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 sexual partner 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 sexual partner should be treated with metronidazole tablets usp in cases of reinfection. amebiasis metronidazole tablets usp are indicated in the treatment of acute intestinal amebiasis (amebic dysentery) and amebic liver abscess. in amebic liver abscess, metronidazole tablets usp therapy does not obviate the need for aspiration or drainage of pus. anaerobic bacterial infections metronidazole tablets usp are indicated in the treatment of serious infections caused by susceptible anaerobic bacteria. indicated surgical procedures should be performed in conjunction with metronidazole tablets usp therapy. in a mixed aerobic and anaerobic infection, antimicrobials appropriate for the treatment of the aerobic infection should be used in addition to metronidazole tablets usp. 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 postsurgical 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. to reduce the development of drug-resistant bacteria and maintain the effectiveness of metronidazole tablets usp and other antibacterial drugs, metronidazole tablets 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.

earance of abnormal neurologic signs and symptoms demands the prompt evaluation of the benefit/risk ratio of the continuation of therapy (see adverse reactions ).

a, sometimes accompanied by headache, anorexia, and occasionally vomiting; diarrhea; epigastric distress; and 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 therapy. dermatologic: erythematous rash and pruritus. 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 candida in the vagina, dyspareunia, decrease of libido, proctitis, and fleeting joint pains sometimes resembling “serum sickness.” 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 metronidazole tablets.

found in plasma. bactericidal concentrations of metronidazole have also been detected in pus from hepatic abscesses. metabolism/excretion 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. both the parent compound and the hydroxyl metabolite possess in vitro antimicrobial activity. renal clearance of metronidazole is approximately 10 ml/min/1.73 m 2 . the average elimination half-life of metronidazole in healthy subjects is eight hours. renal impairment decreased renal function does not alter the single-dose pharmacokinetics of metronidazole. subjects with end-stage renal disease (esrd; cl cr = 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 c max of hydroxy-metronidazole and 5 fold higher c max of metronidazole acetate, compared to healthy subjects with normal renal function (cl cr = 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. hepatic impairment following a single intravenous infusion of 500 mg metronidazole, the mean auc 24 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 auc 24 of hydroxyl-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 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. microbiology 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 created and 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. 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 protozoal parasites entamoeba histolytica trichomonas vaginalis the following in vitro data are available, but their clinical significance is unknown : metronidazole exhibits in vitro minimum 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 tests methods when available, the clinical microbiology laboratory should provide the 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. anaerobic techniques quantitative methods are used to determine minimum inhibitory concentrations provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. for anaerobic bacteria susceptibility to metronidazole can be determined by the reference broth or agar dilution method 1, 2 . the mic values obtained should be interpreted according to the following criteria: susceptibility test interpretive criteria for metronidazole mic (mcg/ml) interpretation ≤ 8 susceptible (s) 16 intermediate (i) ≥ 32 resistant (r) for protozoal parasites: standardized tests do not exist for use in clinical microbiology laboratories. 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 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. quality control standardized susceptibility 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 following table: agar and broth acceptable quality control ranges for metronidazole acceptable quality control ranges for metronidazole qc strain minimum inhibitory concentration (mcg/ml) agar broth bacteroides fragilis atcc 25285 0.25 to 1 0.25 to 2 bacteroides thetaiotaomicron atcc 29741 0.5 to 2 0.5 to 4

document m100-s23. clsi document m100-s23, clinical and laboratory standards institute, 950 west valley road, suite 2500, wayne, pennsylvania 19087, usa, 2013. manufactured in czech republic by: teva czech industries s.r.o. opava-komarov, czech republic manufactured for: teva pharmaceuticals usa sellersville, pa 18960 repackaged by: proficient rx lp thousand oaks, ca 91320 rev. b 9/2013