metronidazole (Rx)

Brand and Other Names:Flagyl, Flagyl ER, more...Flagyl IV RTU
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Dosing & Uses

AdultPediatric

Dosage Forms & Strengths

capsule

  • 375mg

tablet

  • 250mg
  • 500mg

tablet, extended-release

  • 750mg

infusion solution

  • 500mg/100mL

Anaerobic Bacterial Infections

Loading dose: 15 mg/kg IV; not to exceed 4 g/day 

Maintenance dose: 7.5 mg/kg PO/IV (over 1 h) q6hr x 7-10 days (or 2-3 weeks if severe)

Sexually Transmitted Disease

Prevention following sexual assault

2 g PO as a single dose; 3-drug regimen that also includes ceftriaxone or cefixime, PLUS azithromycin or doxycycline (CDC STD guidelines, 2010)

Bacterial Vaginosis

Nonpregnant women

  • 500 mg PO BID x 7 days, OR
  • 2 g PO qDay single dose, OR
  • Extended-release: 750 mg PO qDay x 7 days

Pregnant women

  • 500 mg PO BID x 7 days, OR
  • 250 mg PO TID x 7 days

Colorectal Surgical Infection

Prophylaxis; start after mechanical bowel preparation the afternoon and evening before surgery

1 g PO q6-8hr for 3 doses

15 mg/kg IV over 30-60 min; complete approximately 1 hr before surgery; may administer 7.5 mg/kg IV over 30-60 min at 6 and 12 hr after initial dose for maintenance; discontinue within 12 hr after surgery

Trichomoniasis

250 mg PO q8hr for 7 days; alternatively, 375 mg PO q12hr for 7 days

2 g PO qDay single dose; alternatively, 1g PO q12hr for 2 doses

Amebiasis

500-750 mg PO q8hr for 5-10 days

Giardiasis (Off-label)

500 mg PO q12hr for 5-7 days

Gardnerella Infection

Immediate release: 500 mg PO q12hr

Extended-release: 750 mg PO qDay for 7 days; take on empty stomach

Helicobacter Pylori Infection (Off-label)

250-500 mg PO QID in combination with tetracycline (500 mg) and bismuth subsalicylate (525 mg) x 14 days

Nongonococcal Urethritis (Off-label)

2 g PO qDay single dose with erythromycin (500 mg QID) or erythromycin ethylsuccinate (800 mg QID) x 7 days

Pelvic Inflammatory Disease (Off-label)

500 mg PO q12hr for 14 days in conjunction with ofloxacin or levofloxacin

Dosing Considerations

Hepatic failure

  • Mild to moderate hapatic impairment (Child-Pugh A or B): No dosage adjustment needed but patients should be monitored for metronidazole associated adverse events
  • Severe hepatic impairment: Reduce dose of by 50%

Renal failure

  • Mild to moderate renal impairment: Dose adjustment not considered necessary as elimination half-life not significantly altered
  • Severe renal impairment or end stage of renal disease: Metronidazole and metronidazole metabolites may accumulate significantly because of reduced urinary excretion; monitor in severe renal impairment or end stage of renal disease, not undergoing hemodialysis
  • Hemodialysis removes significant amounts of metronidazole and its metabolites from systemic circulation; supplementation may be necessary
  • Peritoneal dialysis: Monitor for signs of toxicity due to potential accumulation of metronidazole metabolites

Pouchitis (Orphan)

Orphan indication sponsor

  • Formac Pharmaceuticals, NV; Gaston Geenslaan 1; Belgium

Crohn Disease (Orphan)

Topical treatment of active perianal Crohn disease

Orphan indication sponsor

  • Braintree Laboratories, Inc; 60 Columbian Street West; PO Box 850929; Braintree, MA 02185-0929

Perioral Dermatitis (Orphan)

