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Metronidazole (Vaginal)


VA CLASSIFICATION
Primary: GU301

Commonly used brand name(s): Flagyl; MetroGel-Vaginal; Nidagel.

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



Category:


Anti-infective (vaginal)—

Indications

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

Accepted

Vaginosis, bacterial (treatment)—Vaginal metronidazole is indicated in the local treatment of bacterial vaginosis (previously known as Haemophilus vaginitis, Gardnerella vaginitis, nonspecific vaginitis, Corynebacterium vaginitis, or anaerobic vaginosis). {01} {22} {39}
—There are only limited clinical data regarding metronidazole gel's efficacy in treating bacterial vaginosis during pregnancy. {13} {21} {46} {48} {52} {53}

[Trichomoniasis (treatment)]—Metronidazole vaginal tablets and vaginal cream are indicated in the local treatment of trichomoniasis. {04} {07} {08} {25} {29} {47}

—Not all species or strains of a particular organism may be equally susceptible to metronidazole. {09} {24}

Unaccepted
Vaginal metronidazole is not effective against aerobic or facultative anaerobic bacteria, or in the treatment of vulvovaginitis caused by Chlamydia trachomatis , Neisseria gonorrhoeae , Candida albicans , or Herpes simplex virus. {01} {04} {16} {25} Metronidazole vaginal gel has not been proven to be clinically effective in the treatment of Trichomonas vaginalis . {01} {16} {25}


Pharmacology/Pharmacokinetics

Physicochemical characteristics:

Chemical group—
    Imidazole {01}.
Molecular weight—
    171.16 {01}

Mechanism of action/Effect:

The exact mechanism of action has not been completely established. Metronidazole is thought to be microbicidal against most obligate anaerobic bacteria {01} {04} and protozoa. {04} To be active, it must undergo intracellular chemical reduction via mechanisms unique to anaerobic metabolism. The short-lived reduced forms are cytotoxic and interact with DNA to cause a loss of helical structure and strand breakage resulting in inhibition of nucleic acid synthesis and cell death. {01} {04} {06} {16} {17}

Note: Metronidazole permits natural vaginal flora recovery because it has little effect on Lactobacillus sp {22}.



Other actions/effects:

Metronidazole may produce a local antioxidant and anti-inflammatory effect on inflamed tissue by affecting neutrophil function. {14} {15} {27}

Absorption:

Vaginal cream or

Vaginal tablets—Approximately 20% of the administered dose of metronidazole (500 mg) is absorbed systemically, producing plasma concentrations approximately 12% of that resulting from a single 500-mg oral dose. The rate of absorption is less predictable with the vaginal tablets than with the cream. {08}

Vaginal gel—Approximately 56% of the administered dose of metronidazole (37.5 mg) is absorbed systemically, producing plasma concentrations approximately 2% of that resulting from a single 500-mg oral dose. {01} {41} {42}

Distribution:

Systemically absorbed metronidazole may be distributed into breast milk and to most tissues. It crosses the blood-brain barrier and placenta. {01} {08} {11}

Protein binding:

Low (< 20%). {04} {10}

Biotransformation:

Systemically absorbed metronidazole is metabolized primarily by side-chain oxidation by the hepatic cytochrome P450 enzyme system to two active metabolites, 1-[2-hydroxyethyl]-2-hydroxymethyl-5-nitroimidazole and 1-acetic acid-2-methyl-5-nitroimidazole. The hydroxylated metabolite is approximately 30% as potent as the parent compound while the acetic acid metabolite is 5% as potent. {11} {35} Small amounts of other metabolites (including glucuronide and sulfide conjugates) are also formed.

Half-life:

Elimination (determined with systemic administration)—Normal hepatic function: 8 hours (range, 6 to 12 hours) for unchanged metronidazole. {04} {10}

Time to peak serum concentration:

Vaginal cream—11 hours. {01}

Vaginal gel—6 to 12 hours. {01}

Vaginal tablet—20 hours. {08}

Peak serum concentration:

Vaginal cream—1.86 mg per liter (mg/L) (10.87 micromole/L). {01}

Vaginal gel—0.152 to 0.368 mg/L (0.89 to 2.15 micromole/L). {01}

Vaginal tablet—1.89 mg/L (11.04 micromole/L). {08}

Elimination:
    Renal—60 to 80% of a systemic dose; of this amount, approximately 20% is excreted unchanged. {04} {19}
    Fecal—6 to 15% of a systemic dose. {06} {20}


Precautions to Consider

Note: Some of the following information relates to the oral formulation. Depending on the vaginal product's strength and formulation, the vaginal administration of metronidazole may yield 2 to 12% of the blood concentrations achieved after a single 500-mg oral dose. The possibility of systemic effects may need to be considered until further studies quantify the degree of clinical significance. {42} {54}


