ion 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. 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 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.

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

iously unrecognized candidiasis may present more prominent symptoms during therapy with metronidazole and requires treatment with a candidacidal agent. use in patients with blood dyscrasias metronidazole is a nitroimidazole and should be used with caution in patients with evidence of or history of blood dyscrasia. a mild leucopenia 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. drug-resistant bacteria and parasites prescribing metronidazole extended-release tablets 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 and parasites.

pending on the patient’s clinical situation (see clinical pharmacology ).

%) nausea 28 (10%) 8 (3%) taste perversion (metallic taste) 23 (9%) 1 (0%) infection bacterial 19 (7%) 17 (6%) influenza-like symptoms 17 (6%) 20 (7%) pruritus genital 14 (5%) 25 (9%) abdominal pain 10 (4%) 13 (5%) dizziness 11 (4%) 3 (1%) diarrhea 11 (4%) 3 (1%) upper respiratory tract infection 11 (4%) 10 (4%) rhinitis 12 (4%) 10 (4%) sinusitis 7 (3%) 6 (2%) urine abnormal 7 (3%) 4 (1%) pharyngitis 8 (3%) 4 (1%) dysmenorrhea 9 (3%) 7 (2%) moniliasis 9 (3%) 8 (3%) mouth dry 5 (2%) 2 (1%) urinary tract infection 6 (2%) 16 (6%) vulvovaginal candidiasis is a recognized consequence of treatment with many anti-infective agents. in these multicenter clinical trials, there were no statistically significant differences in the incidence rates of yeast vaginitis for groups of patients treated with metronidazole extended-release tablets or the vaginal comparator. the following reactions have 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 headache, syncope, 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, sometimes accompanied by headache, anorexia, and occasionally vomiting, diarrhea, epigastric distress; 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. hepatic: cases of severe irreversible hepatotoxicity/acute liver failure, including cases with fatal outcomes with very rapid onset after initiation of systemic use of metronidazole, have been reported in patients with cockayne syndrome (latency from drug start to signs of liver failure as short as 2 days) ( see contraindications ). 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 extended-release 750 mg tablets.

ion 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. 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 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.

onidazole exposure during 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 about four times the recommended human dose based on body surface area comparisons. there was no evidence of harm to the fetus due to metronidazole.

4.2 ± 2.2 t max (hrs) 4.6 ± 2.4 6.8 ± 2.8 t ½ (hrs) 7.4 ± 1.6 8.7 ± 2.2 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 characteristics. distribution 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 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 . 1 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 cmax 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 auc24 of hydroxyl-metronidazole in these hepatically impaired patients. metronidazole extended-release 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 metronidazole extended-release tablet 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 intra-cellular 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 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 bacteroides species gardnerella vaginalis mobiluncus species peptostreptococcus species susceptibility testing 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.

es test. studies in mammals in vivo have failed to demonstrate a potential for genetic damage. metronidazole failed to produce any adverse effects on fertility or testicular function in male rats at doses up to 400 mg/kg/day (approximately 5 times the recommended dose based on body surface area comparisons) for 28 days. however, rats treated at the same dose for 6 weeks, or longer were infertile and showed severe degeneration of the seminiferous epithelium in the testes as well as marked decreases in testicular spermatid counts and epididymal sperm counts. fertility was restored in most rats after an eight week, drug-free recovery period.

dy results are presented in the table below: clinical cure rates at one month metronidazole extended-release tablets % (n/n) 2% clindamycin cream % (n/n) study 1 61% (77/126) 59% (80/135) study 2 62% (74/119)* 43% (50/117) *p<0.05 versus clindamycin cream at one month post-therapy the ph of the vagina returned to normal earlier and in a greater percentage of patients in the metronidazole extended-release tablets treatment group when compared to the 2% clindamycin vaginal cream group; 72% vs. 65%, respectively. likewise, metronidazole extended-release tablets 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.

a will develop resistance and will not be treatable by metronidazole extended-release tablets in the future.