Spl unclassified section
Rx onlyRev. 08/10
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.
Boxed warning section
Metronidazole has been shown to be carcinogenic in mice and rats. (See PRECAUTIONS.) Unnecessary use of the drug should be avoided. Its use should be reserved for the conditions described in the INDICATIONS AND USAGEsection below.
Metronidazole is an oral synthetic antiprotozoal and antibacterial agent, 2-Methyl-5-nitroimidazole-1-ethanol, which has the following structural formula:
Metronidazole capsules contain 375 mg of metronidazole USP. Inactive ingredients include corn starch, gelatin, magnesium stearate, pregelatinized starch, titanium dioxide, FD&C Green No. 3, D&C Yellow No. 10, and synthetic black iron oxide, pharmaceutical glaze, propylene glycol, FD&C Blue No. 2, FD&C Red No. 40, FD&C Blue No. 1, and D&C Yellow No. 10.
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-(-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 2.
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 vitrobactericidal activity against most strains of anaerobic bacteria and in vitrotrichomonacidal 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.
Metronidazole capsules have been shown to have a rate and extent of absorption similar to metronidazole tablets 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 metronidazole capsules under fasted conditions produced a mean ( 1 SD) peak plasma concentration (C max) of 21.4 ( 2.8) mcg/mL with a mean T maxof 1.6 ( 0.7) hours and a mean area under the plasma concentration-time curve (AUC) of 223 ( 44) mcghr/mL. In the same study, three 250 mg metronidazole tablets produced a mean C maxof 20.4 ( 3.8) mcg/mL with a mean T maxof 1.4 ( 0.4) hours and a mean AUC of 218 ( 50) mcghr/mL.
Administration of metronidazole capsules with food does not affect the extent of absorption of metronidazole; however, the presence of food results in a lower C maxand a delayed T maxcompared to fasted conditions. In a study of 14 healthy, adult, female volunteers, administration of metronidazole capsules under fasting conditions produced a mean C maxof 10.9 ( 1.5) mcg/mL, a mean T maxof 1.5 ( 1.4) hours, and a mean AUC of 110 ( 34) mcghr/mL compared to a mean C maxof 8.6 ( 1.6) mcg/mL, a mean T maxof 4.2 ( 1.7) hours, and a mean AUC of 99 ( 14) mcghr/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.
Metronidazole exerts antimicrobial 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 microorganism.
Metronidazole has been shown to be active against most strains of the following microorganisms both in vitroand in clinical infections as described in the INDICATIONS AND USAGEsection.
Bacteroides fragilisgroup ( B. fragilis, B. distasonis, B. ovatus, B. thetaiotaomicron,
Metronidazole exhibits in vitrominimal inhibitory concentrations (MIC's) of 8 mcg/mL or less against most ( >90%) strains of the following microorganisms; however, the safety and effectiveness of metronidazole in treating clinical infections due to these microorganisms have not been established in adequate and well-controlled clinical trials.
Bacteroides fragilisgroup ( B. caccae, B. uniformis)
Prevotellaspecies ( P. bivia, P. buccae, P. disiens)
Metronidazole is active against most obligate anaerobes, but does not possess any clinically relevant activity against facultative anaerobes or obligate aerobes.
Spl unclassified section
Quantitative methods that are used to determine minimum inhibitory concentrations provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. For anaerobic bacteria, the susceptibility to metronidazole can be determined by the reference agar dilution method or by alternate standardized test methods 1. The MIC values obtained should be interpreted according to the following criteria:
For protozoal parasites: Standardized tests do not exist for use in clinical microbiology laboratories.
A report of "Susceptible" indicates that the pathogen is likely to be inhibited by usually achievable concentrations of the antimicrobial compound in the blood. 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 high dosage of drug can be used. This category also provides a buffer zone which prevents small uncontrolled technical factors from causing major discrepancies in interpretation. A report of "Resistant" indicates that usually achievable concentrations of the antimicrobial compound in the blood are unlikely to be inhibitory and other therapy should be selected.
Standardized susceptibility test procedures require the use of laboratory control microorganisms that are used to control the technical aspects of the laboratory procedures.
