METRONIDAZOLE
  • METRONIDAZOLE

  • (Generic for FLAGYL)
  • QTY 14 • 500 MG • Tablet • Near 77381

METRONIDAZOLE (me troe NI da zole) is an antiinfective. It is used to treat certain kinds of bacterial and protozoal infections. It will not work for colds, flu, or other viral infections.

METRONIDAZOLE Pediatric Monographs
  • General Administration Information
    For storage information, see the specific product information within the How Supplied section.

    Route-Specific Administration

    Oral Administration
    -Oral absorption is nearly complete; therefore, parenteral administration is often unnecessary unless patients cannot take PO.
    Oral Solid Formulations
    -Regular-release tablets or capsules: Administer without regard to meals.
    -Extended-release tablets: Swallow whole; do not crush, break, or chew. Administer on an empty stomach, at least 1 hour before or 2 hours after meals.

    Oral Liquid Formulations
    Reconstitution for powder for oral suspension
    -Available as a compounding kit containing 1 bottle of metronidazole powder and 1 bottle of grape-flavored diluent.
    -Various bottle sizes are available that when reconstituted produce either a 50 mg/mL or 100 mg/mL metronidazole oral suspension. Select the appropriate bottle size and concentration for the individual patient.
    -Tap the bottom edges of the bottle containing the metronidazole powder on a hard surface to loosen the powder.
    -Remove the cap from the bottle containing the metronidazole powder. Tap the top of the induction seal to loosen any powder which may have adhered to the seal. Slowly peel back the foil seal.
    -Shake the diluent bottle for a few seconds prior to removing the cap.
    -Open the diluent bottle and pour about half of the diluent into the metronidazole powder bottle.
    -Replace the cap and shake the mixture bottle vigorously for approximately 60 seconds.
    -Empty the remaining diluent into the metronidazole powder bottle. Allow remaining diluent to drain into the powder bottle for 10 seconds.
    -Replace the cap and shake the mixture bottle vigorously for approximately 60 seconds.
    -Wait at least 1 hour before administering the first dose.
    -Storage: Store reconstituted solution at room temperature (15 to 30 degrees C; 59 to 86 degrees F); Do not freeze. Keep container tightly closed and protect from light. Discard any unused solution after 30 days.

    Administration for oral suspension
    -Shake bottle vigorously prior to each administration.
    -Measure dosage with calibrated spoon, cup, or oral syringe.

    Extemporaneous Compounding-Oral
    NOTE: Extemporaneously prepared suspensions are not FDA-approved.

    Extemporaneous preparation of 50 mg/mL metronidazole oral suspension:
    -Using a mortar and pestle, grind 24 x 250 mg metronidazole tablets to a fine powder.
    -To make the base solution: In a separate container, mix 1 of the following combinations: 1) 60 mL of Ora-Sweet with 60 mL of Ora-Plus; or 2) 60 mL of Ora-Sweet SF with 60 mL of Ora-Plus; or 3) 120 mL cherry syrup (cherry syrup concentrate diluted 1:4 with simple syrup).
    -Add a small amount of the base solution to the fine powder and mix into a uniform paste. Add geometric amounts of the base solution and mix well after each addition.
    -Transfer to a graduated cylinder and add additional base solution to make a total of 120 mL. Mix well.
    -Place in amber plastic bottles. Shake well before each use.
    -Storage: This oral suspension is stable for at least 60 days when stored at room temperature or refrigerated.

    Extemporaneous preparation of 10 mg/mL metronidazole oral suspension:
    -Using a mortar and pestle, grind 5 x 250 mg metronidazole tablets to a fine powder.
    -To make the base solution: In a separate container, mix 62.5 mL of Ora-Sweet with 62.5 mL of Ora-Plus and shake well.
    -Add a small amount of the base solution to the fine powder and mix into a uniform paste. Add geometric amounts of the base solution and mix well after each addition.
    -Transfer to a graduated cylinder and add additional base solution to make a total of 125 mL. Mix well.
    -Place in amber plastic bottles. Shake well before each use.
    -Storage: This oral suspension is stable for at least 90 days when stored at room temperature.



    Injectable Administration
    -Administer by slow IV infusion only, either as a continuous or intermittent infusion.
    -Do not admix with other drugs. If used with a primary intravenous fluid system, the primary solution should be discontinued during metronidazole infusion.
    -Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.
    Intravenous Administration
    Preparation of Intravenous Infusion
    -Supplied as 5 mg/mL ready to use single-use infusion bags. No dilution required prior to administration.
    -Do not refrigerate.

    Intermittent Intravenous Infusion
    -Remove from foil wrapping just prior to administration.
    -Infuse by slow intermittent IV infusion over 30 to 60 minutes.
    -Do not use in series connections; air embolism may occur.
    -Do not use equipment containing aluminum (e.g., needles, cannulae) that would come in contact with the drug solution during administration as precipitates may form.



    Topical Administration
    -Topical products differ in pH from vaginal products; therefore, topical cream, gel, and lotion are for topical application to the skin only. Do not use topical products orally or vaginally.
    -Avoid contact with the eyes.
    -Prior to administration, cleanse area with a mild, nonirritating cleanser.
    Cream/Ointment/Lotion Formulations
    -Cream/Gel application: A thin layer should be rubbed into the affected areas. Cosmetics, sunscreens, and/or moisturizers may be used after applying cream, if needed.
    -Lotion application: Apply a thin layer to entire affected areas. Cosmetics, sunscreens, and/or moisturizers may be applied after the lotion has dried and 5 minutes have passed.



    Intravaginal Administration
    -Vaginal and topical products differ in pH, therefore, vaginal gel is for vaginal use only; do not use vaginal products orally or topically.
    -Instruct patient on proper use.
    -Use special applicator supplied by the manufacturer.

    Gastrointestinal adverse reactions to metronidazole therapy include nausea (10% systemic; 1.6% to 4% vaginal product), vomiting (less than 1% to 4% vaginal product), xerostomia (dry mouth) (2% systemic and vaginal products), dysgeusia (usually manifested as a metallic taste) (9% systemic; 2% vaginal product), anorexia (less than 1% vaginal product), epigastric distress, abdominal cramping, constipation (less than 1% vaginal product), diarrhea (4% systemic; 1% to 2% vaginal product), abdominal pain or discomfort (4% systemic; 5% vaginal product), gastrointestinal discomfort (7% vaginal product), decreased appetite (1% vaginal product), abdominal bloating/gas, thirst, asthenia, flatulence (less than 1% vaginal product), gingivitis (less than 1% vaginal product), and dyspepsia (less than 1% vaginal product). Although most adverse events have been reported with systemic metronidazole, systemic side effects have been reported with topical and vaginal products.

