Disposition of metronidazole in the body is similar for
both oral and intravenous dosage forms.
FLAGYL ER 750 mg tablets contain 750 mg of metronidazole
in an extended release formulation which allows for once-daily dosing. The
steady state pharmacokinetics were determined in 24 healthy adult female
subjects with a mean ± SD age of 28.8 ± 8.8 years (range: 19–46).2 The
pharmacokinetic parameters of metronidazole after administration of FLAGYL ER
750 mg under fed and fasting conditions are summarized in the following table.
Steady State Pharmacokinetic Parameters of
Metronidazole after 750 mg of FLAGYL ER Given Once a Day for 7 Days
||FLAGYL ER 750 mg daily
Mean ± SD
| Cmax (μg/mL)
Relative to the fasting state,
the rate of metronidazole absorption from the extended release tablet is
increased in the fed state resulting in alteration of the extended release
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
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
2-methyl-5-nitroimidazole-1-ylacetic acid] and glucuronide conjugation, with
unchanged metronidazole accounting for approximately 20% of the total. Both the
parent compound and the hydroxyl metabolite possess in vitro antimicrobial
Renal clearance of
metronidazole is approximately 10 mL/min/1.73 m².1 The
average elimination half-life of metronidazole in healthy subjects is eight
Decreased renal function does
not alter the single-dose pharmacokinetics of metronidazole.
Subjects with end-stage renal
disease (ESRD; CLCR=8.1±9.1mL/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 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.
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 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 hydroxyl-metronidazole in these hepatically impaired
patients. FLAGYL ER tablets should not be administered to patients with severe
(Child-Pugh C) hepatic impairment unless it is deemed that the benefits
outweigh the risks in these patients. No dosage adjustment is needed for
patients with mild to moderate hepatic impairment. Patients with hepatic
impairment who receive the usual recommended dose of FLAGYL ER tablet should be
monitored for metronidazole associated adverse events (see PRECAUTIONS and
DOSAGE AND ADMINISTRATION).
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
In one study, newborn infants appeared to demonstrate
diminished capacity to eliminate metronidazole. The elimination half-life,
measured during the first 3 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.
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 intracellular electron transport
proteins. Because of this alteration to the metronidazole molecule, a
concentration gradient is maintained which promotes the drug's intracellular
transport. Presumably, free radicals are formed which, in turn, react with
cellular components resulting in death of the bacteria.
Metronidazole is active against most obligate anaerobes,
but does not possess any clinically relevant activity against facultative
anaerobes or obligate aerobes.
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.
Peptococcus species Peptostreptococcus species
Bacteroides fragilis group (B. fragilis, B.
distasonis, B. ovatus, B. thetaiotaomicron, B. vulgatus)
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.
Bacteroides fragilis group (B. caccae, B.
Prevotella species (P. bivia, P. buccae,
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 and
community-acquired pathogens. These reports should aid the physician in
selecting an antibacterial drug product for treatment.
Quantitative methods are used to determine antimicrobial
inhibitory concentrations (MICs) provide reproducible 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 dilution method3,4. The MIC values obtained should be
interpreted according to the following criteria:
Susceptibility Test Interpretive Criteria for
| ≤ 8
| ≥ 32
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.
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
Acceptable Quality Control Ranges for Metronidazole
||Minimum Inhibitory Concentration (mcg/mL)
|Bacteroides fragilis ATCC 25285
|Bacteroides thetaiotaomicron ATCC 29741
Bacterial vaginosis (BV) is a clinical syndrome that
results from a replacement of the normal, Lactobacillus-dominant flora
with several other organisms including Gardnerella vaginalis, Mobiluncus
spp, Mycoplasma hominis and anaerobes (Peptostreptococcus spp
and Bacteroides spp).
FLAGYL ER was studied in patients with BV in two
randomized, multicenter, well-controlled, investigator blind clinical trials.5,6
A total of 557 otherwise healthy nonpregnant patients with BV were randomized
to treatment with FLAGYL ER once a day for 7 days (n=270) or 2% clindamycin
vaginal cream one applicator full (5 grams) once a day for 7 days (n=287).
The primary efficacy endpoint for each treatment regimen
was defined as clinical cure assessed at 28–32 days post-therapy. Clinical cure
was defined as a return to normal of the vaginal pH ( ≤ 4.5), absence of a
“fishy” amine odor, and absence of clue cells.
The study results are presented in the table below:
Clinical Cure Rates at One Month
|2% clindamycin cream
|*p < 0.05 versus clindamycin
At one month post-therapy the
pH of the vagina returned to normal earlier and in a greater percentage of
patients in the FLAGYL ER treatment group when compared to the 2% clindamycin
vaginal cream group; 72% vs. 65%, respectively. Likewise, FLAGYL ER restored
the normal Lactobacillus-predominant vaginal flora in a larger
percentage of patients at one month post-therapy when compared to the 2%
clindamycin treated group; 74% vs. 63%, respectively.
1. Salas-Herrera IG, Pearson RM, Johnston A, and Turner
P. Concentration of metronidazole in cervical mucus and serum after single and
repeated oral doses. J Antimicrobial Chemotherapy 1991; 28:283–289.
2. Metronidazole modified-release tablet multiple-dose
bioequivalency study (fed/fasting). G.D. Searle & Co., Protocol No.
S13-94-02-014; Report No. S13-95-06014, 11 July 1995.
3. Clinical and Laboratory Standards Institute (CLSI). Methods
for Antimicrobial Susceptibility Testing of Anaerobic Bacteria; Approved
Standard -Eighth Edition. CLSI document M11-A8. Clinical and Laboratory
Standards Institute, 950 West Valley Road, Suite 2500, Wayne, PA 19087 USA,
4. Clinical and Laboratory Standards Institute (CLSI). Performance
Standards for Antimicrobial Susceptibility Testing; Twenty-third Informational
Supplement, CLSI document M100-S23. CLSI document M100-S23, Clinical and
Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne,
Pennsylvania 19087, USA, 2013.