Metronidazole (Systemic)

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Metronidazole
Bacterial Vaginosis
Metronidazole (Systemic)
Antibacterial and antiprotozoal; nitroimidazole derivative.
Class: Antiprotozoals, Miscellaneous 8:30.92 (AHFS primary); AP100
(VA primary)
Brands: Flagyl I.V.; Flagyl; Flagyl ER; Flagyl I.V. RTU; Helidac
Therapy; also available generically
Boxed Warning
•
•
Carcinogenic in mice and rats.
Avoid unnecessary use; reserve for use in approved indications. (See Uses.)
Uses
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Treatment of bacterial vaginosis (formerly called Haemophilus vaginitis, Gardnerella vaginitis, nonspecific vaginitis, Corynebacterium vaginitis, or anaerobic vaginosis) in pregnant or nonpregnant women.
CDC recommends treatment of bacterial vaginosis in all symptomatic nonpregnant
women, in symptomatic pregnant women, and asymptomatic pregnant women at
high risk for complications of pregnancy. Treatment recommendations for bacterial
vaginosis in HIV-infected women are the same as those for women without HIV
infection.
Regimens of choice in nonpregnant women are a 7-day regimen of oral metronidazole; a 5-day regimen of intravaginal metronidazole; or a 7-day regimen of intravaginal clindamycin; alternative regimens are a single oral dose of metronidazole;
7-day regimen of oral clindamycin; or 3- to 7-day regimen of intravaginal clindamycin. The preferred regimens for symptomatic or asymptomatic pregnant women
at high risk are a 7-day regimen of oral metronidazole or a 7-day regimen of oral
clindamycin.
Regardless of regimen used, relapse or recurrence is common; an alternative regimen (e.g., topical therapy when oral therapy was used initially) may be used in
such situations. Long-term maintenance therapy does not appear to be beneficial
in women with recurrent or relapsing disease and is not recommended.
Balantidiasis
Alternative to tetracycline for treatment of balantidiasis† caused by Balantidium
coli.
Bone and Joint Infections
Adjunct for treatment of bone and joint infections caused by Bacteroides, including the B. fragilis group (B. fragilis, B. distasonis, B. ovatus, B. thetaiotaomicron,
B. vulgatus).
Endocarditis
Treatment of endocarditis caused by Bacteroides (including the B. fragilis group).
Gynecologic Infections
Treatment of gynecologic infections (including endometritis, endomyometritis,
tubo-ovarian abscess, postsurgical vaginal cuff infection) caused by Bacteroides
(including the B. fragilis group), Clostridium, Peptococcus niger, or Peptostreptococcus.
Treatment of acute pelvic inflammatory disease (PID); used in conjunction with
other anti-infectives. Metronidazole is included in PID regimens to provide coverage against anaerobes.
When a parenteral regimen is indicated for PID and tubo-ovarian abscess is
present, a regimen of metronidazole (or clindamycin) and doxycycline has been
recommended. An alternative parenteral regimen is IV ofloxacin (or IV levofloxacin)
given with or without IV metronidazole.
When an oral regimen is indicated for PID, oral ofloxacin (or oral levofloxacin)
with or without oral metronidazole is one of several regimens recommended by
CDC and others.
Intra-abdominal Infections
Treatment of intra-abdominal infections (including peritonitis, intra-abdominal abscess, liver abscess) caused by susceptible Bacteroides (including the B. fragilis
group), Clostrium, Eubacterium, P. niger, or Peptostreptococcus.
Blastocystis hominis Infections
Treatment of infections caused by Blastocystis hominis†. May be effective, but
metronidazole resistance may be common.
Clinical importance of B. hominis as a cause of GI pathology is controversial; unclear when treatment is indicated. Some clinicians suggest treatment be reserved
for certain individuals (e.g., immunocompromised patients) when symptoms persist and no other pathogen or process is found to explain their GI symptoms.
Clostridium difficile-associated Diarrhea and Colitis
Treatment of Clostridium difficile-associated diarrhea and colitis† (CDAD; also
known as antibiotic-associated diarrhea and colitis, C. difficile diarrhea, C. difficile
colitis, and pseudomembranous colitis).
