metronidazole (Rx)

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

Gastrointestinal: Anorexia,

epigastric distress, abdominal cramping

Mouth: Glossitis, stomatitis

Hematopoietic: Reversible neutropenia (leukopenia); thrombocytopenia, eosinophilia

Hepatobiliary disorders: Hepatotoxicity and liver failure especially in patients with Cockayne syndrome, jaundice

Cardiovascular: QT prolongation

Skin and subcutaneous disorders: Eosinophilia and systemic symptoms (DRESS), erythematous rash, bullae, pruritus, swelling face, urticaria, and hyperhidrosis

Central nervous system: Dizziness, vertigo, incoordination, ataxia, confusion, psychosis, dysarthria, irritability, depression, weakness, headache, and insomnia

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
• QT prolongation reported, particularly when metronidazole administered with drugs with potential for prolonging QT interval; flattening of T-wave may be seen in electrocardiographic tracings

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.

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%)

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