METAGYL

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 powdered cellulose, hydroxypropyl cellulose, low substituted hydroxypropyl cellulose, hypromellose, polyethylene glycol, stearic acid, and titanium dioxide.

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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.

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 m 2.

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.

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 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.

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.

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 and 40 weeks, the corresponding elimination half-lives ranged from to 22.5 hours.

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 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.

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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 to 7 days of doses of 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.

Hypersensitivity reactions including severe cutaneous adverse reactions (SCARs) can be serious and potentially life threatening See ADVERSE REACTIONS.

Severe cutaneous adverse reactions (SCARs) including toxic epidermal necrolysis (TEN), Stevens-Johnson syndrome (SJS), drug reaction with eosinophilia and systemic symptoms (DRESS), and acute generalized exanthematous pustulosis (AGEP) have been reported with the use of metronidazole.

Symptoms can be serious and potentially life threatening (If symptoms or signs of SCARs develop, discontinue metronidazole tablets immediately and institute appropriate therapy. 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.

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.

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

In patients with trichomoniasis, metronidazole tablet are contraindicated during the first trimester of pregnancy.

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.

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.

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.

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.

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.

Treatment should be individualized as it is for the female.

For acute intestinal amebiasis (acute amebic dysentery): 750 mg orally three times daily for to 10 days.

For amebic liver abscess: 500 mg or 750 mg orally three times daily for to 10 days.

Pediatric patients: 35 to 50 mg/kg/24 hours, divided into three doses, orally for 10 days.

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 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% .

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.

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There are no adequate and well controlled studies of metronidazole 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 cleft palate, 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 of antibiotic treatment (including metronidazole) for bacterial vaginosis on the incidence of preterm delivery.

Most studies did not show an increased risk for congenital anomalies 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.

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.

There are no data on the effects of metronidazole on milk production.

Animal studies have shown the potential for tumorigenicity after oral metronidazole was administered chronically to rats and mice.

This drug is not intended to be administered chronically; therefore, the clinical relevance of the findings of the animal studies is unclear.

The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for metronidazole tablets and any potential adverse effects on the breastfed infant from metronidazole tablets or from the underlying maternal condition.

Alternatively, a nursing mother may choose to pump and discard human milk for the duration of metronidazole tablets therapy, and for 48 hours after the last dose and feed her infant stored human milk or formula.

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

In elderly geriatric patients, monitoring for metronidazole associated adverse events is recommended.

Decreased liver function in geriatric patients can result in increased concentrations of metronidazole that may necessitate adjustment of metronidazole dosage See DOSAGE AND ADMINISTRATION.