Drugs of choice are metronidazole and vancomycin; metronidazole generally preferred and vancomycin reserved for those with severe or potentially life-threatening colitis, patients in whom metronidazole-resistant C. difficile is suspected, patients in whom metronidazole is contraindicated or not tolerated, or those who do
not respond to metronidazole.
Crohn’s Disease
Mangement of Crohn’s disease† as an adjunct to conventional therapies.
Has been used with or without ciprofloxacin; for induction of remission of mildly
to moderately active Crohn’s disease†.
Has been used for refractory perianal Crohn’s disease†.
Dientamoeba fragilis Infections
Treatment of infections caused by Dientamoeba fragilis†. Drugs of choice are iodoquinol, paromomycin, tetracycline, or metronidazole.
Meningitis and Other CNS Infections
Dracunculiasis
Treatment of CNS infections (including meningitis, brain abscess) caused by Bac-
Treatment of dracunculiasis† caused by Dracunculus medinensis (guinea worm
teroides (including the B. fragilis group).
Respiratory Tract Infections
Treatment of respiratory tract infections (including pneumonia) caused by Bacteroides (including the B. fragilis group).
Septicemia
Treatment of septicemia caused by Bacteroides (including the B. fragilis group) or
Clostridium.
Skin and Skin Structure Infections
Treatment of skin and skin structure infections caused by Bacteroides (including
disease).
Treatment of choice is slow extraction of worm combined with wound care. Metronidazole is not curative, but decreases inflammation and facilitates worm removal.
Giardiasis
Treatment of giardiasis†. Drugs of choice are metronidazole, tinidazole, or nitazoxanide; alternatives are paromomycin, furazolidone (no longer commercially available in the US), or quinacrine (not commercially available in the US).
Treatment of asymptomatic carriers of giardiasis†. Treatment of such carriers not
generally recommended, except possibly in patients with hypogammaglobulinemia
or cystic fibrosis or in an attempt to prevent household transmission of the disease from toddlers to pregnant women.
the B. fragilis group), Clostridium, Fusobacterium, P. niger, or Peptostreptococcus.
Helicobacter pylori Infection and Duodenal Ulcer Disease
Amebiasis
Treatment of acute intestinal amebiasis and amebic liver abscess caused by Entamoeba histolytica. Oral metronidazole or oral tinidazole followed by a luminal
amebicide (iodoquinol, paromomycin) is the regimen of choice for mild to moderate or severe intestinal disease and for amebic hepatic abscess.
Treatment of Helicobacter pylori infection and duodenal ulcer disease (active or a
history of duodenal ulcer); eradication of H. pylori has been shown to reduce the
risk of duodenal ulcer recurrence.
Used in a multiple-drug regimen that includes metronidazole, tetracycline, and bismuth subsalicylate and a histamine H2-receptor antagonist. If initial 14-day regi-
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men does not eradicate H. pylori, a retreatment regimen that does not include
metronidazole should be used.
Nongonococcal Urethritis
Treatment of recurrent and persistent urethritis† in patients with nongonococcal
urethritis who have already been treated with a recommended regimen (i.e., azithromycin, doxycycline, erythromycin, ofloxacin or levofloxacin).
Metronidazole used in conjunction with erythromycin is the regimen recommended
by CDC for recurrent and persistent urethritis in patients who were compliant with
their initial regimen and have not been re-exposed.
Available as metronidazole and metronidazole hydrochloride; dosage expressed in
terms of metronidazole.
Pediatric Patients
General Dosage in Neonates†
Oral or IV: Neonates ⬍1 week of age: AAP recommends 7.5 mg/kg every
24– 48 hours in those weighing ⬍1.2 g, 7.5 mg/kg every 24 hours in
those weighing 1.2– 2 kg, or 7.5 mg/kg every 12 hours in those weighing
⬎2 kg.
Neonates 1– 4 weeks of age: AAP recommends 7.5 mg/kg every 24– 48
hours in those weighing ⬍1.2 kg, 7.5 mg/kg every 12 hours in those
weighing 1.2– 2 kg, and 15 mg/kg every 12 hours in those weighing ⬎2
kg.
Treatment of inflammatory lesions (papules and pustules) and erythema associ-
Tetanus
Adjunct in treatment of tetanus caused by C. tetani.
Trichomoniasis
Treatment of symptomatic and asymptomatic trichomoniasis when Trichomonas
vaginalis has been demonstrated by wet smear and/or culture.