Standard metronidazole powder should provide the following MIC values:
ATCC 25285 Bacteroides fragilis
Bacteroides thetaiotaomicronATCC 29741
Indications and usage
Symptomatic Trichomoniasis.Metronidazole capsules are indicated for the treatment of symptomatic trichomoniasis in females and males when the presence of the trichomonad has been confirmed by appropriate laboratory procedures (wet smears and/or cultures).
Asymptomatic Trichomoniasis. Metronidazole capsules are indicated in the treatment of asymptomatic females when the organism is associated with endocervicitis, cervicitis, or cervical erosion. Since there is evidence that presence of the trichomonad can interfere with accurate assessment of abnormal cytological smears, additional smears should be performed after eradication of the parasite.
Treatment of Asymptomatic Consorts. T. vaginalisinfection is a venereal disease. Therefore, asymptomatic sexual partners of treated patients should be treated simultaneously if the organism has been found to be present, in order to prevent reinfection of the partner. The decision as to whether to treat an asymptomatic male partner who has a negative culture or one for whom no culture has been attempted is an individual one. In making this decision, it should be noted that there is evidence that a woman may become reinfected if her consort is not treated. Also, since there can be considerable difficulty in isolating the organism from the asymptomatic male carrier, negative smears and cultures cannot be relied upon in this regard. In any event, the consort should be treated with metronidazole in cases of reinfection.
Amebiasis:Metronidazole capsules are indicated in the treatment of acute intestinal amebiasis (amebic dysentery) and amebic liver abscess.
In amebic liver abscess, metronidazole therapy does not obviate the need for aspiration or drainage of pus.
Anaerobic Bacterial Infections. Metronidazole capsules are 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, antimicrobials appropriate for the treatment of the aerobic infection should be used in addition to metronidazole capsules.
In the treatment of most serious anaerobic infections, intravenous metronidazole is usually administered initially. This may be followed by oral therapy with metronidazole capsules at the discretion of the physician.
INTRA-ABDOMINAL INFECTIONS, including peritonitis, intra-abdominal abscess, and liver abscess, caused by Bacteroidesspecies including the B. fragilisgroup ( B. fragilis, B. distasonis, B. ovatus, B. thetaiotaomicron, B. vulgatus), Clostridiumspecies, Eubacteriumspecies, Peptococcus niger, or Peptostreptococcusspecies.
SKIN AND SKIN STRUCTURE INFECTIONS caused by Bacteroidesspecies including the B. fragilisgroup, Clostridiumspecies, Peptococcus niger, Peptostreptococcusspecies, or Fusobacteriumspecies.
GYNECOLOGIC INFECTIONS, including endometritis, endomyometritis, tubo-ovarian abscess, and postsurgical vaginal cuff infection, caused by Bacteroidesspecies including the B. fragilisgroup, Clostridiumspecies, Peptococcus niger,or Peptostreptococcusspecies.
BACTERIAL SEPTICEMIA caused by Bacteroidesspecies including the B. fragilisgroup or Clostridiumspecies.
BONE AND JOINT INFECTIONS (as adjunctive therapy) caused by Bacteroidesspecies including the B. fragilisgroup.
CENTRAL NERVOUS SYSTEM (CNS) INFECTIONS, including meningitis and brain abscess, caused by Bacteroidesspecies including the B. fragilisgroup.
LOWER RESPIRATORY TRACT INFECTIONS, including pneumonia, empyema, and lung abscess, caused by Bacteroidesspecies including the B. fragilisgroup.
ENDOCARDITIS caused by Bacteroidesspecies including the B. fragilisgroup.
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.
Metronidazole capsules are contraindicated in patients with a prior history of hypersensitivity to metronidazole or other nitroimidazole derivatives.
In patients with trichomoniasis, metronidazole capsules are contraindicated during the first trimester of pregnancy. (See PRECAUTIONS.)
Central and Peripheral Nervous System Effects:Convulsive seizures, encephalopathy, aseptic meningitis, optic and peripheral neuropathy, the latter characterized mainly by numbness or paresthesia of an extremity, have been reported in patients treated with metronidazole. The appearance of abnormal neurologic signs demands the prompt discontinuation of metronidazole therapy. Metronidazole should be administered with caution to patients with central nervous system diseases.