    Central and peripheral neurotoxicity has occurred from metronidazole. Severe neurological disturbances that have been reported include encephalopathy, cerebellar symptoms, convulsive seizures, peripheral neuropathy, optic neuropathy, and aseptic meningitis. Encephalopathy may manifest as confusion or decreased level of consciousness, and is associated with widespread lesions on MRI of the brain. Cerebellar toxicity may manifest as ataxia, dizziness (4% ER tab; less than 1% to 2% vaginal product), dysarthria, nystagmus, and saccadic pursuit (saccadic eye movement). It is accompanied by T2 flair lesions within the dentate nuclei seen on MRI. Cerebellar toxicity may concurrently occur with encephalopathy, peripheral neuropathy, or seizures. CNS symptoms and CNS lesions are generally reversible, with symptoms resolving within days to weeks after discontinuation of metronidazole therapy. Peripheral neuropathy, usually symmetric and mainly of sensory type, is characterized by numbness and paresthesias of the extremities. Symptoms may be prolonged after drug discontinuation. Aseptic meningitis may occur within hours of dose administration and generally resolves after discontinuation of therapy. Advise patients to report neurologic symptoms; discontinue treatment if any abnormal neurologic symptoms occur. Other adverse reactions during metronidazole therapy include confusion, depression (less than 1% vaginal product), insomnia (less than 1% vaginal product), hypoesthesia, headache (18% ER tab; 2.2% topical product; 2.2 to 7% vaginal product), somnolence (drowsiness), syncope, vertigo, incoordination, irritability, weakness, and psychosis. Although most adverse events have been reported with systemic metronidazole, systemic side effects have been reported with topical and vaginal products.

    Blood and lymphatic system disorders that have been reported with the use of metronidazole include agranulocytosis, leukopenia, neutropenia, thrombocytopenia, and eosinophilia. Increased/decreased white blood cell counts have been reported in 1.7% of patients receiving the vaginal products. Although most adverse events have been reported with systemic metronidazole, systemic side effects have been reported with topical and vaginal products.

    Hypersensitivity and anaphylactoid reactions have been reported in patients receiving metronidazole. Hypersensitivity or skin adverse events include toxic epidermal necrolysis, swelling of the face (angioedema), pruritus (1.6% to 6% vaginal product; less 3% than topical product), urticaria (less than 1% vaginal product), hyperhidrosis, erythema, rash (1% vaginal product), Stevens-Johnson syndrome, Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), flushing, nasal congestion (1.1% topical product), fever, acne vulgaris (less than 1% vaginal product; 0.5% topical product), sweating/diaphoresis (less than 1% vaginal product), and dryness of the vagina or vulva. Localized effects that have been reported in association with the use of topical (dermal) formulations include contact dermatitis (1.3% to 3%), application site reaction (0.5%), aggravated condition (0.5% to less than 3%), ocular irritation, skin irritation (burning/stinging) (less than 3%), transient skin erythema (less than 3% to 6%), dry skin/xerosis (1.1%), and redness. Although most adverse events have been reported with systemic metronidazole, systemic side effects have been reported with topical and vaginal metronidazole products.

    Phlebitis can occur from IV infusion of metronidazole and can be prevented by avoiding prolonged use of indwelling IV catheters. Patients receiving parenteral metronidazole should be monitored for an injection site reaction.

    Urinary side effects of metronidazole include chromaturia (urine discoloration), dysuria (less than 1% vaginal product), cystitis, polyuria, urinary incontinence, increased urinary frequency (less than 1% vaginal product), and a sense of pelvic pressure. Although the pigment that is responsible darkened urine has not been positively identified, it is likely a metabolite of metronidazole and seems to have no clinical significance. Abnormal urine was noted in 3% of patients receiving the ER tablet. Although most adverse events have been reported with systemic metronidazole, systemic side effects have been reported with topical and vaginal products.

    Pancreatitis has been reported with the use of metronidazole. Although most adverse events have been reported with systemic metronidazole, systemic side effects have been reported with topical and vaginal products.

    As with any antibiotic, the use of metronidazole alters the normal flora and may result in superinfection. Metronidazole therapy may cause Candida overgrowth and candidiasis (3% ER tabs; 12% vaginal product) including oral candidiasis or vaginal candidiasis (0.2% topical product; 5.6% to 10% vaginal product). Other adverse effects include furry tongue, glossitis, and stomatitis which may be related to Candida overgrowth. Other types of infection have been reported in studies including unspecified bacterial infection (7% ER tab), influenza-like symptoms (6% ER tab; 1.4% topical product; less than 1% vaginal product), upper respiratory tract infection (4% ER tab; 2.5% topical product), urinary tract infection (2% ER tab; 1.1% topical product; less than 1% vaginal product), unspecified infection (1% vaginal product), pyelonephritis (less than 1% vaginal product), and salpingitis (less than 1% vaginal product). Although most adverse events have been reported with systemic metronidazole, systemic side effects have been reported with topical and vaginal products.

    Metronidazole is mutagenic in vitro and carcinogenic in rodents. However, human data are not available to describe the potential for new cancer secondary to use. Crohn's disease patients are known to have an increased incidence of new primary malignancy, including GI and certain extraintestinal cancers. There have been some reports in the medical literature of breast and colon cancer in Crohn's disease patients who have been treated with metronidazole systemically at high doses for extended periods of time. A cause and effect relationship has not been established. Basal cell carcinoma was reported in 0.2% of patients using the topical gel product.

    Genital and reproductive adverse events have been reported with the use of metronidazole and include dyspareunia, proctitis, and libido decrease. Vaginitis was reported in 15% of patients receiving the ER tablet and in less than 1% of patients using the vaginal gel. Dysmenorrhea occurred in 3% of patients using the ER tablet and 1.2% to 3% of patients using the vaginal gel. Genital pruritus/pruritus ani was reported in 5% of patients receiving the ER tablet. Other side effects reported with the vaginal gel include vaginal discharge (12%), vulva or vaginal irritation or dryness (9%), pelvic discomfort (3%), breast pain (1%), and metrorrhagia (1%). Adverse events occurring in less than 1% of patients using the vaginal gel include breast enlargement, female lactation, labial edema, leukorrhea, menorrhagia, and vulvovaginal disorder. Although most adverse events have been reported with systemic metronidazole, systemic side effects have been reported with topical and vaginal products.

    Dyspnea, rhinitis (4% ER tabs; less than 1% vaginal product), sinusitis (3% ER tabs; 1.4% topical product), pharyngitis (3% ER tabs; 3.1% topical product; 2% vaginal product), bronchitis (1.1% topical product), and asthma (less than 1% vaginal product) have been noted in metronidazole clinical studies. Although most adverse events have been reported with systemic metronidazole, systemic side effects have been reported with topical and vaginal products.

    Palpitations and sinus tachycardia have occurred with the use of metronidazole. Hypertension was reported in 1.1% of patients using the topical gel. Also, ST-T wave changes (flattening of the T-wave) have been reported with metronidazole use. QT prolongation has been reported in a limited number of case reports with metronidazole use. One patient had a history of drug-induced QT prolongation associated with moxifloxacin, and therefore, may have been a carrier of a silent mutation in 1 of the congenital long QT syndrome-associated genes. The implication of these findings in pediatric patients is unknown.