Orphan indication sponsor

  • Galderma Laboratories, Inc; P.O. Box 331329; Fort Worth, TX 76163

Dosage Forms & Strengths

capsule

  • 375mg

tablet

  • 250mg
  • 500mg

tablet, extended-release

  • 750mg

infusion solution

  • 500mg/100mL

Neonatal (<28 Days) Anaerobic Infection

<1.2 kg

  • 7.5 mg/kg IV/PO q48hr 

<7 days

  • 1.2-2 kg: 7.5 mg/kg IV/PO qDay
  • >2 kg: 15 mg/kg/day IV/PO divided q12hr

>7 days

  • 1.2-2 kg: 15 mg/kg/day IV/PO divided q12hr
  • >2 kg: 30 mg/kg/day IV/PO divided q12hr

Infants and Children

  • 30 mg/kg/day PO/IV divided q6hr; not to exceed 4 g/day

Clostridium Difficile Colitis

30 mg/kg/day IV/PO divided q6hr IV/PO for 7-10 days (American Academy of Pediatrics) 

Amebiasis

35-50 mg/kg PO divided q8hr for 10 days 

Giardiasis

15 mg/kg/day IV/PO divided q8hr for 5 days 

Trichomoniasis

< 45 kg body weight: 15 mg/kg/day IV/PO divided q8hr for 7 days; not to exceed 2 g/day 

Helicobacter Pylori-Associated Peptic Ulcer Disease (Off-label)

With amoxicillin and bismuth subsalicylate: 15-20 mg/kg/day PO divided q12hr for 4 weeks 

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Interactions

Interaction Checker

and metronidazole

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            Adverse Effects

            Frequency Not Defined

            Appetite loss

            Candidiasis

            Diarrhea

            Dizziness

            Headache

            Nausea

            Vomiting

            Ataxia

            Dark urine

            Disulfiram-type reaction with ethanol

            Furry tongue

            Hypersensitivity

            Neutropenia

            Metallic taste

            Neuropathy

            Pancreatitis

            Seizures

            Thrombophlebitis

            Xerostomia

            Encephalopathy

            Aseptic meningitis

            Optic neuropathy

            Stevens-Johnson syndrome

            Toxic epidermal necrolysis

            Decreased libido

            Postmarketing Reports

            Dyspareunia, proctitis, fleeting joint pains that may resemble serum sickness, Crohn’s disease, hiccup, psychosis

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            Warnings

            Black Box Warnings

            Animal data have shown possible carcinogenic effect

            Contraindications

            Hypersensitivity to metronidazole or other nitroimidazoles (although cautious desensitization has been applied)

            Pregnancy, 1st trimester in patients with trichomoniasis

            Use of disulfiram within past 2 weeks; use of alcohol during therapy or within 3 days of discontinuing therapy

            Cautions

            Seizures and aseptic meningitis reported with increase in dose and chronic therapy

            Cases of encephalopathy and peripheral neuropathy (including optic neuropathy) reported with metronidazole

            Encephalopathy reported in association with cerebellar toxicity characterized by ataxia, dizziness, and dysarthria; CNS lesions seen on MRI described in reports of encephalopathy; CNS symptoms are generally reversible within days to weeks upon discontinuation of therapy; lesions seen on MRI have also been described as reversible

            Peripheral neuropathy, mainly of sensory type reported and characterized by numbness or paresthesia of an extremity

            Prescribing metronidazole tablets in absence of a proven or strongly suspected bacterial or parasitic infection or a prophylactic indication is unlikely to provide benefit to patient and increases risk of development of drug-resistant bacteria and parasites

            Superinfection may occur with prolonged use

            Severe hepatic impairment; administer lower doses with caution

            Use with caution; potential accumulation in end stage renal disease; supplemental doses may be needed in patients receiving hemodialysis

            Use with caution in history of heart failure, hepatic failure, H. pylori infection, renal impairment

            Use with care in patients with evidence of or history of blood dyscrasia; agranulocytosis, leukopenia and neutropenia have been associated with metronidazole administration; monitor complete blood count; monitor complete blood count (CBC) for leukopenia before, during, and after prolonged repeated therapy

            Avoid alcohol while taking medication and for at least three days after discontinuation