Drug of choice is metronidazole or tinidazole. Goal of treatment is to provide
symptomatic relief, achieve microbiologic cure, and reduce transmission; to
achieve this goal, both the index patient and sexual (particularly steady) partner(s)
should be treated.
Resistant infections may respond to higher metronidazole dosage or to tinidazole.
Perioperative Prophylaxis
Perioperative prophylaxis to reduce the incidence of postoperative anaerobic bacterial infections in patients undergoing colorectal surgery. Preferred regimens are
IV cefotetan or IV cefoxitin; IV cefazolin used in conjunction with IV metronidazole;
or oral erythromycin and oral neomycin.
Perioperative prophylaxis in patients undergoing appendectomy†; used in conjunction with gentamicin. The preferred regimen for appendectomy (nonperforated) is
IV cefotetan or IV cefoxitin.
Prophylaxis in Sexual Assault Victims
Empiric anti-infective prophylaxis in sexual assault victims†; used in conjunction
with IM ceftriaxone and oral azithromycin or doxycycline.
Dosage and Administration
Administration
Administer orally or by continuous or intermittent IV infusion. Do not administer
by rapid IV injection because of the low pH of the reconstituted product.
In the treatment of serious anaerobic infections, parenteral route usually is used
initially and oral metronidazole substituted when warranted by patient’s condition.
Oral Administration
Administer extended-release tablets at least 1 hour before or 2 hours after meals.
General Dosage in Children ⱖ1 Month of Age†
Oral: 15– 35 mg/kg daily in 3 divided doses. AAP states oral route inappropriate for severe infections.
Amebiasis
⬎Entamoeba histolytica Infections
Oral: 35– 50 mg/kg daily in 3 divided doses given for 7– 10 (usually 10)
days; follow-up with a luminal amebicide (e.g., iodoquinol, paromomycin).
Bacterial Vaginosis†
Oral: Children weighing ⬍45 kg: 15 mg/kg daily (up to 1 g) in 2 divided
doses given for 7 days.
Adolescents: 500 mg twice daily for 7 days.
Balantidiasis†
Oral: 35– 50 mg/kg daily in 3 divided doses given for 5 days.
Blastocystis hominis Infections†
Oral: 20– 35 mg/kg daily in 3 divided doses given for 10 days may improve symptoms in some patients.
Crohn’s Disease†
Oral: 10– 20 mg/kg daily (up to 1 g daily) has been recommended for children with mild perianal Crohn’s disease† or those intolerant to sulfasalazine or mesalamine.
Clostridium difficile-associated Diarrhea and Colitis†
Oral: 30– 50 mg/kg daily in 3 or 4 equally divided doses given for 7– 10
days (not to exceed adult dosage).
Dientamoeba fragilis Infections†
Oral: 20– 40 mg/kg daily in 3 divided doses given for 10 days.
Dracunculiasis†
Oral: 25 mg/kg daily (up to 750 mg) in 3 divided doses given for 10 days.
Is not curative, but may decrease inflammation and facilitate worm removal.
Giardiasis†
Oral: 15 mg/kg daily in 3 divided doses given for 5– 7 days.
Nongonococcal Urethritis†
Oral: Adolescents: A single 2-g dose given in conjunction with a 7-day
regimen of oral erythromycin.
Tetanus†
Oral: 30 mg/kg daily (up to 4 g daily) in 4 doses given for 10– 14 days.
IV Infusion
For solution and drug compatibility information, see Compatibility under Stability.
Commercially available metronidazole injection for IV infusion does not need to be
diluted or neutralized prior to IV administration.
Metronidazole hydrochloride powder for injection must by reconstituted, diluted,
and then neutralized prior to IV administration.
Reconstitution and Dilution
Reconstitute metronidazole hydrochloride powder for injection by adding 4.4 mL of
sterile or bacteriostatic water for injection, 0.9% sodium chloride injection, or bacteriostatic sodium chloride injection to the vial containing 500 mg of metronidazole. The
reconstituted solution contains approximately 100 mg of metronidazole/mL and has a
pH of 0.5– 2.
The reconstituted metronidazole hydrochloride solution must be further diluted
with 0.9% sodium chloride injection, 5% dextrose injection, or lactated Ringer’s injection to a concentration of ⱕ8 mg/mL.