    Arthralgia, muscle spasms (muscle cramps), myalgia, and fleeting joint pain sometimes resembling serum sickness has been reported with metronidazole use. Back pain was reported in less than 1% of patients receiving the vaginal gel. Although most adverse events have been reported with systemic metronidazole, systemic side effects have been reported with topical and vaginal products.

    General adverse events reported with metronidazole include malaise, face edema, peripheral edema, chest pain (unspecified), chills, and hiccups. Fatigue, unspecified cramping (1%), mucous membrane disorder (less than 1%), and unspecified pain (less than 1%) were reported with the use of metronidazole vaginal gel. Although most adverse events have been reported with systemic metronidazole, systemic side effects have been reported with topical and vaginal products.

    Hepatotoxicity and hepatic failure have been reported in patients with Cockayne syndrome that have been exposed to metronidazole for systemic use. Elevated hepatic enzymes have also been reported with metronidazole. Although most adverse events have been reported with systemic metronidazole, systemic side effects have been reported with topical and vaginal products.

    Metronidazole is contraindicated in patients with a prior history of hypersensitivity to metronidazole or other nitroimidazole derivatives. Systemic metronidazole should be used with care in patients with evidence of or history of hematological disease; monitor complete blood count (CBC) in these patients. Agranulocytosis, leukopenia, and neutropenia have been associated with systemic metronidazole administration.

    Systemic metronidazole and its metabolites may accumulate significantly in patients with severe renal impairment or end stage renal disease (renal failure), including in patients receiving peritoneal dialysis, due to reduced urinary excretion. Monitor for metronidazole-associated adverse events.

    Use metronidazole injection with caution in patients with cardiac disease or heart failure, or in those otherwise predisposed to edema, because it contains 28 mEq of sodium per gram of metronidazole. This large amount of sodium can promote sodium retention and exacerbate peripheral edema or congestive heart failure. Additionally, QT prolongation has been reported with metronidazole use. Use metronidazole with caution in patients with conditions that may increase the risk of QT prolongation including cardiac arrhythmias, congenital long QT syndrome, heart failure, bradycardia, myocardial infarction, hypertension, coronary artery disease, hypomagnesemia, hypokalemia, hypocalcemia, or in patients receiving other medications known to prolong the QT interval or cause electrolyte imbalances. Females, patients with diabetes mellitus, thyroid disease, malnutrition, alcohol dependency, or hepatic disease may also be at increased risk for QT prolongation.

    Metronidazole, when given systemically, has been reported to be carcinogenic in mice and rats. Similar studies in the hamster gave negative results. Also, metronidazole has shown mutagenic activity in a number of in vitro assay systems, but studies in mammals (in vivo) failed to demonstrate a potential for genetic damage. Human data are not available to describe the potential for a new primary malignancy secondary to use. The boxed warning states that systemic metronidazole use should be reserved for conditions where the drug is clearly needed; avoid unnecessary use. Vaginal and topical forms of metronidazole do not carry the boxed warning regarding carcinogenicity.

    Oral, injectable, and intravaginal dosage forms should be used with caution in patients with alcoholism or ethanol intoxication. Metronidazole may interfere with the metabolism of ethanol, resulting in disulfiram-like effects. Adolescent patients of appropriate age should be counseled to avoid ethanol ingestion to avoid the risk of undesirable side effects. It is recommended that alcoholic beverages or medicines not be used concurrently with metronidazole or for at least 3 days following the discontinuation of the drug. Psychotic reactions have been reported in alcoholic patients on metronidazole and disulfiram therapy. Additionally, QT prolongation has been reported in a limited number of case reports with metronidazole; therefore, use it with caution in patients with other conditions that may increase the risk of QT prolongation, including alcoholism.

    Metronidazole use may result in candidal overgrowth. Known or previously unrecognized candida fungal infection may present more prominent symptoms during therapy with metronidazole and requires treatment with an appropriate antifungal agent.

    Crohn's disease patients are known to have an increased incidence of gastrointestinal and certain extraintestinal cancers. There have been some reports in the medical literature of breast and colon cancer in Crohn's disease patients who have been treated with metronidazole at high doses for extended periods of time. A cause and effect relationship has not been established.

    Topical metronidazole gels or creams contain ingredients that may cause burning and irritation of the eye. In the event of accidental ocular exposure, rinse the eye with copious amounts of cool tap water.

    Metronidazole may be used to treat certain sexually transmitted diseases (STD). All patients with a diagnosed or suspected STD should be tested for other STDs, which may include HIV, syphilis, chlamydia, and gonorrhea, at the time of diagnosis. Initiate appropriate therapy and perform follow-up testing as recommended based upon sexually transmitted disease diagnosis.

    Reduce metronidazole dose in patients with severe hepatic disease or impairment (Child-Pugh C) or hepatic encephalopathy due to slowed metabolism and accumulation in plasma, which may cause exacerbations of CNS adverse events in patients with hepatic encephalopathy. Monitor patients with mild to moderate hepatic impairment for metronidazole-associated adverse effects.

    Use metronidazole in patients with Cockayne syndrome only if no alternative treatment is available. Cases of severe hepatotoxicity and acute hepatic failure, including a fatal outcome with very rapid onset after treatment initiation with systemic metronidazole have been reported in these patients. Obtain liver function tests prior to the start of therapy, within the first 2 to 3 days after initiation of therapy, frequently during therapy, and after the end of treatment. Discontinue metronidazole if there is an elevation of liver function tests, and monitor until baseline values are reached. Advise patients with Cockayne syndrome to stop taking metronidazole immediately and contact their healthcare provider if they experience any symptoms of potential hepatic injury, such as abdominal pain, nausea, change in stool color, or jaundice.

    Use intravenous formulations of metronidazole with caution in patients that require sodium restriction, those on corticosteroid therapy, and those predisposed to edema. Certain formulations of intravenous metronidazole may contain sodium.

    Systemic metronidazole therapy may cause laboratory test interference with certain laboratory measurements, such as AST, ALT, LDH, triglycerides, and hexokinase glucose; values of zero may be noted. All of the assays in which interference has been observed use enzymatic coupling of the assay to oxidation reduction of nicotinamide adenine dinucleotide. Interference is due to the similarity in the absorbance peaks of NADH (340 nm) and metronidazole (322 nm) at a pH of 7. Metronidazole causes an increase in ultraviolet absorbance at 340 nm resulting in falsely decreased values. Antimicrobials are also known to suppress H. pylori; thus, ingestion of these agents within 4 weeks of performing diagnostic tests for H. pylori may lead to false negative results. At a minimum, instruct the patient to avoid the use of metronidazole in the 4 weeks prior to the test.