            Antiandrogen: May cause gynecomastia

            Known or previously unrecognized candidiasis may present more prominent symptoms during therapy and requires treatment with a candicidal agent

            Metronidazole injection, USP contains 790 mg of sodium per 100 mL; use care when administering injection to patients receiving a controlled sodium diet or corticosteroids or to patients predisposed to edema

            Severe neurological disturbances, including encephalopathy, cerebellar symptoms, convulsive seizures, and aseptic meningitis, reported in patients treated with metronidazole; advise patients to report neurologic symptoms that occur during metronidazole administration; discontinue metronidazole treatment if any abnormal neurologic symptoms occur such as ataxia, dizziness, confusion or any other CNS adverse reaction

            Cases of severe hepatotoxicity/acute hepatic failure, including cases with a fatal outcome with very rapid onset after treatment initiation in patients with Cockayne syndrome reported with products containing metronidazole for systemic use; in this population, metronidazole should therefore be used after careful benefit-risk assessment and only if no alternative treatment available; obtain liver function tests prior to start of therapy, within first 2-3 days after initiation of therapy, frequently during therapy and after end of treatment; discontinue metronidazole if elevation of liver function occurs, and monitor liver function tests until baseline values are reached; advise patients with Cockayne syndrome to stop taking metronidazole immediately if they experience any symptoms of potential liver injury, such as abdominal pain, nausea, change in stool color or jaundice, and to contact their healthcare provider

            When metronidazole tablets are prescribed to treat a bacterial infection, patients should be told that the medication should be taken exactly as directed; skipping doses or not completing full course of therapy may decrease effectiveness of immediate treatment and increase likelihood that bacteria will develop resistance and will not be treatable by metronidazole tablets in the future

            Drug interaction overview

            • Metronidazole reported to potentiate anticoagulant effect of warfarin and other oral coumarin anticoagulants, resulting in a prolongation of prothrombin time and increased risk of hemorrhages; prothrombin time and international normalized ratio (INR) should be carefully monitored and anticoagulant dose adjusted accordingly; monitor patients for signs and symptoms of bleeding
            • Metronidazole reported to increase plasma concentrations of busulfan, which can result in an increased risk for serious busulfan toxicity such as sinusoidal obstruction syndrome, gastrointestinal mucositis, and hepatic veno-occlusive disease; metronidazole should not be administered concomitantly with busulfan unless benefit outweighs risk
            • Simultaneous administration of drugs that decrease microsomal liver enzyme activity, such as cimetidine, may decrease metabolism and reduce plasma clearance of metronidazole which may result in metronidazole toxicity
            • Simultaneous administration of drugs that induce microsomal liver enzyme activity, such as phenytoin or phenobarbital, may accelerate elimination of metronidazole and therefore decrease its efficacy
            • Concomitant use of metronidazole and CYP3A4 substrates (e.g., amiodarone, tacrolimus, cyclosporine, carbamazepine, phenytoin, and quinidine) may increase respective CYP3A4-substrate plasma levels; monitoring of plasma concentrations of CYP3A4 substrates may be necessary
            • Metronidazole decreases clearance of 5-fluorouracil and may therefore cause 5-fluorouracil toxicity
            • Metronidazole may potentiate effects of vecuronium
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            Pregnancy & Lactation

            Pregnancy

            There are no adequate and well-controlled studies of in pregnant women; there are published data from case-control studies, cohort studies, and 2 meta-analyses that include more than 5000 pregnant women who used metronidazole during pregnancy; many studies included first trimester exposures; one study showed increased risk of cleft lip, with or without cleft palate, in infants exposed to metronidazole in utero; however, these findings were not confirmed

            Metronidazole crosses placental barrier and its effects on human fetal organogenesis are not known; reproduction studies have been performed in rats, rabbits and mice at doses similar to maximum recommended daily dose based on body surface area comparisons; there was no evidence of harm to fetus due to metronidazole; healthcare provider should carefully consider potential risks and benefits for each specific patient before prescribing therapy

            Lactation

            Metronidazole is present in human milk at concentrations similar to maternal serum levels, and infant serum levels can be close to or comparable to infant therapeutic levels

