Flagyl Information
Flagyl ()
Flagyl () Warning
Metronidazole has been shown to be carcinogenic in mice and rats. (See ) Unnecessary use of the drug should be avoided. Its use should be reserved for the conditions described in the section below.
Flagyl () Description
Metronidazole is an oral synthetic antiprotozoal and antibacterial agent, 2-methyl-5-nitroimidazole-1-ethanol, which has the following structural formula:
Flagyl () 375 capsules contain 375 mg of metronidazole USP. Inactive ingredients include corn starch, magnesium stearate, gelatin, black iron oxide, titanium dioxide, FD&C Green No. 3, and D&C Yellow No. 10.
Flagyl () Clinical Pharmacology
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 8 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 m.
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 bactericidal activity against most strains of anaerobic bacteria and trichomonacidal activity.
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.
Flagyl () 375 capsules have been shown to have a rate and extent of absorption similar to metronidazole tablets (Flagyl () ) and were bioequivalent at an equal single dose of 750 mg. In a study conducted with 23 adult healthy female volunteers, oral administration of two 375-mg Flagyl () capsules under fasted conditions produced a mean (±1 SD) peak plasma concentration (C) of 21.4 (±2.8) mcg/mL with a mean T of 1.6 (± 0.7) hours and a mean area under the plasma concentration-time curve (AUC) of 223 (±44) mcg∙hr/mL. In the same study, three 250-mg Flagyl () tablets produced a mean C of 20.4 (± 3.8) mcg/mL with a mean T of 1.4 (± 0.4) hours and a mean AUC of 218 (± 50) mcg∙hr/mL.
Administration of Flagyl () 375 capsules with food does not affect the extent of absorption of metronidazole; however, the presence of food results in a lower C and a delayed T compared to fasted conditions. In a study of 14 healthy adult female volunteers, administration of Flagyl () 375 capsules under fasting conditions produced a mean C of 10.9 (± 1.5) mcg/mL, a mean T of 1.5 (± 1.4) hours, and a mean AUC of 110 (± 34) mcg∙hr/mL compared to a mean C of 8.6 (± 1.6) mcg/mL, a mean T of 4.2 (± 1.7) hours, and a mean AUC of 99 (± 14) mcg∙hr/mL under fed conditions.
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.
Flagyl () Indications And Usage
In amebic liver abscess, metronidazole therapy does not obviate the need for aspiration or drainage of pus.
In the treatment of most serious anaerobic infections, intravenous metronidazole is usually administered initially. This may be followed by oral therapy with Flagyl () 375 capsules at the discretion of the physician.
INTRA-ABDOMINAL INFECTIONS, including peritonitis, intra-abdominal abscess, and liver abscess, caused by species including the group (), species, species, or species.
SKIN AND SKIN STRUCTURE INFECTIONS caused by species including the group, species, species, or species.
GYNECOLOGIC INFECTIONS, including endometritis, endomyometritis, tubo-ovarian abscess, and postsurgical vaginal cuff infection, caused by species including the group, species, or species.
BACTERIAL SEPTICEMIA caused by species including the group or species.
BONE AND JOINT INFECTIONS (as adjunctive therapy) caused by species including the group.
CENTRAL NERVOUS SYSTEM (CNS) INFECTIONS, including meningitis and brain abscess, caused by species including the group.
LOWER RESPIRATORY TRACT INFECTIONS, including pneumonia, empyema, and lung abscess, caused by species including the group.
ENDOCARDITIS caused by species including the group.
To reduce the development of drug-resistant bacteria and maintain the effectiveness of Flagyl () 375 and other antibacterial drugs, Flagyl () 375 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.
Flagyl () Contraindications
Flagyl () 375 capsules are contraindicated in patients with a prior history of hypersensitivity to metronidazole or other nitroimidazole derivatives.
In patients with trichomoniasis, Flagyl () 375 capsules are contraindicated during the first trimester of pregnancy. (See )
Flagyl () Precautions
Patients with severe hepatic disease metabolize metronidazole slowly, with resultant accumulation of metronidazole and its metabolites in the plasma. Accordingly, for such patients, doses below those usually recommended should be administered cautiously.
Known or previously unrecognized candidiasis may present more prominent symptoms during therapy with metronidazole and requires treatment with a candidacidal agent.
Prescribing Flagyl () 375 in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria.