    Description: Metronidazole is a synthetic antibacterial and antiprotozoal agent that belongs to the nitroimidazole class. It is one of the most effective drugs available against anaerobic bacterial infections and is an effective therapy against protozoal infections such as trichomoniasis, amebiasis, and giardiasis. It is commonly used in children for intra-abdominal infections, including perforated appendicitis. Oral metronidazole is also used off-label as first-line therapy to treat Clostridium difficile-associated disease (CDAD). Metronidazole can be used as a component of multiple regimens that have been shown to be effective for treatment of Helicobacter pylori (H. pylori) gastrointestinal infection. Combination therapy is necessary for successful eradication of H. pylori and to avoid the development of resistance, especially metronidazole resistance, which is prevalent in the US (approximately 25% to 37%) and many other countries. High eradication rates for H. pylori gastrointestinal infection have been documented with triple-drug regimens that include a proton pump inhibitor (PPI), clarithromycin, and metronidazole (or amoxicillin). Neurotoxicity, generally reversible, has been reported with metronidazole therapy. The immediate-release oral formulations are FDA approved for use in pediatric patients as young as infants. Although not FDA approved in children, the intravenous formulation is used off-label in pediatric patients as young as neonates. Vaginal products are FDA approved for use in adolescent females; topical formulations are not FDA approved for use in pediatric patients.

    Per the manufacturer, this drug has been shown to be active against most strains of the following microorganisms either in vitro and/or in clinical infections: Bacteroides caccae, Bacteroides fragilis, Bacteroides ovatus, Bacteroides sp., Bacteroides thetaiotaomicron, Bacteroides uniformis, Bacteroides ureolyticus, Bacteroides vulgatus, Clostridium difficile, Clostridium perfringens, Clostridium sp., Entamoeba histolytica, Eubacterium sp., Fusobacterium sp., Mobiluncus sp., Parabacteroides distasonis, Peptococcus niger, Peptococcus sp., Peptostreptococcus sp., Porphyromonas asaccharolytica, Porphyromonas gingivalis, Porphyromonas sp., Prevotella bivia, Prevotella buccae, Prevotella disiens, Prevotella intermedia, Prevotella melaninogenica, Prevotella oralis, Prevotella sp., Trichomonas vaginalis
    NOTE: The safety and effectiveness in treating clinical infections due to organisms with in vitro data only have not been established in adequate and well-controlled clinical trials.

    This drug may also have activity against the following microorganisms: Balantidium coli, Blastocystis hominis, Campylobacter fetus, Dientamoeba fragilis, Dracunculus medinensis, Entamoeba polecki, Gardnerella vaginalis, Giardia lamblia, Helicobacter pylori, Mycoplasma hominis, Veillonella sp.
    NOTE: Some organisms may not have been adequately studied during clinical trials; therefore, exclusion from this list does not necessarily negate the drug's activity against the organism.

    For the treatment of serious anaerobic infections (e.g., skin and skin structure infections*, CNS infection including meningitis* and brain abscess*, bone and joint infections*, endocarditis*, bacteremia*, and gynecologic infections* ):
    Intravenous dosage:
    Neonates 34 weeks postmenstrual age and younger: 15 mg/kg IV loading dose, then 7.5 mg/kg/dose IV every 12 hours.
    Neonates 35 to 40 weeks postmenstrual age: 15 mg/kg IV loading dose, then 7.5 mg/kg/dose IV every 8 hours.
    Neonates older than 40 weeks postmenstrual age: 15 mg/kg IV loading dose, then 10 mg/kg/dose IV every 8 hours.
    Infants, Children, and Adolescents: 22.5 to 40 mg/kg/day IV divided every 6 to 8 hours (Usual Max: 500 mg/dose). The maximum recommended dose in adults is 4 g/day. Although metronidazole has traditionally been dosed as multiple-daily dosing, pharmacokinetic and clinical studies in adults have demonstrated that once daily dosing (1 to 1.5 g every 24 hours) is similar in efficacy to multiple-daily dosing and offers an advantageous dosing strategy. It has been suggested that metronidazole displays concentration-dependent killing, and the goal of dosing regimens for these agents is to maximize the concentration (peak/MIC or peak/AUC ratios), which once-daily dosing does.
    Oral dosage:
    Neonates 34 weeks postmenstrual age and younger: 7.5 mg/kg/dose PO every 12 hours. Although oral dosing is not specified in the guidelines for neonates, oral absorption of metronidazole is nearly complete, and the same dose that is given IV is given orally.
    Neonates 35 to 40 weeks postmenstrual age: 7.5 mg/kg/dose PO every 8 hours. Although oral dosing is not specified in the guidelines for neonates, oral absorption of metronidazole is nearly complete, and the same dose that is given IV is given orally.
    Neonates older than 40 weeks postmenstrual age: 10 mg/kg/dose PO every 8 hours. Although oral dosing is not specified in the guidelines for neonates, oral absorption of metronidazole is nearly complete, and the same dose that is given IV is given orally.
    Infants, Children, and Adolescents: 15 to 50 mg/kg/day PO divided every 8 hours (Max: 2,250 mg/day).

    For the treatment of serious anaerobic intraabdominal infections*, including intraabdominal abscess*, peritonitis*, perforated appendicitis*, and necrotizing enterocolitis*:
    Intravenous dosage:
    Neonates 34 weeks postmenstrual age and younger: 15 mg/kg IV loading dose, then 7.5 mg/kg/dose IV every 12 hours. Guidelines suggest as part of broad-spectrum combination therapy for necrotizing enterocolitis. Regimens could include ampicillin or vancomycin plus gentamicin or ampicillin or vancomycin plus cefotaxime.
    Neonates 35 to 40 weeks postmenstrual age: 15 mg/kg IV loading dose, then 7.5 mg/kg/dose IV every 8 hours. Guidelines suggest as part of broad-spectrum combination therapy for necrotizing enterocolitis. Regimens could include ampicillin or vancomycin plus gentamicin or ampicillin or vancomycin plus cefotaxime.
    Neonates older than 40 weeks postmenstrual age: 15 mg/kg IV loading dose, then 10 mg/kg/dose IV every 8 hours. Guidelines suggest as part of broad-spectrum combination therapy for necrotizing enterocolitis. Regimens could include ampicillin or vancomycin plus gentamicin or ampicillin or vancomycin plus cefotaxime.
    Infants, Children, and Adolescents: 30 to 40 mg/kg/day IV divided every 6 to 8 hours (Usual Max: 500 mg/dose) for 4 to 7 days as part of broad-spectrum combination therapy for complicated intraabdominal infections. The maximum recommended dose in adults is 4 g/day. Depending on origin of infection and pathogens, regimens could include an advanced-generation cephalosporin, fluoroquinolone, or an aminoglycoside with or without ampicillin.
    Oral dosage:
    Neonates 34 weeks postmenstrual age and younger: 7.5 mg/kg/dose PO every 12 hours. Although oral dosing is not specified in the guidelines for neonates, oral absorption of metronidazole is nearly complete, and the same dose that is given IV is given orally.
    Neonates 35 to 40 weeks postmenstrual age: 7.5 mg/kg/dose PO every 8 hours. Although oral dosing is not specified in the guidelines for neonates, oral absorption of metronidazole is nearly complete, and the same dose that is given IV is given orally.
    Neonates older than 40 weeks postmenstrual age: 10 mg/kg/dose PO every 8 hours. Although oral dosing is not specified in the guidelines for neonates, oral absorption of metronidazole is nearly complete, and the same dose that is given IV is given orally.
    Infants, Children, and Adolescents: 15 to 50 mg/kg/day PO divided every 8 hours (Max: 2,250 mg/day). Guidelines suggest as part of combination step-down oral therapy with a second- or third-generation cephalosporin or a fluoroquinolone.
    -for the treatment of perforated appendicitis*:
    Intravenous dosage:
    Infants, Children, and Adolescents: 30 mg/kg/dose IV every 24 hours in combination with ceftriaxone for 5 days. Some studies have used a maximum dose of 1,000 mg for metronidazole while others have used 1,500 mg. Single daily dosing of metronidazole and ceftriaxone was as effective as standard triple antibiotic therapy (ampicillin, gentamicin, and clindamycin) in a prospective randomized trial in 100 children with perforated appendicitis. No difference in wound infections or abscess rate was noted between the 2 groups. In another retrospective study in 123 children with perforated appendicitis, there was no statistically significant difference in postoperative length of stay (5.7 vs. 5.8 days; p = 0.83), abscess rate (8% vs. 4%; p = 0.57), wound infection (5% vs. 2%; p = 0.73), and 30-day readmissions (3% vs. 11%; p = 0.19) in patients who received metronidazole and ceftriaxone compared with other standard antibiotic regimens.

