Flagyl

DESCRIPTION

FLAGYL (metronidazole) tablets, 250 mg or 500 mg is an oral formulation of the synthetic nitroimidazoleantimicrobial, 2-methyl-5-nitro-1H-imidazole-1-ethanol, which has the following structural formula:

FLAGYL (metronidazole) tablets contain 250 mg or 500 mg of metronidazole. Inactive ingredients include cellulose, FD&C Blue No. 2 Lake, hydroxypropyl cellulose, hypromellose, polyethylene glycol, stearic acid, and titanium dioxide.

INDICATIONS

Symptomatic Trichomoniasis.FLAGYL is indicated for the treatment ofT. vaginalisinfection in females and males when the presence of the trichomonad has been confirmed by appropriate laboratory procedures (wet smears and/or cultures).

Asymptomatic Trichomoniasis.FLAGYL is indicated in the treatment of asymptomaticT. vaginalisinfection in females when the organism is associated with endocervicitis,cervicitis, orcervicalerosion. 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 theparasite.

Treatment of Asymptomatic Sexual Partners.T. vaginalisinfection is avenereal 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 FLAGYL in cases of reinfection.

Amebiasis.FLAGYL is indicated in the treatment of acute intestinalamebiasis(amebic dysentery) and amebic liverabscess.

In amebic liver abscess, FLAGYL therapy does not obviate the need foraspirationor drainage ofpus.

Anaerobic Bacterial Infections.FLAGYL is indicated in the treatment of serious infections caused by susceptibleanaerobicbacteria. Indicated surgical procedures should be performed in conjunction with FLAGYL therapy. In a mixedaerobicand anaerobic infection, antimicrobials appropriate for the treatment of the aerobic infection should be used in addition to FLAGYL.

INTRA-ABDOMINAL INFECTIONS, including peritonitis, intra-abdominal abscess, and liver abscess, caused by Bacteroides species including theB. fragilisgroup (B.fragilis, B. distasonis, B. ovatus, B. thetaiotaomicron, B. vulgatus),Clostridiumspecies,Eubacteriumspecies,Peptococcusspecies, andPeptostreptococcusspecies.

SKIN AND SKIN STRUCTURE INFECTIONS caused byBacteroidesspecies including theB. fragilisgroup,Clostridiumspecies,Peptococcusspecies,Peptostreptococcusspecies, andFusobacteriumspecies.

GYNECOLOGIC INFECTIONS, including endometritis, endomyometritis, tubo-ovarian abscess, and postsurgical vaginal cuff infection, caused byBacteroidesspecies including theB. fragilisgroup,Clostridiumspecies,Peptococcusspecies,Peptostreptococcusspecies, andFusobacteriumspecies.

BACTERIALSEPTICEMIAcaused byBacteroidesspecies including theB. fragilisgroup andClostridiumspecies.

BONE AND JOINT INFECTIONS, (as adjunctive therapy), caused byBacteroidesspecies including theB. fragilisgroup.

CENTRAL NERVOUS SYSTEM(CNS) INFECTIONS, includingmeningitisand brain abscess, caused byBacteroidesspecies including theB. fragilisgroup.

LOWER RESPIRATORY TRACT INFECTIONS, includingpneumonia,empyema, and lung abscess, caused byBacteroidesspecies including theB. fragilisgroup.

ENDOCARDITIScaused byBacteroidesspecies including theB. fragilisgroup.

To reduce the development of drug-resistant bacteria and maintain the effectiveness of FLAGYL and other antibacterial drugs, FLAGYL 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.

DOSAGE AND ADMINISTRATION

Trichomoniasis

In The Female

One-day treatment - two grams of FLAGYL, given either as a single dose or in two divided doses of onegrameach, 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.

的给药方案应该是个性化的。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 (seeCONTRAINDICATIONS). 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 thefetal circulation(seePRECAUTIONS,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 FLAGYL should be reduced by 50% (seeCLINICAL PHARMACOLOGYandPRECAUTIONS).

Patients Undergoing Hemodialysis

Hemodialysisremoves significant amounts of metronidazole and its metabolites from systemiccirculation. The clearance of metronidazole will depend on the type ofdialysismembrane 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 (seeCLINICAL PHARMACOLOGY).

HOW SUPPLIED

FLAGYL 250-mgtablets are round, blue, film coated, with SEARLE and 1831 debossed on one side and FLAGYL and 250 on the other side; supplied as bottles of 50 and 100.

NDC Number	Size
0025-1831-50	bottle of 50
0025-1831-31	bottle of 100

FLAGYL 500-mgtablets are oblong, blue, film coated, with FLAGYL debossed on one side and 500 on the other side; bottles of 50 and 100.

