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Metronidazole topical

Class: Antibacterials
VA Class: DE101
Chemical Name: 2-Methyl-5-nitro-1H-imidazole-1-ethanol
Molecular Formula: C6H9N3O3
CAS Number: 443-48-1
Brands: MetroCream, MetroGel, MetroGel-Vaginal, MetroLotion, Noritate, Vandazole

Medically reviewed on July 2, 2018

Introduction

Antibacterial and antiprotozoal;1 2 27 29 47 183 also has anti-inflammatory and immunosuppressive effects;1 2 14 17 21 28 180 nitroimidazole derivative.3

Uses for Metronidazole

Rosacea

Treatment of inflammatory lesions (papules and pustules) associated with rosacea (acne rosacea);1 2 8 9 10 16 17 18 19 20 21 47 180 184 207 topical gel designated an orphan drug by FDA for use in this condition.23

Has no beneficial effects on telangiectasia,2 9 10 17 19 21 47 rhinophyma,47 or ocular manifestations of rosacea.47 83

Optimal treatment not determined; inflammatory lesions may respond to long-term treatment with topical anti-infectives (e.g., metronidazole) or oral anti-infectives (e.g., doxycycline, tetracycline, erythromycin, ampicillin, metronidazole).10 11 12 13 15 16 17 20 21 47 80 82 2 8 9 10 16 17 18 19 20 21 47 80 81 82 Topical metronidazole may be preferred to oral metronidazole;17 147 has been effective in patients with inadequate response or relapse with other therapies (e.g., oral tetracycline).2 10 17 21 62

Effects appear palliative;17 18 19 47 81 61 99 manifestations recur commonly following discontinuance of therapy.17 18 19 47 61 99

Adjunctive measures recommended to decrease exposure to factors that exacerbate rosacea (e.g., excessive sunlight, wind, hot liquids, spicy food, alcohol, extremes of heat and cold).2 12 80

Bacterial Vaginosis

Treatment of bacterial vaginosis (formerly called Haemophilus vaginitis, Gardnerella vaginitis, nonspecific vaginitis, Corynebacterium vaginitis, anaerobic vaginosis)109 111 112 114 115 119 120 122 123 139 153 183 214 in nonpregnant women.214

CDC recommends treatment of bacterial vaginosis in all symptomatic women (including pregnant women).109 In addition, asymptomatic pregnant women at high risk for complications of pregnancy should be screened (preferably at the first prenatal visit) and treatment initiated if needed.109

Treatment recommendations for bacterial vaginosis in HIV-infected women are the same as those for women without HIV infection.109

Regimens of choice in nonpregnant women are a 7-day regimen of oral metronidazole, a 5-day regimen of intravaginal metronidazole gel, or a 7-day regimen of intravaginal clindamycin cream;109 114 alternative regimens are a 7-day regimen of oral clindamycin or 3-day regimen of intravaginal clindamycin suppositories.109 114 The preferred regimens for pregnant women are a 7-day regimen of oral metronidazole or a 7-day regimen of oral clindamycin.109

Regardless of regimen used, relapse or recurrence is common;109 110 120 122 138 153 162 an alternative regimen (e.g., oral therapy when topical was used initially) may be used in such situations.109 122

Routine treatment of asymptomatic male sexual contacts of women who have relapsing or recurrent bacterial vaginosis not recommended.109 113 201 202 203

Decubitus and Other Ulcers

Treatment of infected decubitus ulcers;27 39 40 41 42 212 topical metronidazole designated an orphan drug by FDA for use in treatment of grade III or IV, anaerobically infected, decubitus ulcers.23

Perioral Dermatitis

Treatment of perioral dermatitis;210 211 topical gel designated an orphan drug by FDA for treatment of this condition.23

Trichomoniasis

Has been used intravaginally as an adjunct to oral metronidazole for treatment of trichomoniasis caused by Trichomonas vaginalis in selected cases (e.g., refractory infections),156 205 but not included in CDC recommendations for treatment of trichomoniasis.109 Intravaginal metronidazole not effective used alone.114

Drug of choice for treatment of trichomoniasis is oral metronidazole or oral tinidazole.109 114 123 215 216

Metronidazole Dosage and Administration

Administration

Administer topically to the skin2 180 184 207 or intravaginally183 214 in appropriate formulations.

