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Metronidazole (Systemic)


VA CLASSIFICATION
Primary: AM900
Secondary: AP109; AP200; GA900

Commonly used brand name(s): Apo-Metronidazole; Flagyl; Flagyl ER; Flagyl I.V.; Flagyl I.V. RTU; Metric 21; Metro I.V.; Novonidazol; Protostat; Trikacide.

Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).



Category:


Antibacterial (systemic)—

antiprotozoal—

bowel disease (inflammatory) suppressant—

anthelmintic (systemic)—

Indications

Note: Bracketed information in the Indications section refers to uses that are not included in U.S. product labeling.

Accepted

Amebiasis, extraintestinal (treatment)—Metronidazole is indicated in the treatment of extraintestinal amebiasis, including amebic liver abscess, caused by Entamoeba histolytica . When used in the treatment of invasive amebiasis, metronidazole should be administered concurrently or sequentially with a luminal amebicide (e.g., iodoquinol, paromomycin, tetracycline, diloxanide furoate). {11}When used in the treatment of amebic liver abscesses, metronidazole therapy does not obviate the need for aspiration of the abscess.{62}
{64}
Amebiasis, intestinal (treatment)—Oral metronidazole is indicated in the treatment of acute intestinal amebiasis caused by Entamoeba histolytica . Metronidazole may not eradicate intestinal amebic infections, requiring treatment with a luminal amebicide.

Bone and joint infections (treatment)—Metronidazole is indicated in the treatment of bone and joint infections caused by Bacteroides species, including the B. fragilis group ( B. fragilis , B. distasonis , B. ovatus , B. thetaiotaomicron , B. vulgatus ).

Brain abscess (treatment)—Metronidazole is indicated in the treatment of brain abscess caused by Bacteroides species, including the B. fragilis group.

Central nervous system (CNS) infections (treatment)—Metronidazole is indicated in the treatment of CNS infections, including meningitis, caused by Bacteroides species, including the B. fragilis group.

Endocarditis, bacterial (treatment)—Metronidazole is indicated in the treatment of endocarditis caused by Bacteroides species, including the B. fragilis group.

Intra-abdominal infections (treatment)—Metronidazole is indicated in the treatment of intra-abdominal infections, including peritonitis, intra-abdominal abscess, and liver abscess, caused by Bacteroides species, including the B. fragilis group, Clostridium species, Eubacterium species, Peptococcus species, and Peptostreptococcus species.

Pelvic infections, female (treatment)—Metronidazole is indicated in the treatment of female pelvic infections, including endometritis, endomyometritis, tubo-ovarian abscess, and postsurgical vaginal cuff infections, caused by Bacteroides species, including the B. fragilis group, Clostridium species, Peptococcus species, and Peptostreptococcus species.

Perioperative infections, colorectal (prophylaxis)—Intravenous metronidazole is indicated for the prophylaxis of perioperative infections during colorectal surgery.

Pneumonia, Bacteroides species (treatment) —Metronidazole is indicated in the treatment of lower respiratory tract infections, including pneumonia, empyema, and lung abscess, caused by Bacteroides species, including the B. fragilis group.

Septicemia, bacterial (treatment)—Metronidazole is indicated in the treatment of bacterial septicemia caused by Bacteroides species, including the B. fragilis group, and Clostridium species.

Skin and soft tissue infections (treatment)—Metronidazole is indicated in the treatment of skin and soft tissue infections caused by Bacteroides species, including the B. fragilis group, Clostridium species, Fusobacterium species, Peptococcus species, and Peptostreptococcus species.

Trichomoniasis (treatment)—Oral metronidazole is indicated in the treatment of symptomatic and asymptomatic trichomoniasis, in males and females, caused by Trichomonas vaginalis .

Vaginosis, bacterial (treatment)—Oral metronidazole (extended release formulation) is indicated in the treatment of bacterial vaginosis caused byGardnerella vaginalis,Mobiluncus spp, mycoplasma hominisand anaerobes ( Peptostreptococcus spp and Bacteroidesspp)..{45}{63}

[Balantidiasis (treatment)]1—Metronidazole is used in the treatment of Balantidium coli infection. {45}

[Bowel disease, inflammatory (treatment) ]1—Metronidazole is used in the treatment of inflammatory bowel disease.

