Flagyl Prescribing Information
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.
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 in 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 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 PHARMACOLOGYandPRECAUTIONS).
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).
Hypersensitivity
Metronidazole tablets are contraindicated in patients with a prior history of hypersensitivity to metronidazole or other nitroimidazole derivatives.
In patients with trichomoniasis, metronidazole is 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).
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.
Metronidazole, USP is an oral synthetic antiprotozoal and antibacterial agent, 1H-Imidazole-1-ethanol, 2-methyl-5-nitro.
Each tablet for oral administration contains 250 mg or 500 mg of metronidazole, USP. Inactive ingredients include silicified microcrystalline cellulose, crospovidone, colloidal silicon dioxide and hydrogenated vegetable oil.
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 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 (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 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 (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.
PLEASE REVIEW THE MANUFACTURER'S COMPLETE DRUG INFORMATION INCLUDING ALL OF THE SUSCEPTIBILITY TEST METHODS AT THE FDA SITE: http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=291a45f6-ed27-4dcc-8364-358d08623797&CFID=19698&CFTOKEN=609ac8b08c4f1e1e-30173D7B-F4DA-D75D-F59581A3FE4C3FFD
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).