    For surgical infection prophylaxis*, including bowel preparation* in patients undergoing colorectal surgery:
    Intravenous dosage:
    Premature Neonates weighing less than 1.2 kg: 7.5 mg/kg IV as a single dose within 60 minutes prior to the surgical incision. No intraoperative redosing and a duration of prophylaxis less than 24 hours for most procedures are recommended by clinical practice guidelines. Guidelines recommend metronidazole in combination with cefazolin for uncomplicated appendectomy, obstructed small intestine, and clean-contaminated head and neck or urologic procedures or in combination with cefazolin or ceftriaxone for colorectal procedures. Metronidazole is also recommended in combination with an aminoglycoside or fluoroquinolone as alternate therapy in patients with beta-lactam allergy for biliary tract, uncomplicated appendectomy, obstructed small intestine, colorectal, or clean-contaminated urologic procedures.
    Neonates weighing 1.2 kg or more: 15 mg/kg IV as a single dose within 60 minutes prior to the surgical incision. No intraoperative redosing and a duration of prophylaxis less than 24 hours for most procedures are recommended by clinical practice guidelines. Guidelines recommend metronidazole in combination with cefazolin for uncomplicated appendectomy, obstructed small intestine, and clean-contaminated head and neck or urologic procedures or in combination with cefazolin or ceftriaxone for colorectal procedures. Metronidazole is also recommended in combination with an aminoglycoside or fluoroquinolone as alternate therapy in patients with beta-lactam allergy for biliary tract, uncomplicated appendectomy, obstructed small intestine, colorectal, or clean-contaminated urologic procedures.
    Infants, Children, and Adolescents: 15 mg/kg IV as a single dose (Max: 500 mg/dose) within 60 minutes prior to the surgical incision. No intraoperative redosing and a duration of prophylaxis less than 24 hours for most procedures are recommended by clinical practice guidelines. Guidelines recommend metronidazole in combination with cefazolin for uncomplicated appendectomy, obstructed small intestine, and clean-contaminated head and neck or urologic procedures or in combination with cefazolin or ceftriaxone for colorectal procedures. Metronidazole is also recommended in combination with an aminoglycoside or fluoroquinolone as alternate therapy in patients with beta-lactam allergy for biliary tract, uncomplicated appendectomy, obstructed small intestine, colorectal, or clean-contaminated urologic procedures.
    -as a bowel preparation* in patients undergoing colorectal surgery:
    Oral dosage:
    Infants, Children, and Adolescents: 15 mg/kg/dose (Max: 1 g/dose) PO in combination with neomycin for 3 doses given over 10 hours beginning the afternoon and evening prior to the surgery. Intravenous antibmicrobial prophylaxis should also be given prior to the surgical incision.

    For the treatment of antibiotic-associated pseudomembranous colitis* due to Clostridium difficile:
    Oral dosage:
    Infants, Children, and Adolescents: 7.5 mg/kg/dose (Max: 500 mg/dose) PO every 6 to 8 hours for 10 days. Clinical practice guidelines recommend oral metronidazole as a first line therapy option for nonsevere initial episodes or first recurrence.
    Intravenous dosage:
    Infants, Children, and Adolescents: 7.5 mg/kg/dose (Max: 500 mg/dose) IV every 6 to 8 hours for 10 days. Clinical practice guidelines recommend intravenous metronidazole in combination with oral vancomycin for initial severe or fulminant cases.

