BIODAZOLE

Metronidazole is a commonly used antibiotic, belonging to the nitroimidazole class of antibiotics.

It is frequently used to treat gastrointestinal infections as well as trichomoniasis and giardiasis, and amebiasis which are parasitic infections. 4, 5 Metronidazole has been used as an antibiotic for several decades 15, with added antiparasitic properties that set it apart from many other antibacterial drugs, allowing it to treat a wide variety of infections.

It is available in capsule form, tablet form, and topical form, and suppository preparations for the treatment of various infections.

Metronidazole is indicated for the treatment of confirmed trichomoniasis caused by Trichomonas vaginalis (except for in the first trimester of pregnancy) and the patient's sexual partners, bacterial vaginosis, 16, 23 certain types of amebiasis, and various anaerobic infections. 11, 23 The above anaerobic infections may occur on the skin and skin structures, the abdomen, the heart, reproductive organs, central nervous system, and the respiratory system.

Some may also be present in the bloodstream in cases of septicemia.

Common infections treated by metronidazole are

Bacteroides species infections, Clostridium infections, and Fusobacterium infections, as well as Peptococcus and Peptostreptococcus infections.

Topical formulations of metronidazole are indicated for the treatment of inflammatory lesions of rosacea.

It is also used off-label in the treatment of Crohn's disease, as a prophylactic agent after surgery 5, and in the treatment of Helicobacter pylori infection.

It has also been studied in the prevention of preterm births and to treat periodontal disease. 1,

Metronidazole treats amebiasis, trichomoniasis, and giardiasis, exerting both antibacterial and antiprotozoal activities.

Metronidazole is an effective treatment for some anaerobic bacterial infections.

Metronidazole has shown antibacterial activity against the majority of obligate anaerobes, however, during in vitro studies, it does not demonstrate significant action against facultative anaerobes or obligate aerobes.

The nitro group reduction of metronidazole by anaerobic organisms is likely responsible for the drug's antimicrobial cytotoxic effects, causing DNA strand damage to microbes. 5, 7 A note on convulsions and neuropathy and carcinogenesis It is important to be aware of the risk of peripheral neuropathy and convulsions associated with metronidazole, especially at higher doses.

If convulsions or numbness of an extremity occur, discontinue the drug immediately.

Metronidazole has been found to be carcinogenic in mice and rats.

The relevance to this effect in humans is unknown.

It is advisable to only administer metronidazole when clinically necessary and only for its approved indications.

NADPH nitroreductase (Helicobacter pylori (strain ATCC 700392 / 26695)) Potentiator.

After the intravenous infusion of a 1.5 g dose, peak concentration was reached within 1 hour and was peak level of 30-40 mg/L.

When a multiple-dose regimen of 500 mg three times a day administered Intravenous, steady-state concentrations were achieved within about 3 days and peak concentration was measured at 26 mg/L.

When administered

Oral in the tablet form, metronidazole is absorbed entirely absorbed, showing a bioavailability of greater than 90%.

One resource indicates that

Cmax after a single oral dose of 500 mg metronidazole ranges from 8-13 mg/L, with a Tmax of 25 minutes to 4 hours.

AUC following a single 500 mg oral dose of metronidazole was 122 ± 10.3 mg/L.

A note on the absorption of topical preparations Insignificant percutaneous absorption of metronidazole occurs after the application of 1% metronidazole cream topically.

Healthy volunteers applied one 100 mg dose of 14C-labelled metronidazole 2% cream to unbroken skin.

After 12 hours, metronidazole was not detected in the plasma.

Approximately 0.1% to 1% of the administered metronidazole was measured in the urine and feces.

Metronidazole is widely distributed throughout the body and various body fluids.

They include the bile, saliva, breastmilk, cerebrospinal fluid, and the placenta.

Steady-state volume distribution of metronidazole in adults ranges from 0.51-1.1 L/kg. It attains 60-100% of plasma concentrations in various tissues, such as the central nervous system, however, is not measured in high concentrations in the placental tissue.

Metronidazole undergoes hepatic metabolism via hydroxylation, oxidation, and glucuronidation.

The metabolism of metronidazole yields 5 metabolites.

The hydroxy metabolite, 1-(2-hydroxy-ethyl)-2-hydroxy methyl-5-nitroimidazole, is considered the major active metabolite. 7, 13 Unchanged metronidazole is found in the plasma along with small amounts of its 2.

• hydroxymethyl metabolite.

Several metabolites of metronidazole are found in the urine.

They are primarily a product of side-chain oxidation in addition to glucuronide conjugation.

Only 20% of the dose found in the urine is accounted for by unchanged metronidazole.

The two main oxidative metabolites of metronidazole are hydroxy and acetic acid metabolites. 6, 9 Hover over products below to view reaction partners Metronidazole 2-hydroxymetronidazole.

Metronidazole and metabolites are 60-80% eliminated in the urine, and 6-15% excreted in the feces. 7, 14.

The elimination half-life of metronidazole is 7.3 ± 1.0 after a single 500 mg Intravenous dose in healthy subjects.

Another resource indicates that the elimination half-life for metronidazole ranges from 6-10 hours.

Dose adjustments may be required in patients with hepatic impairment, as clearance is impaired in these patients.

The clearance of metronidazole in the kidneys is estimated at 10 mL/min/1.73 m2.

The total clearance from serum is about 2.1-6.4 L/h/kg.

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LD50 information The oral LD50 of metronidazole in rats is 5000 mg/kg 16 Overdose information Adverse effects that may be exaggerated with an overdose include peripheral neuropathy, central nervous system toxicity, seizures, disulfiram-like effect (if combined with alcohol) dark urine, a metallic taste in the mouth, nausea, epigastric discomfort, and vertigo, in addition to neutropenia. 10, 16 There is no specific antidote for metronidazole overdose.

Symptomatic and supportive treatment should be employed in addition to the administration of activated charcoal to remove the unabsorbed drug from the gastrointestinal tract.

In addition to the above measures, contact the local poison control center for updated information on the management of a metronidazole overdose.

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.