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.

Metronidazole tablets USP, 250 mg or 500 mg is an oral formulation of the synthetic nitroimidazole antimicrobial, 2-methyl-5-nitro-1H-imidazole-1-ethanol, which has the following structural formula: 

Metronidazole tablets USP contain 250 mg or 500 mg of metronidazole USP. Inactive ingredients include colloidal silicon dioxide, hydroxypropyl cellulose, microcrystalline cellulose, pregelatinized starch (maize), sodium starch glycolate, and stearic acid.

Absorption



Disposition of metronidazole in the body is similar for both oral and intravenous dosage forms. Following oral administration, metronidazole is well absorbed, with peak plasma concentrations occurring between one and two hours after administration.



Plasma concentrations of metronidazole are proportional to the administered dose. Oral administration of 250 mg, 500 mg, or 2,000 mg produced peak plasma concentrations of 6 mcg/mL, 12 mcg/mL, and 40 mcg/mL, respectively. Studies reveal no significant bioavailability differences between males and females; however, because of weight differences, the resulting plasma levels in males are generally lower.



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-(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, 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.



Drug 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.



Activity In Vitro and in Clinical Infections



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 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.

For protozoal parasites:



Standardized tests do not exist for use in clinical microbiology laboratories.

Symptomatic Trichomoniasis. Metronidazole tablets USP are indicated for the treatment of T. vaginalis infection 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 tablets USP are indicated in the treatment of asymptomatic T. vaginalis infection in 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 Sexual Partners. T. vaginalis infection 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 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.

Hypersensitivity



Metronidazole tablets are contraindicated in patients with a prior history of hypersensitivity to metronidazole or other nitroimidazole derivatives.



In patients with trichomoniasis, metronidazole tablets are contraindicated during the first trimester of pregnancy (see PRECAUTIONS).



Psychotic Reaction with Disulfiram



Use of oral metronidazole is associated with psychotic reactions in alcoholic patients who were using disulfiram concurrently. Do not administer metronidazole to patients who have taken disulfiram within the last two weeks (see PRECAUTIONS, Drug Interactions).



Interaction with Alcohol



Use of oral metronidazole is associated with a disulfiram-like reaction to alcohol, including abdominal cramps, nausea, vomiting, headaches, and flushing. Discontinue consumption of alcohol or products containing propylene glycol during and for at least three days after therapy with metronidazole (see PRECAUTIONS, Drug Interactions).

Central and Peripheral Nervous System Effects

 

Encephalopathy and Peripheral Neuropathy



Cases of encephalopathy and peripheral neuropathy (including optic neuropathy) have been reported with metronidazole.



Encephalopathy has been reported in association with cerebellar toxicity characterized by ataxia, dizziness, and dysarthria. CNS lesions seen on MRI have been described in reports of encephalopathy. CNS symptoms are generally reversible within days to weeks upon discontinuation of metronidazole. CNS lesions seen on MRI have also been described as reversible.



Peripheral neuropathy, mainly of sensory type has been reported and is characterized by numbness or paresthesia of an extremity.



Convulsive seizures have been reported in patients treated with metronidazole.



Aseptic Meningitis



Cases of aseptic meningitis have been reported with metronidazole. Symptoms can occur within hours of dose administration and generally resolve after metronidazole therapy is discontinued.



The appearance 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.

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; 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.

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 of Overdosage



There is no specific antidote for metronidazole overdose; therefore, management of the patient should consist of symptomatic and supportive therapy.

Trichomoniasis



In the Female



One-day treatment − two grams of metronidazole tablets, given either as a single dose or in two divided doses of one gram each, given in the same day.



Seven-day course of treatment − 250 mg three times daily for seven consecutive days. There is some indication from controlled comparative studies that cure rates as determined by vaginal smears and signs and symptoms, may be higher after a seven-day course of treatment than after a one-day treatment regimen.



The dosage regimen should be individualized. Single-dose treatment can assure compliance, especially if administered under supervision, in those patients who cannot be relied on to continue the seven-day regimen. A seven-day course of treatment may minimize reinfection by protecting the patient long enough for the sexual contacts to obtain appropriate treatment. Further, some patients may tolerate one treatment regimen better than the other.



Pregnant patients should not 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).

Metronidazole Tablets USP, 500 mg are white to off-white, oblong shaped uncoated tablets, debossed with ‘K’ on one side and ‘11’ on other side.

NDC 60760-664-14 BOTTLES OF 14

NDC 60760-664-40 BOTTLES OF 40

Storage and Stability







Store at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature].







Dispense in a tight, light-resistant container as defined in the USP, with a child-resistant closure (as required).

Distributed by:

Rising Pharmaceuticals, Inc.

Saddle Brook, NJ 07663



Made in India



Code: TS/DRUGS/22/2009



Issued: 11/2019