    For Helicobacter pylori (H. pylori) eradication*:
    NOTE: Eradication is recommended in pediatric patients with H. pylori-positive peptic ulcer disease (gastric or duodenal ulceration or erosions).
    -in combination with amoxicillin and a proton pump inhibitor (PPI):
    Oral dosage:
    Children weighing 15 to 24 kg: 250 mg PO twice daily in combination with amoxicillin and a proton pump inhibitor (PPI) for 14 days. Triple therapy with standard-dose amoxicillin, metronidazole, and a PPI is a first-line treatment option for patients infected with H. pylori strains with known susceptibility to metronidazole and resistance to clarithromycin. Triple therapy with high-dose amoxicillin, metronidazole, and a PPI is a first-line treatment option for patients infected with H. pylori strains with dual resistance to clarithromycin and metronidazole or strains with unknown susceptibility.
    Children and Adolescents weighing 25 to 34 kg: 500 mg PO in the morning and 250 mg PO in the evening (tablets) OR 375 mg PO twice daily (oral suspension) in combination with amoxicillin and a proton pump inhibitor (PPI) for 14 days. Triple therapy with standard-dose amoxicillin, metronidazole, and a PPI is a first-line treatment option for patients infected with H. pylori strains with known susceptibility to metronidazole and resistance to clarithromycin. Triple therapy with high-dose amoxicillin, metronidazole, and a PPI is a first-line treatment option for patients infected with H. pylori strains with dual resistance to clarithromycin and metronidazole or strains with unknown susceptibility.
    Children and Adolescents weighing 35 kg or more: 500 mg PO twice daily in combination with amoxicillin and a proton pump inhibitor (PPI) for 14 days. Triple therapy with standard-dose amoxicillin, metronidazole, and a PPI is a first-line treatment option for patients infected with H. pylori strains with known susceptibility to metronidazole and resistance to clarithromycin. Triple therapy with high-dose amoxicillin, metronidazole, and a PPI is a first-line treatment option for patients infected with H. pylori strains with dual resistance to clarithromycin and metronidazole or strains with unknown susceptibility.
    -in combination with clarithromycin and a proton pump inhibitor (PPI) for penicillin-allergic patients:
    Oral dosage:
    Children weighing 15 to 24 kg: 250 mg PO twice daily in combination with clarithromycin and a proton pump inhibitor (PPI) for 14 days. Triple therapy with metronidazole, clarithromycin, and a PPI is recommended for penicillin-allergic patients infected with fully susceptible H. pylori strains.
    Children and Adolescents weighing 25 to 34 kg: 500 mg PO in the morning and 250 mg PO in the evening (tablets) OR 375 mg PO twice daily (oral suspension) in combination with clarithromycin and a proton pump inhibitor (PPI) for 14 days. Triple therapy with metronidazole, clarithromycin, and a PPI is recommended for penicillin-allergic patients infected with fully susceptible H. pylori strains.
    Children and Adolescents weighing 35 kg or more: 500 mg PO twice daily in combination with clarithromycin and a proton pump inhibitor (PPI) for 14 days. Triple therapy with metronidazole, clarithromycin, and a PPI is recommended for penicillin-allergic patients infected with fully susceptible H. pylori strains.
    -as part of a sequential therapy regimen:
    Oral dosage:
    Children weighing 15 to 24 kg: 250 mg PO twice daily in combination with clarithromycin and a proton pump inhibitor (PPI) for 5 days, after initial therapy with amoxicillin and a PPI for 5 days. Sequential therapy is a first-line treatment option for patients infected with fully susceptible H. pylori strains. Sequential therapy is not recommended if susceptibility testing is unavailable.
    Children and Adolescents weighing 25 to 34 kg: 500 mg PO in the morning and 250 mg PO in the evening (tablets) OR 375 mg PO twice daily (oral suspension) in combination with clarithromycin and a proton pump inhibitor (PPI) for 5 days, after initial therapy with amoxicillin and a PPI for 5 days. Sequential therapy is a first-line treatment option for patients infected with fully susceptible H. pylori strains. Sequential therapy is not recommended if susceptibility testing is unavailable.
    Children and Adolescents weighing 35 kg or more: 500 mg PO twice daily in combination with clarithromycin and a proton pump inhibitor (PPI) for 5 days, after initial therapy with amoxicillin and a PPI for 5 days. Sequential therapy is a first-line treatment option for patients infected with fully susceptible H. pylori strains. Sequential therapy is not recommended if susceptibility testing is unavailable.
    -as part of a quadruple therapy regimen:
    Oral dosage:
    Children weighing 15 to 24 kg: 250 mg PO twice daily in combination with amoxicillin, clarithromycin, and a proton pump inhibitor (PPI) for 14 days. Concomitant quadruple therapy with amoxicillin, metronidazole, clarithromycin, and a PPI is a first-line treatment option for patients infected with H. pylori strains with dual resistance to clarithromycin and metronidazole or strains with unknown susceptibility.
    Children and Adolescents weighing 25 to 34 kg: 500 mg PO in the morning and 250 mg PO in the evening (tablets) OR 375 mg PO twice daily (oral suspension) in combination with amoxicillin, clarithromycin, and a proton pump inhibitor (PPI) for 14 days. Concomitant quadruple therapy with amoxicillin, metronidazole, clarithromycin, and a PPI is a first-line treatment option for patients infected with H. pylori strains with dual resistance to clarithromycin and metronidazole or strains with unknown susceptibility.
    Children and Adolescents weighing 35 kg or more: 500 mg PO twice daily in combination with amoxicillin, clarithromycin, and a proton pump inhibitor (PPI) for 14 days. Concomitant quadruple therapy with amoxicillin, metronidazole, clarithromycin, and a PPI is a first-line treatment option for patients infected with H. pylori strains with dual resistance to clarithromycin and metronidazole or strains with unknown susceptibility.

    For the treatment of amebiasis (amebic dysentery) and amebic hepatic abscess:
    Oral dosage:
    Infants, Children, and Adolescents: 35 to 50 mg/kg/day (Max: 2,250 mg/day) PO divided every 8 hours for 7 to 10 days.
    Intravenous dosage*:
    Infants, Children, and Adolescents: 35 to 50 mg/kg/day (Max: 2,250 mg/day) IV divided every 8 hours for 7 to 10 days for severe intestinal or extraintestinal disease.

    For the treatment of trichomoniasis*:
    Oral dosage:
    Children weighing less than 45 kg: 45 mg/kg/day PO in 3 divided doses for 7 days is recommended by the American Academy of Pediatrics (AAP).
    Children weighing 45 kg or more and Adolescents: 2 g PO as a single dose is recommended by the CDC and American Academy of Pediatrics (AAP). Alternatively, 500 mg PO twice daily for 7 days is recommended by the CDC. HIV-infected patients should receive the 7-day course. If treatment failure occurs with the single 2 g dose, the CDC recommends retreatment with 500 mg PO twice daily for 7 days. If this regimen fails, consider treatment with 2 g PO for 7 days. For male partners of women with treatment failures, use the same treatment regimen as the patient.

    For the treatment of bacterial vaginosis:
    Vaginal dosage (0.75% gel):
    Adolescent females (post-menarchal): 1 applicatorful (5 g of 0.75% metronidazole gel) intravaginally once daily for 5 days; administer at bedtime. In patients with multiple recurrences, metronidazole gel administered twice weekly for 4 to 6 months has been shown to reduce recurrences, but the benefit may not persist when therapy is stopped. Limited data suggest that an oral nitroimidazole followed by intravaginal boric acid with suppressive metronidazole gel may be an option for recurrent bacterial vaginosis.
    Vaginal dosage (1.3% gel):
    Adolescent females 12 to 17 years: 1 applicatorful (5 g of 1.3% gel containing 65 mg of metronidazole) intravaginally as a single dose at bedtime.
    Oral dosage* (regular-release):
    Female Children weighing less than 45 kg: 45 mg/kg/day PO in 3 divided doses for 7 days is recommended by the American Academy of Pediatrics (AAP).
    Female Children weighing 45 kg or more and Adolescent females: 500 mg PO twice daily for 7 days is recommended by the CDC and American Academy of Pediatrics (AAP). For patients with multiple recurrences, limited data suggest that an oral nitroimidazole, such as metronidazole 500 mg PO twice daily for 7 days, followed by intravaginal boric acid with suppressive metronidazole gel may be an option. Monthly oral metronidazole 2 g PO with fluconazole has been evaluated as suppressive therapy.

    For the treatment of pelvic inflammatory disease (PID)*, including tubo-ovarian abscess*:
    Oral dosage:
    Adolescent females: 500 mg PO twice daily in combination with doxycycline for 14 days and either single dose ceftriaxone IM, cefoxitin IM plus probenecid, or other parenteral third generation cephalosporin is recommended by the CDC for patients with mild-to-moderate PID. Patients who do not respond to oral therapy within 72 hours should be switched to parenteral therapy. If tubo-ovarian abscess is present, oral metronidazole should be used with oral doxycycline as part of a 14-day course of stepdown therapy following IV therapy. For patients with cephalosporin allergy, if the community prevalence and individual risk of gonorrhea are low, and if follow-up is assured, metronidazole in combination with a fluoroquinolone for 14 days may be considered.