            Because of potential for tumorigenicity shown for metronidazole in mouse and rat studies, a decision should be made whether to discontinue nursing or to discontinue drug, taking into account importance of drug to mother; alternatively, a nursing mother may choose to pump and discard human milk for duration of metronidazole therapy, and for 24 hours after therapy ends and feed her infant stored human milk or formula

            Study Data

            There are published data from case-control studies, cohort studies, and 2 meta-analyses that included more than 5000 pregnant women who used metronidazole systemically during pregnancy

            Many studies included first trimester exposures

            One study showed an increased risk of cleft lip, with or without cleft palate, in infants exposed to metronidazole in utero; however, these findings were not confirmed

            In addition, more than 10 randomized, placebo-controlled clinical trials that together enrolled over 5000 pregnant women assessed the possible effect of systemic antibiotic treatment (including with metronidazole) for bacterial vaginosis on the incidence of preterm delivery; most studies did not show an increased risk of congenital anomalies or other adverse fetal outcomes following metronidazole exposure during pregnancy

            Three studies conducted to assess the risk of infant cancer following systemic metronidazole exposure during pregnancy did not show an increased risk; however, the ability of these studies to detect such a signal was limited

            Pregnancy Categories

            A:Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

            B:May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

            C:Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

            D:Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

            X:Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

            NA:Information not available.

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            Pharmacology

            Mechanism of Action

            Inhibits nucleic acid synthesis by disrupting DNA and causing strand breakage; amebicidal, bactericidal, trichomonacidal

            Absorption

            Bioavailability: 80% absorption from GI tract (PO)

            Protein binding (<20%)

            Peak serum time: 1-2 hr

            Distribution

            Widely distributed; similar pattern for PO and IV

            Metabolism

            Liver

            Enzymes inhibited: Hepatic CYP2C9

            Elimination

            Half-life: 25-75 hr (neonates); 8 hr (others); prolonged in patients with hepatic impairment

            Excretion: Urine (77%); feces (14%)

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            Administration

            IV Incompatibilities

            Some drugs may be incompatible with reconstituted solution from powder (which contains metronidazole HCl) but compatible with RTU IV solution (which contains metronidazole), and vice versa

            Additive: Aztreonam, cefepime(?), ciprofloxacin (may be compatible with RTU solution), dopamine, meropenem

            Y-site: Amphotericin B cholesteryl sulfate, aztreonam, filgrastim, meropenem, warfarin

            IV Preparation

            Reconstitute powder with 4.4 mL sterile water for injection, bacteriostatic water for injection, NS, or bacteriostatic NS to a final concentration of 100 mg/mL (pH 0.5-2)

            Further dilute in glass or plastic container to no more than 8 mg/mL with NS, D5W, or LR

            Neutralize with approximately 5 mEq NaHCO3 per 500 mg metronidazole; final pH 6-7

            No dilution or buffering necessary for ready-to-use IV solution

            IV Administration

            Infusion only

            Avoid contact between drug and aluminum in infusion set (less critical for RTU infusion solution containing metronidazole rather than metronidazole HCl)

            Storage

            Store at 15-30°C

            Protect from light

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            Formulary

            FormularyPatient Discounts

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            Tier Description
            1 This drug is available at the lowest co-pay. Most commonly, these are generic drugs.
            2 This drug is available at a middle level co-pay. Most commonly, these are "preferred" (on formulary) brand drugs.
            3 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs.
            4 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
            5 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
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            NC NOT COVERED – Drugs that are not covered by the plan.
            Code Definition
            PA Prior Authorization
            Drugs that require prior authorization. This restriction requires that specific clinical criteria be met prior to the approval of the prescription.
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            Drugs that have quantity limits associated with each prescription. This restriction typically limits the quantity of the drug that will be covered.
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            Drugs that have step therapy associated with each prescription. This restriction typically requires that certain criteria be met prior to approval for the prescription.
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            Medscape prescription drug monographs are based on FDA-approved labeling information, unless otherwise noted, combined with additional data derived from primary medical literature.