[Colitis, antibiotic-associated (treatment) ]1—Metronidazole is used in the treatment of antibiotic-associated diarrhea and colitis caused by C. difficile . {47}

[Dracunculiasis (treatment)]1—Metronidazole is used in the treatment of dracunculiasis (guinea worm infection) caused by Dracunculus medinensis . It decreases the inflammation around the ulcer, increasing the ease of removing the worm. {45}

[Gastritis, Helicobacter pylori –associated (treatment adjunct)]1or
[Ulcer, duodenal, Helicobacter pylori –associated (treatment adjunct)]1—Some studies indicate that metronidazole may be effective, in combination with bismuth subsalicylate or colloidal bismuth subcitrate, and other oral antibiotic therapy, such as ampicillin or amoxicillin, in the treatment of Helicobacter pylori –associated gastritis and duodenal ulcer. However, metronidazole resistance may occur, especially in patients who have been previously exposed to metronidazole. {54} {55} {58} {59} {60} {61}

[Giardiasis (treatment)]1—Oral metronidazole is used in the treatment of giardiasis caused by Giardia lamblia . {45}

[Periodontal infections (treatment) ]1—Metronidazole is used in the treatment of periodontal infections caused by Bacteroides species.

—Not all species or strains of a particular organism may be equally susceptible to metronidazole.

Unaccepted
Metronidazole is not effective against facultative anaerobes, obligate aerobes, Propionibacterium acnes , Actinomyces species, or Candida albicans .

1 Not included in Canadian product labeling.



Pharmacology/Pharmacokinetics

Physicochemical characteristics:
Molecular weight—
    Metronidazole: 171.16 {31}
    Metronidazole hydrochloride: 207.62 {31}

Mechanism of action/Effect:

Antibacterial (systemic); antiprotozoal—Microbicidal; active against most obligate anaerobic bacteria and protozoa {06} by undergoing intracellular chemical reduction via mechanisms unique to anaerobic metabolism. Reduced metronidazole, which is cytotoxic but short-lived, interacts with DNA to cause a loss of helical structure, strand breakage, and resultant inhibition of nucleic acid synthesis and cell death. {34}

Absorption:

Well absorbed orally; {14} bioavailability at least 80%. {45}

Distribution:

Distributed to saliva, bile, seminal fluid, breast milk, bone, liver and liver abscesses, lungs, and vaginal secretions; crosses the placenta and blood-brain barrier, also. {14}


Vol D:

In adults: Approximately 0.55 L/kg. {43}

In neonates: 0.54–0.81 L/kg. {51}


Protein binding:

Low (<20%). {14}

Biotransformation:

Hepatic; metabolized primarily by side-chain oxidation and glucuronide conjugation to 2-hydroxymethyl (also active) and other metabolites. {16}

Half-life:


In adults {43}:

Normal liver function: 8 hours (range, 6 to 12 hours).

Alcoholic liver disease: 18 hours (range, 10 to 29 hours).



In neonates {51}:

28 to 30 weeks gestational age: Approximately 75 hours.

32 to 35 weeks gestational age: Approximately 35 hours.

36 to 40 weeks gestational age: Approximately 25 hours.