    For the treatment of giardiasis*:
    Oral dosage:
    Infants, Children, and Adolescents: 15 mg/kg/day PO divided every 8 hours (Max: 750 mg/day) for 5 to 7 days.

    For the treatment of Crohn's disease*:
    Oral dosage:
    Children and Adolescents: 15 to 20 mg/kg/day PO in 2 to 3 divided doses based on limited data in pediatric patients. In adult studies of patients with Crohn's disease, usual doses have ranged from 1,000 to 1,500 mg/day in 2 to 4 divided doses. Metronidazole, in combination with ciprofloxacin or azithromycin, has been shown to improve the clinical symptoms of Crohn's disease and may be effective in inducing remission in patients with active Crohn's disease.

    For the treatment of dental infection* or dentoalveolar infection*, including periodontitis*:
    Oral dosage:
    Adolescents 16 years and older: 250 mg PO 3 or 4 times daily for 10 days or 500 mg PO three 3 daily for 8 days has been recommended. For severe periodontitis, 250 mg PO 3 times daily with amoxicillin for 7 to 10 days has been used.

    For bacterial vaginosis prophylaxis* or trichomoniasis prophylaxis* in victims of sexual assault:
    Oral dosage:
    Adolescents: 2 g PO as a single dose in combination with ceftriaxone plus azithromycin (for gonorrhea and chlamydia prophylaxis) is recommended by the CDC.

    For the treatment of serious anaerobic lower respiratory tract infections*, including pleural empyema*, pneumonia*, and lung abscess*:
    Intravenous dosage:
    Neonates 34 weeks postmenstrual age and younger: 15 mg/kg IV loading dose, then 7.5 mg/kg/dose IV every 12 hours.
    Neonates 35 to 40 weeks postmenstrual age: 15 mg/kg IV loading dose, then 7.5 mg/kg/dose IV every 8 hours.
    Neonates older than 40 weeks postmenstrual age: 15 mg/kg IV loading dose, then 10 mg/kg/dose IV every 8 hours.
    Infants, Children, and Adolescents: 22.5 to 40 mg/kg/day IV divided every 6 to 8 hours (Usual Max: 500 mg/dose). The maximum recommended dose in adults is 4 g/day. Although metronidazole has traditionally been dosed as multiple-daily dosing, pharmacokinetic and clinical studies in adults have demonstrated that once daily dosing (1 to 1.5 g every 24 hours) is similar in efficacy to multiple-daily dosing and offers an advantageous dosing strategy. It has been suggested that metronidazole displays concentration-dependent killing, and the goal of dosing regimens for these agents is to maximize the concentration (peak/MIC or peak/AUC ratios), which once-daily dosing does.
    Oral dosage:
    Neonates 34 weeks postmenstrual age and younger: 7.5 mg/kg/dose PO every 12 hours. Although oral dosing is not specified in the guidelines for neonates, oral absorption of metronidazole is nearly complete, and the same dose that is given IV is given orally.
    Neonates 35 to 40 weeks postmenstrual age: 7.5 mg/kg/dose PO every 8 hours. Although oral dosing is not specified in the guidelines for neonates, oral absorption of metronidazole is nearly complete, and the same dose that is given IV is given orally.
    Neonates older than 40 weeks postmenstrual age: 10 mg/kg/dose PO every 8 hours. Although oral dosing is not specified in the guidelines for neonates, oral absorption of metronidazole is nearly complete, and the same dose that is given IV is given orally.
    Infants, Children, and Adolescents: 15 to 50 mg/kg/day PO divided every 8 hours (Max: 2,250 mg/day).

    For the treatment of tetanus*:
    Oral dosage:
    Infants, Children, and Adolescents: 30 mg/kg/day (Max: 4 g/day) PO in divided doses every 6 hours for 7 to 10 days.
    Intravenous dosage:
    Neonates 34 weeks postmenstrual age and younger: 15 mg/kg IV loading dose, then 7.5 mg/kg/dose IV every 12 hours.
    Neonates 35 to 40 weeks postmenstrual age: 15 mg/kg IV loading dose, then 7.5 mg/kg/dose IV every 8 hours.
    Neonates older than 40 weeks postmenstrual age: 15 mg/kg IV loading dose, then 10 mg/kg/dose IV every 8 hours.
    Infants, Children, and Adolescents: 30 mg/kg/day (Max: 4 g/day) IV in divided doses every 6 hours for 7 to 10 days.

    Maximum Dosage Limits:
    -Neonates
    Post-menstrual age (PMA) 34 weeks and younger: Safety and efficacy have not been established; however, doses up to 15 mg/kg/day IV have been used off-label.
    PMA 35 to 40 weeks: Safety and efficacy have not been established; however, doses up to 22.5 mg/kg/day IV have been used off-label.
    PMA older than 40 weeks: Safety and efficacy have not been established; however, doses up to 30 mg/kg/day IV have been used off-label.
    -Infants
    50 mg/kg/day PO; safety and efficacy of IV use have not been established; however, doses up to 40 mg/kg/day IV have been used off-label.
    -Children
    50 mg/kg/day PO (Max: 2,250 mg/day); safety and efficacy of IV use have not been established; however, doses up to 40 mg/kg/day IV have been used off-label (Max: 4 g/day).
    -Adolescents
    50 mg/kg/day PO (Max: 2,250 mg/day); safety and efficacy of IV use have not been established; however, doses up to 40 mg/kg/day IV have been used off-label (Max: 4 g/day).

    Patients with Hepatic Impairment Dosing
    Reduce the dose of systemic metronidazole by 50% in patients with severe hepatic impairment (Child-Pugh C). Single systemic doses may not need to be adjusted.

    Patients with Renal Impairment Dosing
    CrCl 10 ml/minute/1.73 m2 or more: No dosage adjustment is necessary.
    CrCl less than 10 ml/minute/1.73 m2: 16 mg/kg/day IV/PO (i.e., 4 mg/kg/dose IV/PO every 6 hours).

    Intermittent hemodialysis
    16 mg/kg/day IV/PO (i.e., 4 mg/kg/dose IV/PO every 6 hours). Systemically administered metronidazole is significantly removed (up to 65% of a dose) during a standard hemodialysis session.

    Peritoneal dialysis
    16 mg/kg/day IV/PO (i.e., 4 mg/kg/dose IV/PO every 6 hours).

    Continuous Renal Replacement Therapy
    No dosage adjustment is necessary.

    *non-FDA-approved indication

    Monograph content under development

    Mechanism of Action: Metronidazole is amebicidal, bactericidal, and trichomonicidal. Unionized metronidazole is readily taken up by passive diffusion and activated in the cytoplasm of susceptible anaerobic organisms and cells. Its selectivity for anaerobic bacteria is a result of the ability of these organisms to reduce metronidazole to its active form intracellularly. 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. The electron transport proteins necessary for this reaction are found only in anaerobic bacteria. Due to the alteration of the metronidazole molecule, a concentration gradient is created and maintained which promotes the drug's intracellular transport. Reduced metronidazole and free radicals can interact with DNA leading to inhibition of DNA synthesis and DNA degradation. This eventually results in bacterial cell death. Metronidazole is equally effective against dividing and nondividing cells. The precise mechanism of action is unclear.

