um 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. busulfan metronidazole has been reported to increase plasma concentrations of busulfan, which can result in an increased risk for serious busulfan toxicity. metronidazole should not be administered concomitantly with busulfan unless the benefit outweighs the risk. if no therapeutic alternatives to metronidazole are available, and concomitant administration with busulfan is medically needed, frequent monitoring of busulfan plasma concentration should be performed and the busulfan dose should be adjusted accordingly. drugs that inhibit cyp450 enzymes 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. drugs that induce cyp450 enzymes 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. drugs that prolong the qt interval qt prolongation has been reported, particularly when metronidazole was administered with drugs with the potential for prolonging the qt interval. 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 glucose hexokinase. 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.

ether 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 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 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 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. 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 and other antibacterial drugs, metronidazole tablets 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 ). risk of hepatotoxicity and death in patients with cockayne syndrome cases of severe hepatotoxicity/acute hepatic failure, including cases with a fatal outcome with very rapid onset after treatment initiation in patients with cockayne syndrome have been reported with products containing metronidazole for systemic use. in this population, metronidazole should therefore be used after careful benefit-risk assessment and only if no alternative treatment is available. obtain liver function tests prior to the start of therapy, within the first 2 to 3 days after initiation of therapy, frequently during therapy and after end of treatment. discontinue metronidazole if elevation of liver function tests occurs, and monitor liver function tests until the baseline values are reached. advise patients with cockayne syndrome to stop taking metronidazole immediately if they experience any symptoms of potential liver injury, such as abdominal pain, nausea, change in stool color or jaundice, and to contact their healthcare provider.

t be treated during the first trimester (see contraindications ). in pregnant patients for whom alternative treatment has been inadequate, the one-day course of therapy should not be used, as it results in higher serum levels which can reach the fetal circulation (see precautions, pregnancy ). 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-treatment. in the male: treatment should be individualized as it is for the female. amebiasis adults: for acute intestinal amebiasis (acute amebic dysentery): 750 mg orally three times daily for 5 to 10 days. for amebic liver abscess: 500 mg or 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 six hours (approx. 500 mg for a 70-kg adult). 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. dosage adjustments patients with severe hepatic impairment for patients with severe hepatic impairment (child-pugh c), the dose of metronidazole tablets should be reduced by 50% (see clinical pharmacology and precautions ). patients undergoing hemodialysis: hemodialysis removes significant amounts of metronidazole and its metabolites from systemic circulation. the clearance of metronidazole will depend on the type of dialysis membrane used, the duration of the dialysis session, and other factors. if the administration of metronidazole cannot be separated from the hemodialysis session, supplementation of metronidazole dosage following the hemodialysis session should be considered, depending on the patient's clinical situation (see clinical pharmacology ).

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 : qt prolongation has been reported, particularly when metronidazole was administered with drugs with the potential for prolonging the qt interval. 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. to report suspected adverse reactions, contact viona pharmaceuticals inc. at 1-888-304-5011 or fda at 1-800-fda-1088 or www.fda.gov/medwatch.

um 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. busulfan metronidazole has been reported to increase plasma concentrations of busulfan, which can result in an increased risk for serious busulfan toxicity. metronidazole should not be administered concomitantly with busulfan unless the benefit outweighs the risk. if no therapeutic alternatives to metronidazole are available, and concomitant administration with busulfan is medically needed, frequent monitoring of busulfan plasma concentration should be performed and the busulfan dose should be adjusted accordingly. drugs that inhibit cyp450 enzymes 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. drugs that induce cyp450 enzymes 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. drugs that prolong the qt interval qt prolongation has been reported, particularly when metronidazole was administered with drugs with the potential for prolonging the qt interval. 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 glucose hexokinase. 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.

g pregnancy did not show an increased risk; however, the ability of these studies to detect such a signal was limited. metronidazole crosses the placental barrier and its effects on the human fetal organogenesis are not known. reproduction studies have been performed in rats, rabbits, and mice at doses similar to the maximum recommended human dose based on body surface area comparisons. there was no evidence of harm to the fetus due to metronidazole.

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-(ß-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 cmax 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, 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 intracellular electron transport proteins such as ferredoxin, transfer of an electron to the nitro group of the metronidazole, and 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 can interact with dna leading to inhibition of dna synthesis and dna degradation leading to death of the bacteria. the precise mechanism of action of metronidazole is unclear. 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 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 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 tests : for specific information regarding susceptibility test interpretive criteria and associated test methods and quality control standards recognized by fda for this drug, please see: https://www.fda.gov/stic.

eatable by metronidazole in the future.