Topical skin preparations (cream, gel, lotion) are for external use only and should not be used orally, intravaginally, or near or in eyes.1 177 180 184 207

Intravaginal preparations are for intravaginal administration only and should not be used orally, topically on the skin, or near or in eyes.183 214

Topical Administration

Apply topically to the skin as a 0.75 or 1% cream, 1% gel, or 0.75% lotion.1 19 180 184 207

Prior to topical application, wash affected area with mild, nonirritating cleanser.1 2 180 184 207 To minimize risk of local irritation, some clinicians suggest application be delayed until about 15–20 minutes after skin cleansing.99

Rub cream, gel, or lotion into affected area.1 19 180 184 207 Avoid contact with eyes.1 19 180 184 207

If irritation occurs at application site, reduce application frequency or discontinue.1 19 180 184 207

Cosmetics may be applied to skin after application of cream, gel, or lotion;1 47 180 184 207 allow lotion to dry ≥5 minutes before applying cosmetics.207

Intravaginal Topical Administration

Administer intravaginally as a 0.75% gel using vaginal applicators provided by the manufacturers.183 214

If once-daily regimen used, administer dose at bedtime.183 214

If once-daily regimen used, use new vaginal applicator for each dose.214 If twice-daily regimen used, use new applicator each day; wash, rinse, and dry applicator after morning dose and discard after evening dose.214

Dosage

Pediatric Patients

Bacterial Vaginosis
Treatment in Nonpregnant Postmenarchal Females
Intravaginal

0.75% gel: One applicatorful (approximately 37.5 g of metronidazole) once daily (at bedtime) or twice daily (in morning and evening) given for 5 consecutive days.214

Adults

Rosacea
Topical

0.75% cream or lotion: Apply thin film to cleansed, affected area twice daily (morning and evening)180 207 or as directed by clinician.207

1% cream or gel: Apply thin film to cleansed, affected area once daily.1 184

Optimum treatment duration not established;10 17 18 19 21 47 81 has been continued for ≥21 weeks in clinical studies.2 9 10 16 17 18 19 20 21 29

Chronic therapy (usually intermittent) may be necessary, particularly for moderate to severe disease.61 99

Clinical improvement usually occurs within 3 weeks.17 21 Once adequate response occurs, adjust frequency and duration of treatment according to disease course.47

Although disease may remit during treatment,17 18 19 relapse occurs commonly following discontinuance.17 18 19 47 61 99

Bacterial Vaginosis
Treatment in Nonpregnant Women
Intravaginal

0.75% gel: One applicatorful (approximately 37.5 g of metronidazole) once daily (at bedtime) or twice daily (in morning and evening) given for 5 consecutive days.109 111 112 114 115 183 214

Cautions for Metronidazole

Contraindications

  • Known hypersensitivity to metronidazole, other nitroimidazole derivatives, or any ingredient in the formulation.1 180 183 184 207 214

Warnings/Precautions

Warnings

Seizures and Peripheral Neuropathy

Convulsive seizures and peripheral neuropathy (characterized by numbness or paresthesia of an extremity) reported with oral or IV nitroimidazoles (e.g., metronidazole, tinidazole).183 217 214

If abnormal neurologic signs develop with vaginal gel, promptly discontinue drug.183 214

Use vaginal gel with caution in patients with history of CNS disease.183 214

Interactions

Psychotic reactions reported in alcoholic patients receiving oral metronidazole and disulfiram concurrently;183 214 disulfiram-like reactions to alcohol reported in patients receiving oral metronidazole.106 183 214 Similar reactions could occur with intravaginal metronidazole.183 214

Avoid intravaginal metronidazole in patients who have received disulfiram within the last 2 weeks.183 214 Caution patients to avoid drinking alcohol while being treated with intravaginal metronidazole.183 214 (See Specific Drugs under Interactions.)