Time to peak serum concentration:

1 to 2 hours (oral). {14}

Peak serum concentration:

Peak serum concentrations following a 250-mg, 500-mg, and 2-gram oral dose are approximately 6, 12, and 40 mcg/mL, respectively. {16}

At recommended intravenous doses, peak steady-state serum concentrations are approximately 25 mcg/mL; trough concentrations are approximately 18 mcg/mL. {34}

Elimination:
        Renal—60 to 80%; of this amount, approximately 20% excreted unchanged in urine. Renal clearance approximately 10 mL/min/1.73 M 2. {14}

        Fecal—6 to 15%; inactive metabolites also present in feces. {06}

        In dialysis—
        Hemodialysis: Metronidazole and primary metabolites rapidly removed from the blood by hemodialysis (half-life shortened to approximately 2.6 hours). {14}
        Peritoneal dialysis: Metronidazole is not significantly removed by peritoneal dialysis. {14}



Precautions to Consider

Carcinogenicity/Tumorigenicity

Metronidazole has been shown to be carcinogenic in a number of studies in mice. Pulmonary tumorigenesis has been reported in six studies in mice, including one study in which the animals were dosed on an intermittent schedule (every four weeks). Malignant hepatic tumors have also been reported in male mice given very high doses (approximately 500 mg/kg/day). Malignant lymphomas have been reported in one lifetime feeding study in mice. {02} {16}

Metronidazole has also been shown to be carcinogenic in rats. Several long-term, oral-dosing studies in rats have shown that metronidazole causes a statistically significant increase in the incidence of various neoplasms, especially mammary and hepatic tumors, in female rats. {02} {16}

Two lifetime tumorigenicity studies in hamsters have given negative results. {02} {16}

Metronidazole has not been shown to be carcinogenic or tumorigenic in humans. {11}

Mutagenicity

Studies have shown that metronidazole is mutagenic in bacteria and fungi, although this has not been confirmed in mammals. {16}

Pregnancy/Reproduction

Pregnancy—
Fertility; pregnancy—
Metronidazole crosses the placenta and enters the fetal circulation rapidly. Adequate and well-controlled studies in humans have not been done. Studies in rats, given doses of up to 5 times the human dose, have not shown that metronidazole causes impaired fertility or birth defects in the fetus. Metronidazole, administered intraperitoneally to pregnant mice at approximately the human dose, has been shown to cause fetotoxicity. When administered orally, no fetotoxicity was seen in pregnant mice. {09} {16} However, the use of metronidazole in the treatment of trichomoniasis is not recommended during the first trimester. If metronidazole is used during the second and third trimesters for trichomoniasis, it is recommended that its use be limited to those patients whose symptoms are not controlled by local palliative treatment. Also, the 1-day course of therapy should not be used since this results in higher maternal and fetal serum concentrations. {16}

Studies in rats given doses of up to 5 times the usual human dose have not shown that metronidazole causes impaired fertility or birth defects in the fetus. Metronidazole, administered intraperitoneally to pregnant mice at approximately the human dose, has been shown to cause fetotoxicity. When metronidazole was administered orally, no fetotoxicity was seen in pregnant mice. {09} {16}

FDA Pregnancy Category B.

Breast-feeding

Metronidazole is distributed into breast milk; concentrations are similar to those found in the maternal plasma. {16} Use is not recommended in nursing mothers since some studies in rats and mice have shown that metronidazole is carcinogenic and may cause adverse effects in the infant. However, use in the treatment of anaerobic bacterial infections or a short course of treatment with metronidazole for amebiasis, severe periodontal infections, or trichomoniasis may be necessary in nursing mothers. During treatment with metronidazole, the breast milk should be expressed and discarded. Breast-feeding may be resumed 24 to 48 hours after treatment is completed.

Pediatrics

When used for the treatment of anaerobic infections and amebiasis, metronidazole has not demonstrated any pediatrics-specific problems that would limit its usefulness in children.


Geriatrics


No information is available on the relationship of age to the effects of metronidazole in geriatric patients. However, elderly patients are more likely to have an age-related decrease in hepatic function, which may require an adjustment in dosage in patients receiving metronidazole. {16}


Dental

Metronidazole may cause dry mouth, an unpleasant or sharp metallic taste, and alteration of taste sensation. Dry mouth may contribute to the development of caries, periodontal disease, oral candidiasis, and discomfort. {05}

Drug interactions and/or related problems
The following drug interactions and/or related problems have been selected on the basis of their potential clinical significance (possible mechanism in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):


Note: Combinations containing any of the following medications, depending on the amount present, may also interact with this medication.