    The susceptibility interpretive criteria for metronidazole are delineated by pathogen. The MICs are defined for anaerobes as susceptible at 8 mcg/mL or less, intermediate at 16 mcg/mL, and resistant at 32 mcg/mL or more.

    Pharmacokinetics: Metronidazole is administered orally, intravenously, intravaginally, and topically. Protein binding is less than 20%. Metronidazole is widely distributed into various body tissues and fluids including cerebrospinal fluid (CSF), pelvic tissue and peritoneal fluid, pancreas, colorectal tissue, bone, saliva, and gingival fluid. CSF concentrations of metronidazole are similar to plasma concentrations. Bactericidal concentrations of metronidazole have also been detected in pus from hepatic abscesses.

    Metronidazole is extensively metabolized in the liver by hydroxylation, oxidation, and glucuronide conjugation. The major metabolite is 2-hydroxymethyl metronidazole, which has some antibacterial and antiprotozoal activity (30% to 65% of metronidazole). The major route of elimination of metronidazole and its metabolites is via the urine (60% to 80% of the dose), with approximately 20% appearing as unchanged metronidazole. Fecal excretion accounts for 6% to 15% of the dose. Metronidazole is cleared by the kidneys at a rate of 10 mL/minute/1.73 m2. The mean elimination half-life is approximately 8 hours.

    Affected cytochrome P450 isoenzymes and drug transporter: none
    Although previously reported as an inhibitor of CYP3A4 based on assumptions inferred from isolated case reports, controlled in vitro and in vivo studies show that metronidazole does not significantly inhibit CYP3A4/5 activity. Additionally, a study in humans examined S-warfarin and tolbutamide as probes for the CYP2C9 isoenzyme. Metronidazole interacted with S-warfarin, but not tolbutamide. This lessens the likelihood of a potential CYP2C9 interaction, which was originally postulated. It is unknown whether metronidazole alters transport proteins.


    -Route-Specific Pharmacokinetics
    Oral Route
    Immediate-release formulations
    Metronidazole is well absorbed after oral administration (bioavailability more than 90%). Peak concentrations (Cmax) occur 1 to 2 hours after administration.

    Extended-release tablets
    Food increases the rate of absorption. The Cmax occurs approximately 4.6 and 6.8 hours after administration under fed and fasted conditions, respectively.

    Intravenous Route
    After IV administration, the plasma concentrations are proportional to the administered dose. An 8-hour IV infusion of 100 to 4,000 mg of metronidazole showed a linear relationship between dose and peak plasma concentration.

    Topical Route
    Topically applied metronidazole products are only minimally absorbed. Peak concentrations of the lotion are approximately 80 times lower than the peak concentrations of a single 250 mg oral dose. The mean Cmax and AUC are less than 1% of the value reported for a single 250 mg oral dose.

    Other Route(s)
    Intravaginal Route
    Intravaginally administered metronidazole is absorbed systemically; but peak serum concentrations (Cmax) and exposure (AUC) are 2% and 4%, respectively, of the concentrations achieved with 500 mg oral doses. The Cmax is achieved approximately 9.5 hours (range, 4 to 17 hours) after administration.


    -Special Populations
    Pediatrics
    Neonates
    The clearance of metronidazole is significantly longer in neonates compared with children and adults. Elimination half-life has been shown to be inversely related to gestational age. In a small study in neonates (n = 11; 28 to 40 weeks gestational age), mean elimination half-life values were 75.3, 35.4, and 24.8 hours for neonates 28 to 30 weeks, 32 to 35 weeks, and 36 to 40 weeks gestational age, respectively. Volume of distribution ranged from 0.54 to 0.81 L/kg. In another population pharmacokinetic study in preterm neonates (n = 32; 30 infants younger than 32 weeks gestational age), a mean elimination half-life of 29 hours was reported in neonates with a postmenstrual age (PMA) younger than 32 weeks (n = 20) and 15.7 hours for neonates with a PMA 32 weeks or older (n = 12). The predicted elimination half-life for neonates with a PMA of 25 weeks was 40 hours, decreasing to 19 hours at 32 weeks' PMA. Volume of distribution ranged from 0.5 to 0.99 L/kg.

    Infants and Children
    The elimination half-life of metronidazole in infants (older than 8 weeks) and children is similar to that seen in adults (7 to 9 hours). In a study in infants (n = 12), a mean elimination half-life of 18.4 hours was observed in infants younger than 8 weeks of age (n = 7) after a single IV dose of 20 mg/kg.

    Hepatic Impairment
    Patients with hepatic impairment metabolize metronidazole slowly, with resultant accumulation of metronidazole in the plasma. After a single 500 mg IV dose, the mean AUC of metronidazole was 54%, 53%, and 114% higher in patients with mild (Child-Pugh A) impairment, moderate (Child-Pugh B) impairment, and severe (Child-Pugh C) hepatic impairment, respectively, compared to healthy controls. There was no significant change in the AUC of hydroxy-metronidazole (the active metabolite) in these hepatically impaired patients. Metronidazole half-life increases are dependent on the degree of hepatic insufficiency, with Child-Pugh scores predicting decreased elimination. In a study of 35 patients with cirrhosis, the half-life increased from 7.4 hours in healthy volunteers to 10.7 hours in patients with Child-Pugh class A, 13.5 hours in patients with Child-Pugh class B, and 21.5 hours in patients with Child-Pugh class C.

    Renal Impairment
    The half-life of metronidazole is not significantly altered in patients with mild to moderate renal impairment. In patients with severe renal impairment or end-stage renal disease (ESRD), metronidazole and its metabolites may accumulate significantly. Decreased renal function does not alter the single-dose pharmacokinetics of metronidazole. Patients with ESRD (CrCl = 8.1 +/- 9.1 mL/minute) who received a single 500 mg IV dose had no significant change in metronidazole pharmacokinetics, but had a 2-fold higher Cmax of hydroxy-metronidazole (the active metabolite) and a 5-fold higher Cmax of metronidazole acetate, compared to healthy subjects with normal renal function (CrCl = 126 +/- 16 mL/minute).

    Hemodialysis removes significant amounts of metronidazole and its metabolites from systemic circulation. After a single 500 mg IV or PO dose, the clearance of metronidazole was studied in ESRD patients undergoing hemodialysis. 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.

    Accumulation of metronidazole metabolites may occur with peritoneal dialysis. After a single 500 mg IV or PO dose, the clearance of metronidazole was studied in ESRD patients undergoing continuous ambulatory peritoneal dialysis (CAPD). A peritoneal dialysis session lasting for 7.5 hours removed approximately 10% of the administered metronidazole dose.

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