NDC Number	Size
0025-1821-50	bottle of 50
0025-1821-31	bottle of 100

Storage And Stability

Store below 25°C (77°F) and protect from light.

Distributed by: Pfizer Labs, Division of Pfizre Inc., NY, NY 10017. Revised: Dec 2021

SIDE EFFECTS

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,asepticmeningitis, optic andperipheral neuropathy, the latter characterized mainly by numbness orparesthesiaof an extremity. Since persistent peripheralneuropathyhas 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警告).

Gastrointestinal

The most common adverse reactions reported have been referable to thegastrointestinal 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 andpruritus.

Hematopoietic

Reversibleneutropenia(leukopenia); rarely, reversiblethrombocytopenia.

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,nasalcongestion, dryness of the mouth (orvaginaor vulva), and fever.

Renal

Dysuria,cystitis,polyuria,incontinence, and asenseofpelvicpressure. 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/acuteliver 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) (seeCONTRAINDICATIONS).

Other

Proliferation of Candida in the vagina, dyspareunia, decrease oflibido,proctitis, and fleeting joint pains sometimes resembling “serum sickness.” Rare cases ofpancreatitis, which generally abated on withdrawal of the drug, have been reported.

Patients with Crohn's disease are known to have an increased incidence ofgastrointestinaland certain extraintestinal cancers. There have been some reports in the medical literature of breast andcoloncancer 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 FLAGYL tablets.

DRUG INTERACTIONS

Disulfiram

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 two weeks (seeCONTRAINDICATIONS).

Alcoholic Beverages

Abdominal cramps, nausea, vomiting, headaches, and flushing may occur if alcoholic beverages or products containing propylene glycol are consumed during or following metronidazole therapy (seeCONTRAINDICATIONS).

Warfarin And Other Oral Anticoagulants

Metronidazole has been reported to potentiate theanticoagulant华法林和其他口服香豆素anticoa的效果gulants, resulting in a prolongation ofprothrombin time. When FLAGYL is prescribed for patients on this type of anticoagulant therapy,prothrombintime and INR should be carefully monitored.

Lithium

In patients stabilized on relatively high doses oflithium、短期associ灭滴灵治疗ated 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.

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.

警告

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 (seeADVERSE REACTIONS).

PRECAUTIONS

General

Hepatic Impairment

Patients with hepatic impairment metabolize metronidazole slowly, with resultant accumulation of metronidazole in the plasma. For patients with severe hepatic impairment (Child-Pugh C), a reduced dose of FLAGYL is recommended. For patients with mild to moderate hepatic impairment, no dosage adjustment is needed but these patients should be monitored for metronidazole associated adverse events (seeCLINICAL PHARMACOLOGYandDOSAGE AND ADMINISTRATION).

Renal Impairment

Patients withend-stage renal diseasemay excrete metronidazole and metabolites slowly in the urine, resulting in significant accumulation of metronidazole metabolites. Monitoring for metronidazole associated adverse events is recommended (seeCLINICAL PHARMACOLOGY).

Fungal Superinfections

Known or previously unrecognizedcandidiasismay present more prominent symptoms during therapy with FLAGYL 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 blooddyscrasia. 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.

Drug-Resistant Bacteria And Parasites

Prescribing FLAGYL in the absence of a proven or strongly suspected bacterial orparasiticinfection or aprophylacticindication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria and parasites.

Drug/Laboratory Test Interactions

Metronidazole may interfere with certain types of determinations of serum chemistry values, such asaspartate 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.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment Of Fertility

Tumors affecting the liver,lungs, mammary, and lymphatic tissues have been detected in several studies of metronidazole in rats and mice, but not hamsters.

Pulmonary tumors have been observed in all six reported studies in the mouse, including one study in which the animals were dosed on an intermittent schedule (administration during every fourth week only).Malignantliver tumors were increased in male mice treated at approximately 1500 mg/m² (similar to the maximum recommended daily dose, based on body surface area comparisons). Malignant lymphomas and pulmonary neoplasms were also increased with lifetime feeding of the drug to mice. Mammary and hepatic tumors were increased among female rats administered oral metronidazole compared to concurrent controls. Two lifetime tumorigenicity studies in hamsters have been performed and reported to be negative.

Metronidazole has shown mutagenic activity in in vitro assay systems including the Ames test. Studies in mammals in vivo have failed to demonstrate a potential for genetic damage.

灭滴灵未能产生任何不利影响s on fertility or testicular function in male rats at doses up at 400 mg/kg/day (similar to the maximum recommended clinical 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 seminiferousepitheliumin the testes as well as marked decreases in testicular spermatid counts and epididymalspermcounts. Fertility was restored in most rats after an eight week, drug-free recovery period.