General Precautions

Administration Precautions

Avoid contact with the eyes.1 180 183 184 207 214

Topical cream, gel, or lotion may cause tearing.1 180 184 207

Vaginal gel may cause ocular burning and irritation.183 214

Iirrigate eyes with copious amounts of cool water if contact occurs.183 214

Local Irritation

If reaction suggesting local irritation occurs, advise patient to use the topical preparation less frequently or discontinue use.1 180 184 207

History of Blood Dyscrasia

Use with caution in patients with evidence or history of blood dyscrasia.1 180 184 207

Transient leukopenia and neutropenia reported with systemic metronidazole;30 adverse hematologic abnormalities not reported to date with topical metronidazole.2 21 47

Vaginal Intercourse and Use of Vaginal Products

Patients treated with vaginal gel should not engage in vaginal intercourse111 112 113 183 214 and should not use other vaginal products (tampons, douches) during entire treatment course.111 112 113 214

Vaginal intercourse or other vaginal products could reduce efficacy of intravaginal metronidazole (e.g., by dislodgment and/or dilution, by increased vaginal pH secondary to deposition of semen).111 112 113 214

Superinfection

Symptoms of known or previously unrecognized vaginal candidiasis may become more prominent during intravaginal metronidazole therapy.183 214 Symptomatic Candida vaginitis reported during or immediately after therapy.183 214

Systemic Adverse Effects

Although topical application to skin results in lower systemic absorption than oral or IV administration, adverse systemic effects (e.g., metallic taste,1 180 207 nausea,1 180 207 paresthesia,184 tingling or numbness of extremities1 180 207 ) have been reported with topical metronidazole.1 180

Although intravaginal administration results in lower systemic absorption than oral or IV administration, consider possibility that adverse effects reported with systemic metronidazole could occur when drug is given intravaginally.115 119 183 214

Specific Populations

Pregnancy

Category B.1 180 183 184 207 214

Safety and efficacy of intravaginal metronidazole for treatment of bacterial vaginosis in pregnant women not established.109 119 183 214 Existing data do not support use of intravaginal agents during pregnancy and intravaginal metronidazole not included in current CDC recommendations for treatment of bacterial vaginosis in pregnant women.109

Lactation

Distributed into milk following oral or IV administration;1 30 45 131 180 183 184 207 214 not known whether distributed into milk following topical or intravaginal administration.183 f 214

Discontinue nursing or the drug.1 180 183 184 207 214

Pediatric Use

Safety and efficacy of topical1 180 184 207 or intravaginal183 metronidazole not established in pediatric patients.

One manufacturer states safety and efficacy of vaginal gel established in postmenarchal females based on extrapolation of data from adult women; safety and efficacy of vaginal gel not established in premenarchal females.214

Geriatric Use

Safety and efficacy of topical gel in geriatric patients ≥65 years of age appear similar to those in younger adults.1

Insufficient experience with vaginal gel in patients ≥65 years of age to determine whether geriatric patients respond differently than younger adults.214

Hepatic Impairment

Use vaginal gel with caution in severe hepatic impairment.183 214

Reduced elimination and increased plasma concentrations may occur in severe hepatic dysfunction.183 214

Common Adverse Effects

Topical application to skin: Local effects such as erythema, irritation, stinging/burning, local allergic reactions, contact dermatitis, drying, pruritus, aggravated rosacea.1 47 180 184 207

Intravaginal administration: Vaginal discharge,183 symptomatic Candida cervicitis/vaginitis,183 fungal infection,214 vulvovaginal irritation,183 dysmenorrhea,214 GI effects (abdominal pain, GI discomfort, nausea, vomiting, diarrhea),183 214 headache,183 214 pruritus.214

Interactions for Metronidazole

Because metronidazole can be absorbed systemically following topical application to skin1 2 9 10 21 47 207 or following intravaginal administration,119 131 132 183 214 the possibility that drug and laboratory test interactions could occur with these routes should be considered.106 183 f

Specific Drugs and Laboratory Tests

Drug

Interaction

Comments

Alcohol

Disulfiram-like reactions reported rarely when alcohol ingested during intravaginal metronidazole treatment;106 183 214 such reactions not reported to date with topical application of metronidazole to skin21 47 61 99

Caution patients to avoid alcohol ingestion during intravaginal metronidazole treatment183 214

Anticoagulants, oral (warfarin)

Prolonged PT reported with systemic metronidazole 1 30 45 92 93 94 95 96 183 214

Consider possibility of potentiated anticoagulant effect if topical or intravaginal metronidazole used with oral anticoagulant therapy180 183 214

Cimetidine

Possible prolonged half-life and decreased clearance of metronidazole with concomitant cimetidine and oral or IV metronidazole182 183 214

