METRONIDAZOLE

METRONIDAZOLE- metronidazole solution
B. Braun Medical Inc.

500 mg/ 100 mL (5 mg/mL)

Sterile
For Intravenous Infusion Only.

To reduce the development of drug-resistant bacteria and maintain the effectiveness of Metronidazole Injection USP and other antibacterial drugs, Metronidazole Injection USP should be used only to treat or prevent infections that are proven or strongly suspected to be caused by bacteria.

WARNING

Metronidazole has been shown to be carcinogenic in mice and rats (see PRECAUTIONS). Its use, therefore, should be reserved for the conditions described in the INDICATIONS AND USAGE section below.

DESCRIPTION

Metronidazole Injection USP is a sterile, parenteral dosage form of metronidazole in water.

Each 100 mL of Metronidazole Injection USP contains a sterile, nonpyrogenic, isotonic, buffered solution of Metronidazole USP 500 mg, Sodium Chloride USP 740 mg, Dibasic Sodium Phosphate•7H2 O USP 112 mg, and Citric Acid Anhydrous USP 40 mg in Water for Injection USP. Metronidazole Injection USP has a calculated osmolarity of 297 mOsmol/liter and a pH of 5.8 (4.5–7.0). Sodium content: 13.5 mEq/container.

Metronidazole is classified as a nitroimidazole antimicrobial and is administered by the intravenous route.

Metronidazole USP is chemically designated 2-methyl-5-nitroimidazole-1-ethanol (C6 H9 N3 O3 ):

Chemical Structure

Not made with natural rubber latex, PVC, or DEHP.

The plastic container is a copolymer of ethylene and propylene formulated and developed for parenteral drugs. The copolymer contains no plasticizers. The safety of the plastic container has been confirmed by biological evaluation procedures.

The material passes Class VI testing as specified in the U.S. Pharmacopeia for Biological Tests – Plastic Containers. The container/solution unit is a closed system and is not dependent upon entry of external air during administration. No vapor barrier is necessary.

CLINICAL PHARMACOLOGY

Metronidazole is a synthetic antibacterial compound. Disposition of metronidazole in the body is similar for both oral and intravenous dosage forms, with an average elimination half-life in healthy humans of eight hours.

The major route of elimination of metronidazole and its metabolites is via the urine (60 to 80% of the dose), with fecal excretion accounting for 6 to 15% of the dose. The metabolites that appear in the urine result primarily from side-chain oxidation (1-[β -hydroxyethyl]-2-hydroxymethyl-5-nitroimidazole and 2-methyl-5-nitroimidazole-1-yl-acetic acid) and glucuronide conjugation, with unchanged metronidazole accounting for approximately 20% of the total. Renal clearance of metronidazole is approximately 10 mL/min/1.73 m2.

Metronidazole is the major component appearing in the plasma, with lesser quantities of the 2-hydroxymethyl metabolite also being present. Less than 20% of the circulating metronidazole is bound to plasma proteins. Both the parent compound and the metabolite possess in vitro bactericidal activity against most strains of anaerobic bacteria.

Metronidazole appears in cerebrospinal fluid, saliva, and human milk in concentrations similar to those found in plasma. Bactericidal concentrations of metronidazole have also been detected in pus from hepatic abscesses.

Plasma concentrations of metronidazole are proportional to the administered dose. An eight-hour intravenous infusion of 100 to 4,000 mg of metronidazole in normal subjects showed a linear relationship between dose and peak plasma concentration.

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, peak steady-state plasma concentrations of metronidazole averaged 25 mcg/mL with trough (minimum) concentrations averaging 18 mcg/mL.

Decreased renal function does not alter the single-dose pharmacokinetics of metronidazole. However, plasma clearance of metronidazole is decreased in patients with decreased liver function.

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 donors such as ferredoxin and transfer of an electron to the nitro group of the metronidazole leading to 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 may interact with DNA leading to inhibition of DNA synthesis, DNA degradation, and death of bacteria. The precise mechanism of action of metronidazole is unclear.

Drug 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 clinical infections as described in the INDICATIONS AND USAGE section.

Gram negative anaerobes:

Bacteroides fragilis group (B. fragilis, B. distasonis, B. ovatus, B. thetaiotaomicron, B. vulgatus)

Fusobacterium species

Gram positive anaerobes:

Clostridium species

Eubacterium species

Peptococcus species

Peptostreptococcus 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: http://www.fda.gov/STIC.

INDICATIONS AND USAGE

To reduce the development of drug-resistant bacteria and maintain the effectiveness of Metronidazole Injection USP and other antibacterial drugs, Metronidazole Injection USP 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.

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 Injection USP therapy. In a mixed aerobic and anaerobic infection, antibiotics appropriate for the treatment of the aerobic infection should be used in addition to Metronidazole Injection USP.

Metronidazole Injection USP 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 the 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, and Peptostreptococcus 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.

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