Pregnancy

Teratogenic Effects

There are no adequate and well controlled studies of FLAGYL in pregnant women. There are published data from case-control studies, cohort studies, and 2 meta-analyses that include more than 5000 pregnant women who used metronidazole during pregnancy. Many studies included first trimester exposures. One study showed an increased risk of cleft lip, with or without cleftpalate, in infants exposed to metronidazole in-utero; however, these findings were not confirmed. In addition, more than ten randomized placebo-controlled clinical trials enrolled more than 5000 pregnant women to assess the use ofantibiotictreatment (including metronidazole) forbacterial vaginosison the incidence of preterm delivery. Most studies did not show an increased risk forcongenitalanomalies or other adverse fetal outcomes following metronidazole exposure during pregnancy. Three studies conducted to assess the risk of infant cancer following metronidazole 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 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.

Nursing Mothers

Metronidazole is present in human milk at concentrations similar to maternal serum levels, and infant serum levels can be close to or comparable to infant therapeutic levels. 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. Alternatively, a nursing mother may choose to pump and discard human milk for the duration of metronidazole therapy, and for 24 hours after therapy ends and feed her infant stored human milk or formula.

Geriatric Use

In elderly geriatric patients, monitoring for metronidazole associated adverse events is recommended (seeCLINICAL PHARMACOLOGY,PRECAUTIONS). Decreased liver function in geriatric patients can result in increased concentrations of metronidazole that may necessitate adjustment of metronidazole dosage (seeDOSAGE AND ADMINISTRATION).

Pediatric Use

Safety and effectiveness in pediatric patients have not been established, except for the treatment of amebiasis.

OVERDOSE

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 aradiation敏化剂在恶性肿瘤的治疗。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 specificantidotefor metronidazole overdose; therefore, management of the patient should consist of symptomatic and supportive therapy.

CONTRAINDICATIONS

Hypersensitivity

FLAGYL Tablets is contraindicated in patients with a prior history of hypersensitivity to metronidazole or other nitroimidazole derivatives.

In patients with trichomoniasis, FLAGYL Tablets is contraindicated during the first trimester of pregnancy (seePRECAUTIONS).

Psychotic Reaction With Disulfiram

使用口服灭滴灵与心理有关otic reactions in alcoholic patients who were using disulfiram concurrently. Do not administer metronidazole to patients who have taken disulfiram within the last two weeks (seePRECAUTIONS,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 (seePRECAUTIONS,DRUG INTERACTIONS).

Cockayne Syndrome

FLAGYL Tablets are contraindicated in patients with Cockayne syndrome. Severe irreversible hepatotoxicity/acute liver failure with fatal outcomes have been reported after initiation of metronidazole in patients with Cockayne syndrome (seeADVERSE REACTIONS).

CLINICAL PHARMACOLOGY

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 incerebrospinal fluid,saliva和母乳tho浓度相似se 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-(ßhydroxyethyl)- 2-hydroxymethyl-5-nitroimidazole and 2-methyl-5-nitroimidazole-1-ylacetic 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 m². 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; CLCR= 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 (CLCR= 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 (seePRECAUTIONS).

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 ambulatoryperitoneal 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 (seeDOSAGE AND ADMINISTRATION). Aperitonealdialysis 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 AUC24 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. A reduction in metronidazole dosage by 50% is recommended in patients with severe (Child-Pugh C) hepatic impairment (seeDOSAGE 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 (seePRECAUTIONSandDOSAGE 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 (seePRECAUTIONS).

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 anaerobicenvironmentagainst most obligate anaerobes. Once metronidazole enters the organism by passive diffusion and activated in thecytoplasmof 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

Clostridiumspecies
Eubacteriumspecies
Peptococcusspecies
Peptostreptococcusspecies

Gram-negative Aaerobes

Bacteroides fragilisgroup (B. fragilis, B. distasonis, B. ovatus, B. thetaiotaomicron, B.vulgatus)
Fusobacteriumspecies

Protozoal Parasites

Entamoeba histolytica
阴道毛滴虫

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 fragilisgroup (B. caccae, B. uniformis)
Prevotellaspecies (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.

PATIENT INFORMATION

Interaction With Alcohol

Discontinue consumption of alcoholic beverages or products containing propylene glycol while taking FLAGYL and for at least three days afterward because abdominal cramps, nausea, vomiting, headaches, and flushing may occur (seeCONTRAINDICATIONSandPRECAUTIONS,DRUG INTERACTIONS).

Treatment Of Bacterial And Parasitic Infections

Patients should be counseled that FLAGYL should only be used to treat bacterial and parasitic infections. FLAGYL does not treat viral infections (e.g., thecommon cold). When FLAGYL 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 FLAGYL in the future.