» Alcohol    (it is recommended that metronidazole not be used concurrently with, or for at least 3 days following, ingestion of alcohol; accumulation of acetaldehyde by interference with the oxidation of alcohol may occur, resulting in disulfiram-like effects such as abdominal cramps, nausea, vomiting, headache, or flushing; in addition, modifications in the taste of alcoholic beverages have been reported during concurrent use {09} {14}{63}{64})


» Anticoagulants, coumarin- or indandione-derivative    (effects may be potentiated when these agents are used concurrently with metronidazole, because of inhibition of enzymatic metabolism of anticoagulants; periodic prothrombin time determinations may be required during therapy to determine if dosage adjustments of anticoagulants are necessary {14} {56})


Cimetidine    (hepatic metabolism of metronidazole may be decreased when metronidazole and cimetidine are used concurrently, possibly resulting in delayed elimination and increased serum metronidazole concentrations; monitoring of serum concentrations as a guide to dosage is recommended since dosage adjustments of metronidazole may be necessary during and after cimetidine therapy {09} {28})


» Disulfiram    (it is recommended that metronidazole not be used concurrently with, or for 2 weeks following, disulfiram in alcoholic patients; such use may result in confusion and psychotic reactions because of combined toxicity {09} {14})


» Lithium    (lithium concentrations may increase when metronidazole therapy is introduced; serum lithium and serum creatinine levels should be monitored several days after beginning metronidazole in order to detect impending lithium intoxication{62}{63}{64})


Neurotoxic medications, other (See Appendix II )    (concurrent use of metronidazole with other neurotoxic medications may increase the potential for neurotoxicity {03})


Phenobarbital    (phenobarbital may induce microsomal liver enzymes, increasing metronidazole"s metabolism and resulting in a decrease in half-life and plasma concentration {27} {36} {37})


Phenytoin    (metronidazole may impair the clearance of phenytoin, increasing phenytoin"s plasma concentration {14} {38} {39})



Laboratory value alterations
The following have been selected on the basis of their potential clinical significance (possible effect in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):

With physiology/laboratory test values
Alanine aminotransferase (ALT [SGPT]), serum and
Aspartate aminotransferase (AST [SGOT]), serum and
Hexokinase glucose and
Lactate dehydrogenase (LDH) and
Triglycerides    (metronidazole has a high absorbance at the wavelength at which nicotinamide-adenine dinucleotide [NADH] is determined; therefore, elevated liver enzyme concentrations may appear to be suppressed by metronidazole when measured by continuous-flow methods based on endpoint decrease in reduced NADH; unusually low liver enzyme concentrations, including zero values, have been reported {06} {27}{62}{63}{64}{65})


Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).


Risk-benefit should be considered when the following medical problems exist
» Active organic disease of the CNS, including epilepsy     (metronidazole may cause CNS toxicity, including seizures with high doses, and peripheral neuropathy {16})


» Blood dyscrasias, or history of    (metronidazole may cause leukopenia {16})


Cardiac function impairment    (parenteral dosage forms—because of sodium content {27})


» Hepatic function impairment, severe    (metabolized in the liver; hepatic dysfunction may lead to decreased plasma clearance and accumulation of metronidazole and its metabolites; dosage may need to be reduced with severe hepatic function impairment {27})


Hypersensitivity to metronidazole
» Known or previously unrecognized candidiasis    (metronidazole may cause more prominent symptoms{62}{63}{64}{65})



Patient monitoring
The following may be especially important in patient monitoring (other tests may be warranted in some patients, depending on condition; » = major clinical significance):


For giardiasis
» Stool examinations    (3 stool examinations, taken several days apart, beginning 3 to 4 weeks following treatment are recommended if symptoms persist; however, in some successfully treated patients, the lactose intolerance brought on by the infection may persist for a period of some weeks or months, mimicking the symptoms of giardiasis; in cases of treatment failure, alternate drugs may be used {12})




Side/Adverse Effects
The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:

Those indicating need for medical attention
Incidence less frequent {06} {27}
    
Peripheral neuropathy (numbness, tingling, pain, or weakness in hands or feet)— usually with high doses or prolonged use
    
seizures —usually with high doses

Incidence rare
    
CNS toxicity (ataxia—clumsiness or unsteadiness; encephalopathy—mood or other mental changes)
    
hypersensitivity (skin rash, hives, redness, or itching)
    
leukopenia (sore throat and fever)
    
pancreatitis {10}{40}{41}{42}(severe abdominal and back pain; anorexia; nausea and vomiting)
    
thrombocytopenia (unusual bleeding or bruising; black, tarry stools; blood in urine or stools; pinpoint red spots on skin)—reversible
{62}{63}{64}{65}    
thrombophlebitis (pain, tenderness, redness, or swelling at site of injection)
    
Urinary tract effects (frequent or painful urination; inability to control urine flow; sense of pelvic pressure )
{62}{63}{64}{65}    
vaginal candidiasis (any vaginal irritation, discharge, or dryness not present before therapy)



Those indicating need for medical attention only if they continue or are bothersome
Incidence more frequent {27}
    
CNS effects (dizziness or light–headedness ; headache)
    
gastrointestinal disturbance (diarrhea; loss of appetite; nausea or vomiting; stomach pain or cramps)

Incidence less frequent or rare {05} {27}
    
Change in taste sensation
    
dryness of mouth
    
unpleasant or sharp metallic taste



Those not indicating need for medical attention
Incidence less frequent or rare {27}
    
Dark urine





Overdose
For more information on the management of overdose or unintentional ingestion, contact a poison control center (see Poison Control Center Listing ).

Clinical effects of overdose
The following effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:

Ataxia

nausea and vomiting

peripheral neuropathy

seizures
{62}{63}{64}{65}
Treatment of overdose
Since there is no specific antidote, treatment for metronidazole overdose should be symptomatic and supportive. Patients in whom intentional overdose is confirmed or suspected should be referred for psychiatric consultation.{27}{62}{63}{64}{65}


Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Metronidazole (Systemic).

In providing consultation, consider emphasizing the following selected information (» = major clinical significance):

Before using this medication
»   Conditions affecting use, especially:
Hypersensitivity to metronidazole

Pregnancy—Metronidazole crosses the placenta; use is not recommended during the first trimester of pregnancy





Breast-feeding—Metronidazole is distributed into breast milk; metronidazole is not recommended during breast-feeding





Dental—Metronidazole may cause dry mouth, an unpleasant or sharp metallic taste, and alteration of taste sensation
Other medications, especially alcohol, coumarin- or indandione-derivative anticoagulants, disulfiram, or lithium
Other medical problems, especially active organic disease of the CNS, a history of blood dyscrasias, known or previously unrecognized candidiasis, or severe hepatic function impairment

Proper use of this medication
Taking with meals or a snack to minimize gastrointestinal irritation

Taking extended–release formulation on an empty stomach to maximize dosage form characteristics

» Compliance with full course of therapy

» Importance of not missing doses and taking at evenly spaced times

» Proper dosing
Taking as soon as possible; not taking if almost time for next dose; not doubling doses

» Proper storage

Precautions while using this medication
Follow-up visit to physician after treatment for giardiasis to ensure that infection has been eradicated.

Checking with physician if no improvement within a few days

» Avoiding use of alcoholic beverages or other alcohol-containing preparations while taking and for at least 3 days after discontinuing this medication

Possible dryness of mouth; using sugarless candy or gum, ice, or saliva substitute for relief; checking with dentist if dry mouth continues for more than 2 weeks

» Caution if dizziness or light–headedness occurs

Prevention of reinfection in trichomoniasis; possible need for concurrent treatment of male sexual partner and use of a condom


Side/adverse effects
Signs of potential side effects, especially CNS toxicity, hypersensitivity, leukopenia, pancreatitis, peripheral neuropathy, seizures, thrombocytopenia, thrombophlebitis, urinary tract effects and vaginal candidiasis.