Alcoholic beverages should be avoided while taking Flagyl () 375 capsules and for at least three days afterward. (See .)
Patients should be counseled that antibacterial drugs including Flagyl () 375 should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When Flagyl () 375 is prescribed to treat a bacterial infection, patients should be told that although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed. Skipping doses or not completing the full course of therapy may (1) decrease the effectiveness of the immediate treatment and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by Flagyl () 375 or other antibacterial drugs in the future.
Metronidazole has been reported to potentiate the anticoagulant effect of warfarin and other oral coumarin anticoagulants, resulting in a prolongation of prothrombin time. This possible drug interaction should be considered when metronidazole is prescribed for patients on this type of anticoagulant therapy.
The simultaneous administration of drugs that induce microsomal liver enzymes, such as phenytoin or phenobarbital, may accelerate the elimination of metronidazole, resulting in reduced plasma levels; impaired clearance of phenytoin has also been reported.
The simultaneous administration of drugs that decrease microsomal liver enzyme activity, such as cimetidine, may prolong the half-life and decrease plasma clearance of metronidazole. 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. Serum lithium and serum creatinine levels should be obtained several days after beginning metronidazole to detect any increase that may precede clinical symptoms of lithium intoxication.
Alcoholic beverages should not be consumed during metronidazole therapy and for at least three days afterward because abdominal cramps, nausea, vomiting, headaches, and flushing may occur.
Psychotic reactions have been reported in alcoholic patients who are using metronidazole and disulfiram concurrently. Metronidazole should not be given to patients who have taken disulfiram within the last 2 weeks.
Metronidazole has shown evidence of carcinogenic activity in a number of studies involving chronic, oral administration in mice and rats, but similar studies in the hamster gave negative results.
Prominent among the effects in the mouse was the promotion of pulmonary tumorigenesis. This has been observed in all six reported studies in that species, including one study in which the animals were dosed on an intermittent schedule (administration during every fourth week only). At very high dose levels (approximately 1500 mg/mwhich is approximately 3 times the most frequently recommended human dose for a 50 kg adult based on mg/m), there was a statistically significant increase in the incidence of malignant liver tumors in males. Also, the published results of one of the mouse studies indicate an increase in the incidence of malignant lymphomas as well as pulmonary neoplasms associated with lifetime feeding of the drug. All these effects are statistically significant.
Several long-term, oral-dosing studies in the rat have been completed. There were statistically significant increases in the incidence of various neoplasms, particularly in mammary and hepatic tumors, among female rats administered metronidazole over those noted in the concurrent female control groups.
Two lifetime tumorigenicity studies in hamsters have been performed and reported to be negative.
Metronidazole has shown mutagenic activity in a number of assay systems. studies have failed to demonstrate a potential for genetic damage.
Fertility studies have been performed in mice at doses up to six times the maximum recommended human dose based on mg/mand have revealed no evidence of impaired fertility.
Flagyl () Adverse Reactions
The following reactions have also been reported during treatment with metronidazole:
A sharp, unpleasant metallic taste is not unusual. Furry tongue, glossitis, and stomatitis have occurred; these may be associated with a sudden overgrowth of which may occur during therapy. Rare cases of pancreatitis, which generally 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 Flagyl () 375 capsules.
Flagyl () Overdosage
Single oral doses of metronidazole, up to 15 g, have been reported in suicide attempts and accidental overdoses. Symptoms reported include 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.
Flagyl () 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.
In the treatment of most serious anaerobic infections, intravenous metronidazole is usually administered initially.
The usual adult oral dosage is 7.5 mg/kg every 6 hours. 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.
Patients with severe hepatic disease metabolize metronidazole slowly, with resultant accumulation of metronidazole and its metabolites in the plasma. Accordingly, for such patients, doses below those usually recommended should be administered cautiously. Close monitoring of plasma metronidazole levelsand toxicity is recommended.
The dose of metronidazole should not be specifically reduced in anuric patients because accumulated metabolites may be rapidly removed by dialysis.
Flagyl () How Supplied
Flagyl () 375 capsules have an iron gray opaque body imprinted with 375 mg and a light green opaque cap imprinted with Flagyl () , supplied as:
0025-1942-50 Bottle of 50
Flagyl ()
Flagyl () Principal Display Panel - Capsule Bottle Label
NDC 0025-1942-50
metronidazolecapsules
