Metronidazole 250 MG Oral Tablet
Generic Name: METRONIDAZOLE
Brand Name: Metronidazole
- Substance Name(s):
- METRONIDAZOLE
WARNINGS
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 ).
DRUG INTERACTIONS
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 (see CONTRAINDICATIONS ).
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 (see CONTRAINDICATIONS ).
Warfarin and other Oral Anticoagulants Metronidazole has been reported to potentiate the anticoagulant effect of warfarin and other oral coumarin anticoagulants, resulting in a prolongation of prothrombin time.
When metronidazole tablets are prescribed for patients on this type of anticoagulant therapy, prothrombin time and INR should be carefully monitored.
L ithium In patients stabilized on relatively high doses of lithium, short-term metronidazole therapy has been associated 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.
Bu sulfan 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.
OVERDOSAGE
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 5 to 7 days of doses of 6 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.
DESCRIPTION
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 250 mg and 500 mg tablets, USP, for oral administration, contain the inactive ingredients: colloidal silicon dioxide, hydroxypropyl cellulose, lactose (anhydrous), microcrystalline cellulose, sodium starch glycolate, and stearic acid.
Chemical Structure
HOW SUPPLIED
Metronidazole tablets, USP, 250 mg are available as white, round, convex tablets debossed with “3969” on one side and “WPI” on the other side and are packaged as follows: NDC 50268-538-15 (10 tablets per card, 5 cards per carton).
Metronidazole tablets, USP, 500 mg are available as white, oblong tablets, debossed with “3970” on one side and “WPI” on the other side and are packaged as follows: NDC 50268-539-15 (10 tablets per card, 5 cards per carton).
Dispensed in Unit Dose Package.
For Institutional Use Only.
Store at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature].
GERIATRIC USE
Geriatric Use In elderly geriatric patients, monitoring for metronidazole associated adverse events is recommended (see CLINICAL PHARMACOLOGY , PRECAUTIONS ).
Decreased liver function in geriatric patients can result in increased concentrations of metronidazole that may necessitate adjustment of metronidazole dosage (see DOSAGE AND ADMINISTRATION ).
MECHANISM OF ACTION
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.
Drug 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.
Activity In Vitro and in Clinical Infections 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.
G r a m- p ositive anaerobes C lostridium species Eubacterium species e Peptococcus species Peptostreptococcus species G r a m- n e gative anaerobes Bacteroides fragilis group (B.
fragilis, B.
distasonis, B.
ovatus, B.
thetaiotaomicron, B.vulgatus) Fusobacterium species P r o t ozoal parasites Entamoeba histolytica T richomonas 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 (greater than or equal to 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.
G r a m- n e gative anaerobes Bacteroides fragilis group (B.
caccae, B.
uniformis) Prevotella species (P.
bivia, P.
buccae, P.
disiens) Su sceptibility Tests: When available, the clinical microbiology laboratory should provide 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 or community-acquired pathogens.
These reports should aid the physician in selecting an antibacterial drug product for treatment.
INDICATIONS AND USAGE
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 tablet 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 tablet 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.
PEDIATRIC USE
Pediatric Use Safety and effectiveness in pediatric patients have not been established, except for the treatment of amebiasis.
PREGNANCY
Pregnancy: Teratogenic Effects: Pregnancy Category B 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.
NUSRING MOTHERS
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.
BOXED WARNING
WARNING 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.
DOSAGE AND ADMINISTRATION
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 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 (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 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 P atients with Severe Hepatic Impairment For patients with severe hepatic impairment (Child-Pugh C), the dose of metronidazole should be reduced by 50% (see CLINICAL PHARMACOLOGY and PRECAUTIONS ).
P atients 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 ).