Dark urine may be alarming to patient although medically insignificant


General Dosing Information
Patients with severely impaired hepatic function metabolize metronidazole slowly. Close monitoring for toxicity, as well as reduction in dose, may be required. {28}{62}

Anuric patients do not generally require a reduction in dose since metabolites of metronidazole may be rapidly removed by hemodialysis. Also, reduced renal function does not significantly affect single-dose pharmacokinetics of metronidazole. {28}{62}

Patients with candidiasis may present with more prominent symptoms during metronidazole therapy, requiring treatment with a candidacidal agent.{62}{63}{64}{65}

For oral dosage forms only
Metronidazole may be taken with meals or a snack to lessen gastrointestinal irritation.

The extended–release formulation of metronidazole should be taken on an empty stomach, at least one hour before or two hours after meals, in order to ensure maximal performance of the extended–release characteristics.{63}

When metronidazole is used in the treatment of trichomoniasis, sexual partners should receive concurrent therapy since asymptomatic trichomoniasis in the male partner is a frequent source of reinfection in the female. The male partner should be advised to use a condom for the duration of treatment. {06}

For parenteral dosage forms only
Parenteral metronidazole should be administered by slow intravenous infusion only, either continuously or intermittently over a 1-hour period. {27}{65}

If metronidazole is administered concurrently with a primary intravenous solution, the primary solution should be discontinued while metronidazole is being infused. {28}

Serum metronidazole concentrations may be lower in patients whose gastric secretions are removed by continuous nasogastric aspiration, since metronidazole may be removed in the gastric aspirate.{65}


Oral Dosage Forms

Note: Bracketed uses in the Dosage Forms section refer to categories of use and/or indications that are not included in U.S. product labeling.

Note: The dosing and dosage forms available are expressed in terms of metronidazole base.


METRONIDAZOLE CAPSULES

Usual adult and adolescent dose
Antibacterial (systemic)
Anaerobic infections: Oral, 7.5 mg (base) per kg of body weight, up to a maximum of 1 gram, every six hours for seven days or longer. {16}

[Bowel disease, inflammatory ]1: Oral, 500 mg (base) four times a day. {11}

[Colitis, antibiotic-associated]1: Oral, 500 mg (base) three or four times a day. {11}

[Gastritis, Helicobacter pylori –associated (treatment adjunct)]1or

[Ulcer, duodenal, Helicobacter pylori –associated (treatment adjunct)]1—Oral, 500 mg (base) three times a day, in conjunction with bismuth subsalicylate or colloidal bismuth subcitrate and other oral antibiotic therapy, such as ampicillin or amoxicillin, for one to two weeks. {54} {58}

[Vaginosis, bacterial]1: Oral, 500 mg (base) two times a day for seven days. {11}

Antiprotozoal
Amebiasis: Oral, 500 to 750 mg (base) three times a day for five to ten days. {16}

Amebic liver abscess: Oral, 500 to 750 mg (base) three times a day for five to ten days.{62}
{64}
[Balantidiasis]1: Oral, 750 mg (base) three times a day for five or six days.

[Giardiasis]1: Oral, 2 grams (base) once a day for three days; or 250 mg three times a day for five to seven days.

Trichomoniasis: Oral, 2 grams (base) as a single dose; 1 gram two times a day for one day; 375 mg two times a day for seven days; or 250 mg three times a day for seven days. {16}{64}

Anthelmintic (systemic)
[Dracunculiasis]1: Oral, 250 mg (base) three times a day for ten days.


Usual adult prescribing limits
Antibacterial (systemic)
Up to a maximum of 4 grams (base) daily. {16}


Usual pediatric dose
Antibacterial (systemic)
Anaerobic infections1: Oral, 7.5 mg (base) per kg of body weight every six hours, or 10 mg per kg of body weight every eight hours. {52} {53}

Antiprotozoal
Amebiasis: Oral, 11.6 to 16.7 mg (base) per kg of body weight three times a day for ten days. {16}

[ Balantidiasis]1: Oral, 11.6 to 16.7 mg (base) per kg of body weight three times a day for five days. {50}

[Giardiasis]1: Oral, 5 mg (base) per kg of body weight three times a day for five to seven days.