Carcinogenicity

Carcinogenicity studies have not been done using vaginal formulations of metronidazole. Systemic metronidazole has not been shown to be carcinogenic in humans. {01} {16} {17} {18} {38}

Systemic metronidazole has been shown to be carcinogenic in a number of studies in mice and rats, including a study in which it produced malignant lymphomas in mice. {01} {16}

Tumorigenicity

Tumorigenicity studies have not been done using vaginal formulations of metronidazole. Systemic metronidazole has not been shown to be tumorigenic in humans. {01} {16} {17} {18} {38}

Pulmonary tumorigenesis has been reported in six studies in mice, including a study in which the animals were dosed every 4 weeks. Malignant hepatic tumors have also been reported in male mice given very high doses (approximately 500 mg per kg of body weight [mg/kg] per day). {01} {16} Several long-term oral-dose studies in rats have shown that metronidazole causes a statistically significant increase in the incidence of various neoplasms, especially mammary and hepatic tumors in female rats. {01} {16} Two lifetime tumorigenicity studies in hamsters using oral formulations have given negative results. {01} {16}

Mutagenicity

Studies have shown that metronidazole is mutagenic in bacteria and fungi, although this has not been confirmed in mammals. {01} {16}

Pregnancy/Reproduction
Fertility—
No evidence of impaired fertility was found in mice. {01}

Pregnancy—
Metronidazole crosses the placenta, entering the fetal circulation rapidly. {01} Adequate and well-controlled studies in humans have not been done. {01} {04}

Tumorigenicity has been demonstrated in animal studies, which may suggest that metronidazole should be withheld during pregnancy until more clinical data regarding vaginal administration are available {01} {04} {16} {18} {51} {54}.

A small study reported that intrauterine deaths resulted when metronidazole was administered intraperitoneally to pregnant mice in doses comparable to the oral human dose. No fetotoxicity or teratogenicity occurred with orally administered metronidazole. {01}

FDA Pregnancy Category B.

Breast-feeding

Metronidazole is distributed into breast milk; concentrations are similar to those found in the maternal plasma. {01} {49} {52} Use in nursing mothers is not recommended. The theoretical risk is based on tumorigenicity studies in animals; human data have not supported this. {01} {54} Also, metronidazole may change the taste of the breast milk. {52} If a nursing mother is treated with metronidazole, the breast milk may be expressed and discarded and breast-feeding resumed 24 to 48 hours after treatment is completed. {11}

Pediatrics

No information is available on the relationship of age to the effects of vaginal metronidazole in pediatric patients.


Geriatrics


No information is available on the relationship of age to the effects of vaginal metronidazole in geriatric patients. However, elderly patients are more likely to have an age-related decrease in hepatic function, which may affect metronidazole elimination. {01}

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


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

» Alcohol    (caution in concurrent use with vaginal metronidazole and for at least 1 day following completion of treatment is advisable because systemic metronidazole may interfere with the oxidation of alcohol; such use may result in disulfiram-like effects such as abdominal cramps, nausea, vomiting, headache, or flushing of the face from acetaldehyde accumulation; changes in the taste of alcoholic beverages also have been reported during concurrent use {01} {06} {11} {24} {26})


» Anticoagulants, coumarin- or indandione-derivative    (anticoagulant effects may be potentiated when these agents are used concurrently with metronidazole because of inhibition of enzymatic metabolism of anticoagulants; periodic prothrombin time determinations may be required during and following concurrent therapy to determine if dosage adjustments of anticoagulants are necessary {01} {06} {23} {24} {30} {31} {32})


Cimetidine    (hepatic metabolism of metronidazole may be decreased when metronidazole and cimetidine are used concurrently, possibly resulting in delayed elimination and increased serum metronidazole concentrations {06} {33} {44})


» Disulfiram    (it is recommended that metronidazole not be used concurrently with, or for 2 weeks following, disulfiram in alcoholic patients; such use may result in confusion and psychotic reactions because of combined toxicity {01} {06} {23})


Lithium    (concurrent use of systemic metronidazole with lithium has resulted in decreased renal clearance of lithium and lithium toxicity; adjustments of lithium dosage may be required {04} {06} {34})


Neurotoxic medications, other (see Appendix II )    (concurrent use of systemic metronidazole with other neurotoxic medications may increase the potential for neurotoxicity {01} {24})


Phenytoin    (systemic metronidazole may impair the metabolism of phenytoin by inhibiting microsomal enzymes and increasing phenytoin's plasma concentration; the extent to which intravaginal metronidazole affects phenytoin is not presently known {04} {06} {36} {37} {45} {54})



