metronidazole vaginal (Rx)

>10%

Bacterial infection (12%)

1-10%

Headache (7%)

Pruritus (6%)

Abdominal pain (5%)

Nausea (3%)

Dysmenorrhea (3%)

Pharyngitis (2%)

Rash (1%)

Diarrhea (1%)

Breast pain (1%)

Metrorrhagia (1%)

Postmarketing Reports

Severe irreversible hepatotoxicity/acute liver failure (patients with Cockayne syndrome)

Contraindications

Hypersensitivity

Patients with Cockayne syndrome

Within 2 weeks of taking disulfiram

Consumption of alcohol or products containing propylene glycol within least three days of receiving metronidazole

Cautions

Severe irreversible hepatotoxicity/acute liver failure with fatal outcomes reported after initiation of metronidazole, another nitroimidazole drug, structurally related to benznidazole in patients with Cockayne syndrome

Interaction with alcohol (disulfiram-like reaction); abdominal cramps, nausea, vomiting, headache, flushing (see Contraindications)

PO and IV administration associated with seizures, encephalopathy, aseptic meningitis, and peripheral neuropathy

Carcinogenic in mice and rats; avoid unnecessary use

May interfere with lab assessments of AST, ALT, LDH, TG, and glucose hexokinase

Drug interaction overview

• Use of oral metronidazole has been associated with psychotic reactions in alcoholic patients who are using disulfiram concurrently; do not initiate metronidazole in patients who have taken disulfiram within the last 2 weeks
• Disulfiram-like reactions reported with oral metronidazole consumed with alcohol; do not consume ethanol or propylene glycol, during and for at least 24 hr following treatment
• Use of oral metronidazole has been reported to potentiate the anticoagulant effect of warfarin and other coumarin anticoagulants, resulting in a prolongation of prothrombin time
• Short-term use of oral metronidazole has been associated with elevation of serum lithium concentrations
• Cimetidine may decrease plasma clearance and prolong metronidazole half-life

Pregnancy

There are no data on the use of metronidazole intravaginal in pregnant women

Human systemic data

• Blood levels following vaginal administration are lower than those achieved with oral metronidazole; Cmax and AUC of intravaginally administered metronidazole is 2% and 4%, respectively, of those following oral administration
• There are published data from case-control studies, cohort studies, and 2 meta-analyses that include 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, >10 randomized, placebo-controlled clinical trials enrolled >5000 pregnant women to assess the use of systemic antibiotic treatment (including metronidazole) for bacterial vaginosis on the incidence of preterm delivery; most studies did not show an increased risk for congenital anomalies or other adverse fetal outcomes following metronidazole exposure during pregnancy
• Three studies conducted to assess the risk of infant cancer following systemic metronidazole exposure during pregnancy did not show an increased risk; however, the ability of these studies to detect such a signal was limited

Animal data

• In animal reproduction studies, no fetotoxicity or teratogenicity was observed when metronidazole was administered orally to pregnant rats and rabbits, during organogenesis, at up to 30 times and 60 times the recommended human dose based on body surface area comparison, respectively

Lactation

There is no information on the presence of metronidazole in human milk, or the effects on the breast-fed child, or the effects on milk production following intravaginal administration

Metronidazole is present in human milk following oral metronidazole administration, at concentrations similar to those found in plasma; metronidazole vaginal gel achieves 2% of the mean maximum serum concentration of a 500 mg oral metronidazole

Animal studies have shown the potential for tumorigenicity after oral metronidazole administered chronically to rats and mice; the clinical relevance of these findings is unclear

The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for therapy, and any potential adverse effects on breastfed child from the drug or from underlying maternal condition

Alternatively, a lactating patient may interrupt breastfeeding and choose to pump and discard breastmilk during treatment and for 48 hours after last dose and feed her infant previously stored human milk or formula

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

Antibacterial agent; active in vitro to most strains of organisms associated with bacterial vaginosis including Bacteroides spp., Gardnerella vaginalis, Mobiluncus spp., and Peptostreptococcus spp.

Inhibits nucleic acid synthesis by disrupting DNA

Pharmacokinetics

Peak plasma time: 9.5 hr

Peal plasma concentration: 281 ng/mL (2% of PO dose)

AUC: 125,000 ng•hr/mL (5% of single oral dose)