METRONIDAZOLE: Package Insert and Label Information
METRONIDAZOLE — metronidazole tablet, coated
Lupin Pharmaceuticals, Inc.
Metronidazole has been shown to be carcinogenic in mice and rats [see Precautions]. Unnecessary use of the drug should be avoided. Its use should be reserved for the conditions described in the INDICATIONS AND USAGE section below.
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. Inactive ingredients include colloidal silicon dioxide, croscarmellose sodium, FD&C blue #2, hypromellose, low substituted hydroxypropyl cellulose, microcrystalline cellulose, polyethylene glycol, stearic acid, titanium dioxide.
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.
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.
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 m2. The average elimination half-life of metronidazole in healthy subjects is eight hours.
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.
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].
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].
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.
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.
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.
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 :
Bacteroides fragilis group (B. fragilis, B. distasonis, B. ovatus, B. thetaiotaomicron, B.vulgatus)
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.
Bacteroides fragilis group (B. caccae, B. uniformis)
Prevotella species (P. bivia, P. buccae, P. disiens)
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.
INDICATIONS AND USAGE
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).
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.
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.
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.
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.
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.
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.
Metronidazole tablets are contraindicated in patients with a prior history of hypersensitivity to metronidazole or other nitroimidazole derivatives.
In patients with trichomoniasis, Metronidazole Tablets 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].
Metronidazole 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 [see Adverse Reactions].
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.
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