Consider possibility of increased metronidazole adverse effects182

Disulfiram

Psychotic reactions reported in alcoholic patients receiving oral metronidazole and disulfiram concurrently92 97 168 169 183 214

Avoid concomitant use;92 97 214 do not initiate intravaginal metronidazole until 2 weeks after discontinuance of disulfiram183 214

Lithium

Increased lithium concentrations resulting in lithium toxicity reported after initiation of short-term oral metronidazole therapy in patients stabilized on relatively high lithium dosages181 183 214

Tests based on ultraviolet (UV) absorbance

Falsely decreased serum concentrations (including undetectable concentrations) of AST, ALT, LDH, triglycerides, or hexokinase glucose may be reported during metronidazole therapy if results are based on decreases in UV absorbance that occur during oxidation-reduction of NADH/NAD30 183 214

UV absorbance peaks of NADH and metronidazole are similar30 183 214

Use caution when interpreting test results based on UV absorbance during metronidazole therapy30 183 214

Metronidazole Pharmacokinetics

Absorption

Bioavailability

Absorbed systemically following topical application to skin; extent of absorption depends on formulation used (cream, gel, lotion).1 2 9 10 21 47 207

Absorbed systemically following intravaginal administration;119 131 132 183 214 systemic bioavailability of vaginal gel averages 50–56%.119 131 132 183 186

Following repeated topical application to the face of 1% cream (approximately 3.75 mg per dose) in adults with rosacea, serum concentrations were minimal or undetectable.9 Following topical application to the face of 1 g of 1% cream in healthy individuals, serum concentrations were minimal or undetectable and peak serum concentrations were attained within 8–12 hours after the dose.184

Following topical application to the face of 1 g of 1% topical gel in adults with rosacea, peak serum concentrations of metronidazole were attained 6–10 hours after the dose and were <1% of concentrations reported with a single 250-mg oral dose.1

Following topical application to the face of 1 g of 0.75% topical lotion (approximately 7.5 mg of metronidazole) twice daily for 4 days, drug was detectable in plasma of all patients and peak plasma concentrations were approximately 80 times lower than peak concentrations attained with a single 250-mg oral dose.207

Following intravaginal administration of 5 g of 0.75% vaginal gel (approximately 37.5 mg of metronidazole) in healthy women, peak serum concentrations were attained 4–17 hours after the dose and were approximately 2% of that attained after a single 500-mg oral dose.119 132 183 186 214

Distribution

Extent

Not fully characterized following topical application to skin10 or intravaginal administration.176 177

Crosses placenta following oral or IV administration;1 30 45 56 131 180 183 184 207 not known whether crosses placenta following topical application to skin1 or intravaginal administration.183

Distributed into milk following oral or IV administration;1 30 45 56 131 180 183 184 207 214 not known whether distributed into milk following topical application to skin1 or intravaginal administration.183

Elimination

Metabolism

Not fully characterized following topical application to skin10 or intravaginal administration.176 177

Elimination Route

Any systemically absorbed drug probably metabolized in liver and excreted in urine.10 61

Stability

Storage

Topical

Cream

20–25°C.180 184

Gel

20–25°C (may be exposed to 15–30°C).1

Lotion

20–25°C; do not freeze.207

Intravaginal

Gel

MetroGel-Vaginal: 15–30°C; do not freeze.183

Vandazole: 20–25°C; do not freeze.214

Actions

  • Bactericidal, amebicidal, and trichomonacidal in action.2 30 48 52 56

  • Un-ionized at physiologic pH49 and readily taken up by anaerobic organisms or cells.48 49 50 56 72 In susceptible organisms or cells, metronidazole reduced by low-redox-potential electron transport proteins (e.g., nitroreductases such as ferredoxin);48 49 50 56 64 65 66 68 69 70 71 72 the reduction product(s) apparently are responsible for cytotoxic and antimicrobial effects of the drug (e.g., disruption of DNA, inhibition of nucleic acid synthesis).48 56 63 64 65 66 67 68 70 71 72

  • Has direct anti-inflammatory effects2 14 17 21 28 180 and effects on neutrophil motility, lymphocyte transformation, and some aspects of cell-mediated immunity.2 10 32 33 34 35

  • Mechanism of reducing inflammatory lesions (papules and pustules) and erythema in patients with rosacea not elucidated to date;1 2 6 10 11 17 19 21 28 29 184 207 these effects may result from anti-inflammatory or immunosuppressive actions of the drug.1 2 3 10 17 28 29 207