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 metronidazole 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.
Information for patients
Alcoholic beverages should be avoided while taking metronidazole capsules and for at least three days afterward. (See Drug interactions.)
Patients should be counseled that antibacterial drugs including metronidazole should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When metronidazole 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 metronidazole or other antibacterial drugs in the future.
Metronidazole is a nitroimidazole and should be used with caution in patients with evidence of or history of blood dyscrasia. A mild leukopenia has been observed during its administration; however, no persistent hematologic abnormalities attributable to metronidazole have been observed in clinical studies. Total and differential leukocyte counts are recommended before and after therapy for trichomoniasis and amebiasis, especially if a second course of therapy is necessary, and before and after therapy for anaerobic infections.
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.
Drug/laboratory test interactions
Metronidazole may interfere with certain types of determinations of serum chemistry values, such as aspartate aminotransferase (AST, SGOT), alanine aminotransferase (ALT, SGPT), lactate dehydrogenase (LDH), triglycerides, and hexokinase glucose. Values of zero may be observed. All of the assays in which interference has been reported involve enzymatic coupling of the assay to oxidation-reduction of nicotinamide adenine dinucleotide (NAD +NADH). Interference is due to the similarity in absorbance peaks of NADH (340 nm) and metronidazole (322 nm) at pH 7.
Carcinogenesis, mutagenesis, impairment of fertility
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/m 2which is approximately 3 times the most frequently recommended human dose for a 50 kg adult based on mg/m 2) 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 in vitroassay systems. In vivostudies 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/m 2and have revealed no evidence of impaired fertility.
Teratogenic effects section
Metronidazole crosses the placental barrier and enters the fetal circulation rapidly. Reproduction studies have been performed in rats at doses up to five times the human dose and have revealed no evidence of impaired fertility or harm to the fetus due to metronidazole. No fetotoxicity was observed when metronidazole was administered orally to pregnant mice at 60 mg/m 2/day, which is approximately 10% of the human dose when expressed as mg/m 2. However, in a single small study where the drug was administered intraperitoneally, some intrauterine deaths were observed. The relationship of these findings to the drug is unknown. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, and because metronidazole is a carcinogen in rodents, this drug should be used during pregnancy only if clearly needed. (See CONTRAINDICATIONS.)
Metronidazole use in the second and third trimesters of pregnancy should be restricted to those patients in whom alternative treatment has been inadequate. Use of metronidazole in the first trimester should be carefully evaluated because metronidazole crosses the placental barrier and its effects on human fetal organogenesis are not known. (See above.)
Because of the potential for tumorigenicity shown for metronidazole in mouse and rat studies, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Metronidazole is secreted in human milk in concentrations similar to those found in plasma.
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. Therefore, in elderly patients, monitoring of serum levels may be necessary to adjust the metronidazole dosage accordingly.
Safety and effectiveness in pediatric patients have not been established, except in the treatment of amebiasis.
The following reactions have also been reported during treatment with metronidazole:
Central Nervous System:The most serious adverse reactions reported in patients treated with metronidazole 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 dizziness, vertigo, incoordination, ataxia, confusion, dysarthria, irritability, depression, weakness, and insomnia. (See WARNINGS.)
Gastrointestinal:The most common adverse reactions reported have been referable to the gastrointestinal tract, particularly nausea reported by about 12% of patients, sometimes accompanied by headache, anorexia, and occasionally vomiting; diarrhea; epigastric distress; and abdominal cramping. Constipation has also been reported.
A sharp, unpleasant metallic taste is not unusual. Furry tongue, glossitis, and stomatitis have occurred; these may be associated with a sudden overgrowth of Candidawhich may occur during therapy. Rare cases of pancreatitis, which generally abated on withdrawal of the drug, have been reported.
Hematopoietic:Reversible neutropenia (leukopenia); rarely, reversible thrombocytopenia.
Cardiovascular:Flattening of the T-wave may be seen in electrocardiographic tracings.