Trichomoniasis: Oral, 5 mg (base) per kg of body weight three times a day for seven days. {34}

Anthelmintic (systemic)
[Dracunculiasis]1: Oral, 8.3 mg (base) per kg of body weight, up to a maximum of 250 mg, three times a day for ten days.


Strength(s) usually available
U.S.—


375 mg (base) (Rx) [Flagyl (Black iron oxide) (corn starch) (D&C Yellow No. 10 ) (FD&C Green No.3) ( gelatin) (magnesium stearate) ( titanium dioxide)]
{64}
Canada—


500 mg (base) (Rx) [Flagyl (sodium 5.47 mg)] [Trikacide]

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), in a well-closed container, unless otherwise specified by manufacturer. Store in a light-resistant container.

Auxiliary labeling:
   • Avoid alcoholic beverages.
   • May cause dizziness.
   • Continue medicine for full time of treatment.


METRONIDAZOLE TABLETS USP

Usual adult and adolescent dose
See Metronidazole Capsules .

Usual adult prescribing limits
See Metronidazole Capsules .

Usual pediatric dose
See Metronidazole Capsules .

Strength(s) usually available
U.S.—


250 mg (base) (Rx) [Flagyl] [Metric 21] [Protostat (scored) (lactose)]


500 mg (base) (Rx) [Flagyl] [Protostat (scored) (lactose)]

Canada—


250 mg (base) (Rx) [Apo-Metronidazole] [Flagyl (sodium 3.1 mg)] [Novonidazol (scored) (sodium 2.2 mg)] [Trikacide]

Packaging and storage:
Store in a dry place at 25 °C (77 °F); excursions permitted between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer. Store in a well-closed, light-resistant container.

Preparation of dosage form:
For patients who cannot take oral solids—According to the primary manufacturer, the tablets may be crushed and suspended in Cherry Syrup NF to prepare a pediatric dosage form. The recommended concentration per 5 mL is the dose calculated for a particular pediatric patient. The suspension is stable for 30 days if stored at ambient room temperature or refrigerated. Dispense with ``shake well"" instructions.

Auxiliary labeling:
   • Avoid alcoholic beverages.
   • May cause dizziness.
   • Continue medicine for full time of treatment.


METRONIDAZOLE EXTENDED RELEASE TABLETS

Usual adult and adolescent dose
Antibacterial (systemic)
Vaginosis, bacterial: Oral, 750 mg (base) once a day for seven days. {63}


Usual pediatric dose
Safety and efficacy have not been established.

Strength(s) usually available
U.S.—


750 mg (base) [Flagyl ER (FD&C Blue No.2 Aluminum Lake) (hydroxpropyl methylcellulose) (lactose ) (magnesium stearate) ( poly (meth) acrylic acid ester copolymers) (polyethylene glycol) (polysorbate 80) ( silicon dioxide) (simethicone emulsion) (talc) (titanium dioxide)]
{63}
Packaging and storage:
Store in a dry place at 25 °C (77 °F); excursions permitted between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer. Store in a well-closed, light-resistant container.
{63}
Auxiliary labeling:
   • Avoid alcoholic beverages.
   • Continue medicine for full time of treatment.
   • Take on an empty stomach, at least one hour before or two hours after meals.



Parenteral Dosage Forms

Note:  Bracketed uses in the Dosage Forms section refer to categories of use and/or indications that are not included in U.S. product labeling.

Note: The dosing and dosage forms available are expressed in terms of metronidazole base.