  • Suppression of skin bacteria does not appear to play a major role in the mechanism of action of the drug in treatment of inflammatory lesions of rosacea;2 10 11 29 inactive in vitro against Propionibacterium acnes,2 4 5 48 staphylococci, and streptococci,2 48 and has no appreciable effects on the aerobic or anaerobic microflora of the skin of patients with rosacea.2 10 29

  • Spectrum of activity includes most obligately anaerobic bacteria2 7 29 30 45 48 53 56 64 and many protozoa.2 29 30 48 52 64 Inactive against fungi2 3 48 and viruses48 and most aerobic or facultatively anaerobic bacteria.2 7 30 45 48 73 74

  • Gram-positive anaerobes: Active against Clostridium,2 30 45 48 53 55 C. difficile,54 55 C. perfringens,48 55 Eubacterium,2 30 45 48 53 54 Peptococcus,2 30 45 48 53 54 55 and Peptostreptococcus.2 7 30 45 48 53 55 124 128 Actinomyces, Lactobacillus,48 Propionibacterium acnes,2 4 5 48 P. avidum,5 and P. granulosum5 generally are resistant.

    Gram-negative anaerobes: Active against Bacteroides fragilis,2 3 30 45 48 53 54 55 124 126 130 B. distasonis,30 45 54 55 124 B. ovatus,30 45 55 124 B. thetaiotaomicron,30 45 54 55 124 B. vulgatus,30 45 54 55 124 B. ureolyticus,124 126 Fusobacterium,2 7 30 45 48 53 55 Prevotella bivia,53 124 126 128 129 P. disiens,54 128 P. intermedia,7 124 P. melaninogenica,48 54 124 126 128 129 P. oralis,54 124 126 129 Porphyromonas,124 129 and Veillonella.7 54 55

  • Other organisms: Active against Campylobacter fetus.48 Most strains of Gardnerella vaginalis (formerly Haemophilus vaginalis) are susceptible only to relatively high concentrations in vitro.119 126 129 135 140 141 142 Concentrations readily achievable locally (750 mcg/mL) following intravaginal application of 0.75% vaginal gel have inhibited approximately 90% of strains tested in vitro.119 177

  • Natural and acquired resistance has been reported in some T. vaginalis.48 52 75 76 77 78 79 Resistance also reported rarely in B. fragilis and other anaerobic bacteria following long-term therapy.44 48 215

Advice to Patients

  • Importance of using topical or intravaginal metronidazole only as directed and only for the disorder for which drug was prescribed.1 180 183 184 207 f

  • Advise patients that topical cream, gel, and lotion are for external use only and to avoid contact with eyes.1 180 184 207 (See Administration under Dosage and Administration.)

  • Advise patients that vaginal gel is for intravaginal administration only and to avoid contact with eyes.183 214 (See Administration under Dosage and Administration.) If such contact occurs, importance of irrigating eyes with copious amounts of cool water.177 183

  • Instruct patients receiving vaginal gel regarding appropriate use of vaginal applicator.f

  • Advise women using vaginal gel not to engage in vaginal intercourse111 112 113 183 and not to use other vaginal products (tampons, douches) during entire treatment course.111 112 113

  • Advise patients to avoid alcohol while using vaginal gel.183 214 (See Specific Drugs under Interactions.)

  • Importance of notifying clinicians if local reactions or any other adverse reactions occur.1 180 183 184 207

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses.

  • Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.

  • Importance of informing patients of other important precautionary information. (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

metroNIDAZOLE

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Topical

Cream

0.75%*

MetroCream (with benzyl alcohol)

Galderma

metroNIDAZOLE Cream

Fougera, Glades

1%

Noritate (with parabens)

Dermik

Gel

1%

MetroGel (with parabens and propylene glycol)

Galderma

Lotion

0.75%*

MetroLotion

Galderma

metroNIDAZOLE Lotion

Fougera

Vaginal

Gel

0.75%

MetroGel-Vaginal (with parabens and propylene glycol; with vaginal applicators)

3M

Vandazole (with parabens and propylene glycol; with vaginal applicators)

Upsher-Smith

AHFS DI Essentials. © Copyright 2018, Selected Revisions July 1, 2007. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

References

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