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

With diagnostic test results
Alanine aminotransferase (ALT [SGPT]) and
Aspartate aminotransferase (AST [SGOT]) and
Hexokinase glucose and
Lactate dehydrogenase (LDH) and
Triglycerides    (metronidazole has a high absorbance at the wavelength at which nicotinamide-adenine dinucleotide [NADH] is determined; therefore, falsely low values may occur when these substances are measured by continuous-flow methods based on endpoint decrease in reduced NADH {01} {04})


White blood cell count    (may be increased or decreased {01} {04} {22} {24})


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


Risk-benefit should be considered when the following medical problems exist
» Epilepsy or
» Other neurologic disease    (systemic metronidazole has caused CNS toxicity, including seizures and peripheral neuropathy {01} {04})


» Hepatic function impairment, severe    (metronidazole is metabolized in the liver; hepatic function impairment may lead to decreased plasma clearance and accumulation of metronidazole and its metabolites and increased risk of side effects; dosage may need to be reduced in patients with severe hepatic function impairment {01} {10} {11} {12})


Hypersensitivity to metronidazole
Leukopenia, or history of    (oral metronidazole has caused leukopenia; the possibility should be considered that vaginal metronidazole may induce or exacerbate leukopenia, especially with prolonged or multiple courses of therapy {01} {04} {24})



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

Leukocyte count, total and differential    (determinations recommended when metronidazole is used for longer than 10 days or if a second course of therapy is needed {04})




Side/Adverse Effects

Note: Convulsions, peripheral neuropathy, and ataxia have been reported rarely with systemic administration of metronidazole. The possibility should be considered that these effects may also occur with vaginal administration, especially with the higher-potency formulations available in Canada or with prolonged use. If neurological symptoms occur, the medication should be discontinued. Severe symptoms may require immediate medical attention. {04}
The incidences of side effects listed below are those reported in studies with the 0.75% gel. Although specific information about the incidence of side effects with the vaginal tablet or vaginal cream is not available, it is possible that some adverse effects could occur more frequently with these higher-potency formulations than with the gel. Also, the possibility of systemic effects may need to be considered since vaginal administration of metronidazole may yield 2 to 12% of the blood concentrations achieved after a single oral 500-mg dose.

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

Those indicating need for medical attention
Incidence more frequent
    
Candida cervicitis or vaginitis (itching in the vagina; pain during sexual intercourse; thick, white vaginal discharge without odor or with mild odor)—incidence 6 to 15%{01}{15}{22}{28}{38}

Incidence less frequent
    
Abdominal cramping or pain —incidence 3.4%{01}{15}
    
burning or irritation of penis of sexual partner
    
burning or increased frequency of urination {01}{28}
    
vulvitis (itching, stinging or redness of genital area){01}{15}{22}{28}



Those indicating need for medical attention only if they continue or are bothersome
Incidence less frequent
    
Altered taste sensation including metallic taste {01}{15}{24}{28}
    
CNS effects (dizziness or lightheadedness; headache){24}{28}
    
dryness of mouth
    
furry tongue
    
gastrointestinal disturbances (diarrhea, nausea or vomiting)
    
loss of appetite{01}{15}{24}{28}



Those not indicating need for medical attention
Incidence less frequent
    
Dark urine{11}{24}



Those indicating possible need for medical attention if they occur after medication is discontinued
    
Vaginal candidiasis (itching of the vagina or outside genitals; pain during sexual intercourse; thick, white vaginal discharge without odor or with mild odor){01}{15}{22}{28}{38}




Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Metronidazole (Vaginal) .
In providing consultation, consider emphasizing the following selected information (» = major clinical significance):

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

Pregnancy—Metronidazole crosses the placenta; discussing use of medicine with physician before using during pregnancy





Breast-feeding—Metronidazole is distributed into breast milk and is not recommended during breast-feeding
Other medications, especially alcohol, coumarin- or indandione-derivative anticoagulants, or disulfiram
Other medical problems, especially epilepsy or other neurologic disease or severe hepatic function impairment

Proper use of this medication
» Washing hands immediately before and after vaginal administration

Avoiding getting medication into the eyes; washing with large amounts of cool tap water immediately if medication does get into eyes; checking with physician if eyes continue to be painful

Reading patient directions carefully before use

Proper administration technique
Following directions regarding filling the applicator, insertion technique, and cleaning the applicator after each use

For cream or gel dosage forms
Puncturing metal tamper-resistant seal on tube with top of cap

For vaginal tablet dosage form
Placing vaginal tablet into the applicator, immersing exposed tablet in tap water for a few seconds before vaginal insertion to facilitate disintegration {04}
» Compliance with full course of therapy, even during menstruation

» Proper dosing
Missed dose: Inserting as soon as possible; not inserting if almost time for next dose