METRONIDAZOLE INJECTION USP

Usual adult and adolescent dose
Antibacterial (systemic)
Anaerobic infections: Intravenous infusion, 15 mg (base) per kg of body weight initially, then 7.5 mg per kg of body weight, up to a maximum of 1 gram, every six hours for seven days or longer. {27}{65}

Perioperative infections, colonic (prophylaxis): Intravenous infusion, 15 mg (base) per kg of body weight one hour prior to the start of surgery; and 7.5 mg per kg of body weight six and twelve hours after the initial dose. {11} {27}

[Antiprotozoal—Amebiasis ]1
Intravenous infusion, 500 to 750 mg (base) every eight hours for five to ten days. {11}


Usual adult prescribing limits
Antibacterial (systemic)
Up to a maximum of 4 grams (base) daily. {27}


Usual pediatric dose
[Anaerobic infections]1
Preterm infants: Intravenous infusion, 15 mg per kg of body weight (base) as an initial dose, then 7.5 mg per kg of body weight every twelve hours starting 48 hours after the initial dose.{52}{53}

Term infants:Intravenous infusion, 15 mg (base) per kg of body weight as an initial dose, then 7.5 mg per kg of body weight every twelve hours starting 24 hours after the initial dose.{52}{53}

Infants greater than 7 days of age and children:Intravenous infusion, 15 mg (base) per kg of body weight as an initial dose, then 7.5 mg per kg of body weight every six hours.{52}{53}


Strength(s) usually available
U.S.—


500 mg in 100 mL (base) (Rx) [Flagyl I.V. RTU (sodium 14 mEq)] [Metro I.V. (sodium 13.5 mEq)][Generic]

Canada—


500 mg in 100 mL (base) (Rx) [Flagyl][Generic]

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer. Protect from light during storage. {07} {08} Protect from freezing.

Incompatibilities:
Intravenous admixtures of metronidazole and other medications are not recommended. {27}

Additional information:
Metronidazole Injection USP is an isotonic (297 to 310 mOsm per liter), ready-to-use solution, requiring no dilution or buffering prior to administration. {07}

Metronidazole Injection USP in prefilled plastic minibags should not be used in series connections. This may result in air embolism because of residual air (approximately 15 mL), which may be drawn from the primary plastic bag before administration of the infusion from the secondary plastic bag is completed.


METRONIDAZOLE HYDROCHLORIDE FOR INJECTION

Usual adult and adolescent dose
See Metronidazole Injection USP .

Usual adult prescribing limits
See Metronidazole Injection USP .

Usual pediatric dose
See Metronidazole Injection USP .

Size(s) usually available:
U.S.—


500 mg (base) (Rx) [Flagyl I.V. (sodium 5 mEq)]

Canada—
Not commercially available.

Packaging and storage:
Prior to reconstitution, store below 30 °C (86 °F), in a light-resistant container, unless otherwise specified by manufacturer.

Preparation of dosage form:
Metronidazole hydrochloride for injection must not be given by direct intravenous injection since the initial dilution has an extremely low pH (0.5 to 2.0). It must be diluted further and neutralized prior to administration. {27}

To prepare initial dilution for intravenous infusion, add 4.4 mL of sterile water for injection, bacteriostatic water for injection, 0.9% sodium chloride injection, or bacteriostatic sodium chloride injection to each 500-mg vial to provide a concentration of 100 mg per mL (pH 0.5 to 2.0). The resulting solution should be further diluted in 100 mL of 0.9% sodium chloride injection, 5% dextrose injection, or lactated Ringer`s injection. The final dilution must be neutralized with approximately 5 mEq of sodium bicarbonate injection per 500 mg of metronidazole (final pH 6 to 7). Since carbon dioxide gas is produced during neutralization, it may be necessary to relieve the pressure in the final container. The final concentration should not exceed 8 mg per mL since neutralization decreases the solubility of metronidazole and precipitation may occur. {27}

Stability:
After reconstitution, solutions retain their potency for 96 hours if stored below 30 °C (86 °F) in room light. Diluted and neutralized solutions retain their potency for 24 hours. {27}

Do not refrigerate neutralized solutions since precipitation may occur. {27}

Incompatibilities:
Do not use with aluminum needles or hubs. {27}

Intravenous admixtures of metronidazole with other medications are not recommended. {27}



Revised: 04/06/2001



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