, dyspareunia, decrease of libido, proctitis, and fleeting joint pains sometimes resembling "serum sickness." Rare cases of pancreatitis, which abated on withdrawal of the drug, have been reported.

Patients with Crohn's disease are known to have an increased incidence of gastrointestinal and certain extraintestinal cancers. There have been some reports in the medical literature of breast and colon cancer in Crohn's disease patients who have been treated with metronidazole at high doses for extended periods of time. A cause and effect relationship has not been established. Crohn's disease is not an approved indication for Metronidazole Injection, USP.

OVERDOSAGE

Use of dosages of intravenous metronidazole hydrochloride higher than those recommended has been reported. These include the use of 27 mg/kg three times a day for 20 days, and the use of 75 mg/kg as a single loading dose followed by 7.5 mg/kg maintenance doses. No adverse reactions were reported in either of the two cases.

Single oral doses of metronidazole, up to 15 g, have been reported in suicide attempts and accidental overdoses. Symptoms reported included nausea, vomiting, and ataxia.

Oral metronidazole has been studied as a radiation sensitizer in the treatment of malignant tumors. Neurotoxic effects, including seizures and peripheral neuropathy, have been reported after 5 to 7 days of doses of 6 to 10.4 g every other day.

Treatment of Overdosage

There is no specific antidote for metronidazole overdose; therefore, management of the patient should consist of symptomatic and supportive therapy.

DESCRIPTION

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:

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.

CLINICAL PHARMACOLOGY

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 (see PRECAUTIONS).

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 (see PRECAUTIONS and DOSAGE AND ADMINISTRATION).

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 (see PRECAUTIONS).

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.

Microbiology

Mechanism of Action

Metronidazole, a nitroimidazole, exerts antibacterial effects in an anaerobic environment against most obligate anaerobes. Once metronidazole enters the organism by passive diffusion and activated in the cytoplasm of susceptible anaerobic bacteria, it is reduced; this process includes intra-cellular electron transport proteins such as ferredoxin, transfer of an electron to the nitro group of the metronidazole, and formation of a short-lived nitroso free radical. Because of this alteration of the metronidazole molecule, a concentration gradient is created and maintained which promotes the drug's intracellular transport. The reduced form of metronidazole and free radicals can interact with DNA leading to inhibition of DNA synthesis and DNA degradation leading to death of bacteria. The precise mechanism of action of metronidazole is unclear.

Resistance

A potential for development of resistance exists against metronidazole.

Resistance may be due to multiple mechanisms that include decreased uptake of the drug, altered reduction efficiency, overexpression of the efflux pumps, inactivation of the drug, and/or increased DNA damage repair.

Metronidazole does not possess any clinically relevant activity against facultative anaerobes or obligate aerobes.

Antimicrobial Activity

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 Testing

For specific information regarding susceptibility test interpretive criteria and associated test methods and quality control standards recognized by FDA for this drug, please see: https://www.fda.gov/STIC.

HOW SUPPLIED

Metronidazole Injection, USP, sterile, is supplied in 100 mL single dose flexible containers, each containing 500 mg (5 mg/mL) of metronidazole (List 7811).

Metronidazole Injection, USP should be stored at 20 to 25°C (68 to 77°F) [See USP Controlled Room Temperature] and protected from light during storage.

Injection, USP

500 mg (5 mg/mL)

Single Dose Container
Flexible Container

For Intravenous Infusion Only

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 bacteria.

INSTRUCTIONS FOR USE

To Open

Tear outer wrap at notch and remove solution container. Some opacity of the plastic due to moisture absorption during the sterilization process may be observed. This is normal and does not affect the solution quality or safety. The opacity will diminish gradually.

Preparation for Administration

(Use aseptic technique)

1.

Close flow control clamp of administration set.

2.

Remove cover from outlet port at bottom of container.

3.

Insert piercing pin of administration set into port with a twisting motion until the set is firmly seated. NOTE: See full directions on administration set carton.

4.

Suspend container from hanger.

5.

Squeeze and release drip chamber to establish proper fluid level in chamber.

6.

Open flow control clamp and clear air from set. Close clamp.

7.

Attach set to venipuncture device. If device is not indwelling, prime and make venipuncture.

8.

Regulate rate of administration with flow control clamp.

WARNING: Do not use flexible container in series connections. Such use could result in air embolism due to residual air being drawn from the primary container before administration of the fluid from the secondary container is complete.

This product’s labeling may have been updated. For the most recent prescribing information, please visit www.pfizer.com.

LAB-0873-10.0

Revised: 07/2024