» Proper storage

Precautions while using this medication
Checking with physician if no improvement within a few days

Follow-up visit to physician after treatment for bacterial vaginosis to ensure that infection has been eradicated

» Avoiding use of alcoholic beverages or other alcohol-containing preparations while using and for at least 1 day after discontinuing this medication

» Caution if dizziness or lightheadedness occurs

Protecting clothing because of possible soiling with vaginal metronidazole; avoiding use of tampons

» Using hygienic measures to cure infection and prevent reinfection, e.g., wearing freshly washed cotton panties instead of synthetic panties

» Sexual abstinence is recommended during treatment to prevent cross-infection, reinfection, or dilution of the dose {04} {29}. If this recommendation is not followed, use of the vaginal cream and vaginal tablets should be avoided with latex contraceptive devices, such as cervical caps, condoms, or diaphragms, since these products contain oils that damage latex

For trichomoniasis
» Using condoms to prevent reinfection with trichomoniasis after treatment; possible need for concurrent treatment of male partner for trichomoniasis {54}


Side/adverse effects
Signs of potential side effects, especially candida cervicitis or vaginitis, abdominal cramping or pain, burning or irritation of penis of sexual partner, increased frequency of urination, vulvitis, altered taste sensation, CNS effects, dryness of mouth, furry tongue, gastrointestinal disturbances, loss of appetite

Dark urine may be alarming to patient although medically insignificant

Possibility of vaginal candidiasis occurring after medication has been discontinued


General Dosing Information
If sensitization or irritation occurs, treatment with vaginal metronidazole should be discontinued. {01}

The cream and the vaginal tablet (but not the gel) may contain oils that may damage latex contraceptive devices, such as cervical caps, condoms, or diaphragms, and reduce their efficacy. {41} {43}

Vaginal applicators should be used with caution after the sixth month of pregnancy. {40} {49} {50}

If there is no response to therapy, the presence of pathogens unresponsive to metronidazole should be ruled out by potassium hydroxide (KOH) wet mounts before a second course of therapy is initiated. {07} {08} {25}

In treating bacterial vaginosis, concurrent treatment of the male partner generally is unnecessary. {04} {29}

In treating trichomoniasis, both sexual partners should receive metronidazole therapy concurrently since asymptomatic trichomoniasis in the male partner is a frequent source of reinfection in the female. {01} {04} {29}


Vaginal Dosage Forms

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

METRONIDAZOLE VAGINAL CREAM

Usual adult and adolescent dose
Bacterial vaginosis or
[Trichomoniasis]
Intravaginal, 500 mg (one applicatorful) one or two times a day for ten or twenty consecutive days. {04}


Usual pediatric dose
Safety and efficacy have not been established.

Strength(s) usually available
U.S.—
Not commercially available.

Canada—


10% w/w (Rx) [Flagyl (methylparaben) (propylparaben)]

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer. Protect from freezing. {03}

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

Note: Include patient package insert (PPI) when dispensing. {05}



METRONIDAZOLE VAGINAL GEL

Usual adult and adolescent dose
Bacterial vaginosis
Intravaginal, 37.5 mg (one applicatorful) one or two times a day for five days {01} {03}.


Usual pediatric dose
Safety and efficacy have not been established.

Strength(s) usually available
U.S.—


0.75% (Rx) [MetroGel-Vaginal (EDTA) (methylparaben) (propylparaben) (propylene glycol){01}]

Canada—


0.75% (Rx) [Nidagel (EDTA) (methylparaben) (propylparaben) (propylene glycol){03}]

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer. Protect from freezing. Keep out of reach of children. {01}

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

Note: Include patient package insert (PPI) when dispensing. {02}



METRONIDAZOLE VAGINAL TABLETS

Usual adult and adolescent dose
Bacterial vaginosis or
[Trichomoniasis]
Intravaginal, 500 mg placed high into the vagina every night for ten or twenty consecutive days. {04}


Usual pediatric dose
Safety and efficacy have not been established.

Strength(s) usually available
U.S.—
Not commercially available.

Canada—


500 mg (Rx) [Flagyl]

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

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

Note: Include patient package insert (PPI) when dispensing.
Patient should be instructed on technique for placement including immersing the vaginal tablet (in applicator) in tap water for a few seconds before insertion to facilitate disintegration. {04}




Revised: 08/13/1998



References
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  1. MetroGel-Vaginal gel patient package insert (Curatek—US), Rev 1/93, Rec 6/93.
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  1. Flagyl vaginal insert packaging (Rhone-Poulenc Rorer—Canada), Rev none, Rec 5/89.
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  1. Panel comment, 1/94.
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  1. Panel comment, 1/94.
  1. Panel comment, 1/94.
  1. Panel comment, 2/94.
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