Hypersensitivity:Urticaria, erythematous rash, Stevens-Johnson Syndrome, toxic epidermal necrolysis, 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.
Other:Proliferation of Candidain the vagina, dyspareunia, decrease of libido, proctitis, and fleeting joint pains sometimes resembling serum sickness. If patients receiving metronidazole drink alcoholic beverages, they may experience abdominal distress, nausea, vomiting, flushing, or headache. A modification of the taste of alcoholic beverages has also 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 capsules.
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.
Treatment:There is no specific antidote for metronidazole overdose; therefore, management of the patient should consist of symptomatic and supportive 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.
In the Female:
Seven-day course of treatment375 mg two times daily for seven consecutive days.
A seven-day course of treatment may minimize reinfection by protecting the patient long enough for the sexual contacts to obtain treatment. Pregnant patients should not be treated during the first trimester. (See CONTRAINDICATIONSand PRECAUTIONS.)
When repeat courses of the drug are required, it is recommended that an interval of four to six weeks elapse between courses and that the presence of the trichomonad be reconfirmed by appropriate laboratory measures. Total and differential leukocyte counts should be made before and after re-treatments.
In the Male:Treatment should be individualized as for the female.
For acute intestinal amebiasis (acute amebic dysentery):750 mg orally three times daily for 5 to 10 days.
For amebic liver abscess:750 mg orally three times daily for 5 to 10 days.
Pediatric patients:35 to 50 mg/kg/24 hours, divided into three doses, orally for 10 days.
Anaerobic bacterial infections:
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 levels 2and toxicity is recommended.
The dose of metronidazole should not be specifically reduced in anuric patients because accumulated metabolites may be rapidly removed by dialysis.
Metronidazole Capsules USP, 375 mg are light green opaque in color with 375 mg imprinted in band on the body and PLIVA imprinted in band on the cap in black ink, supplied in bottles of 50.
Storage and Stability:Store at controlled room temperature 20 to 25C (68 to 77F) [see USP Controlled Room Temperature]. Dispense in a well-closed container with a child-resistant closure. Protect from light.
1. National Committee for Clinical Laboratory Standards, Methods for Antimicrobial Susceptibility Testing of Anaerobic Bacteria - Third Edition. Approved Standard NCCLS Document M11-A3, Vol. 13, No. 26, NCCLS, Villanova, PA, December, 1993.
2. Ralph ED, Kirby WMM. Bioassay of metronidazole with either anaerobic or aerobic incubation, J. Infect. Dis.1975; 132 (Nov): 587-591 or Gulaid et al. Determination of metronidazole and its major metabolites in biological fluids by high pressure liquid chromatography, Br. J. Clin. Pharmacol.1978; 6:430-432.
Par Pharmaceutical Companies, Inc.
Spring Valley, NY 10977
Teva Pharmaceuticals USA
Sellersville, PA 18960
Ingredients and appearance - Product information
Metronidazole capsule- Metronidazole
|Product Type||HUMAN PRESCRIPTION DRUG LABEL||Item Code (Source)||NDC: 50111-884|
|Route of Administration||Oral|
|Metronidazole ( UNII: 140QMO216E)( Metronidazole - UNII: 140QMO216E )||375 mgin 1|
|Starch, corn||( UNII: O8232NY3SJ)|
|Gelatin||( UNII: 2G86QN327L)|
|Magnesium stearate||( UNII: 70097M6I30)|
|Titanium dioxide||( UNII: 15FIX9V2JP)|
|Fd&c green no. 3||( UNII: 3P3ONR6O1S)|
|Propylene glycol||( UNII: 6DC9Q167V3)|
|Fd&c blue no. 2||( UNII: L06K8R7DQK)|
|Fd&c red no. 40||( UNII: WZB9127XOA)|
|Fd&c blue no. 1||( UNII: H3R47K3TBD)|
|D&c yellow no. 10||( UNII: 35SW5USQ3G)|
|Color||GREEN (light green opaque)||Size||19 mm|
|Marketing Category||Application Number or Monograph Citation||Territorial Authority||Marketing Start Date|
Labeler - Pliva( 118234421)