The reconstituted and diluted metronidazole hydrochloride solution must then be
neutralized by adding approximately 5 mEq of sodium bicarbonate injection for each
500 mg of metronidazole. The addition of sodium bicarbonate to the metronidazole hydrochloride solution may generate carbon dioxide gas and it may be necessary to relieve gas pressure in the container.
Rate of Administration
IV infusions usually are infused over 1 hour.
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Dosage
Rosacea
ated with rosacea† (acne rosacea). Topical metronidazole may be preferred to oral
metronidazole.
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IV: 30 mg/kg daily in 4 doses given for 10– 14 days.
Trichomoniasis†
Oral: Prepubertal children weighing ⬍45 kg: 15 mg/kg daily in 3 divided
doses (up to 2 g daily) given for 7 days.
Adolescents: A single 2-g dose or 500 mg twice daily for 7 days.
Prophylaxis in Sexual Assault Victims†
Oral: Preadolescent children weighing ⬍45 kg: 15 mg/kg daily given in 3
divided doses for 7 days given in conjunction with IM ceftriaxone and either oral azithromycin or oral erythromycin.
Adolescents and preadolescent children weighing ⱖ45 kg: A single 2-g
dose given in conjunction with IM ceftriaxone and either oral azithromycin
or oral doxycycline.
Adults
Anaerobic Bacterial Infections
⬎Serious Infections
Oral: 7.5 mg/kg every 6 hours. Maximum of 4 g daily.
IV, then Oral: An initial IV loading dose of 15 mg/kg followed by IV maintenance doses of 7.5 mg/kg every 6 hours. After clinical improvement occurs, switch to oral metronidazole (7.5 mg/kg every 6 hours).
Total duration of treatment usually is 7– 10 days, but infections of bone
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and joints, lower respiratory tract, or endocardium may require longer
treatment.
nalis is confirmed by wet smear and/or culture and an interval of 4– 6
weeks has passed since the initial course.
If treatment of resistant infection is guided by in vitro susceptibility testing
under aerobic conditions, some clinicians recommend that T. vaginalis
strains exhibiting low-level resistance (minimum lethal concentration [MLC]
⬍100 mcg/mL) be treated with 2 g daily for 3– 5 days, those with moderate (intermediate) resistance (MLC 100– 200 mcg/mL) be treated with 2–
2.5 g daily for 7– 10 days, and those with high-level resistance (MLC
⬎200 mcg/mL) be treated with 3– 3.5 g daily for 14– 21 days. Because
strains with high-level resistance are difficult to treat, CDC recommends
that patients with culture-documented infection who do not respond to repeat regimens at dosages up to 2 g daily for 3– 5 days and in whom the
possibility of reinfection has been excluded should be managed in consultation with an expert (available through CDC).
Gynecologic Infections
⬎Pelvic Inflammatory Disease
Oral: 500 mg twice daily given for 14 days; used in conjunction with a
14-day regimen of oral ofloxacin (400 mg twice daily) or levofloxacin (500
mg once daily).
IV: 500 mg every 8 hours; used in conjunction with IV ofloxacin (400 mg
every 12 hours) or IV levofloxacin (500 mg once daily).
Amebiasis
⬎Entamoeba histolytic Infections
Oral: 750 mg 3 times daily given for 5– 10 (usually 10) days for intestinal
amebiasis or 500– 750 mg 3 times daily given for 5– 10 (usually 10) days
for amebic liver abscess. Alternatively, amebic liver abscess has been
treated with 2.4 g once daily given for 1 or 2 days.
Perioperative Prophylaxis
⬎Colorectal Surgery
IV: 0.5 g given at induction of anesthesia (within 0.5– 1 hour prior to incision); used in conjunction with IV cefazolin (1– 2 g).
Follow-up with a luminal amebicide (e.g., iodoquinol, paromomycin) after
metronidazole.
IV: 500 mg every 6 hours for 10 days.
Manufacturer recommends 15 mg/kg by IV infusion over 30– 60 minutes 1
hour prior to the procedure and, if necessary, 7.5 mg/kg by IV infusion
over 30– 60 minutes at 6 and 12 hours after the initial dose. The initial
preoperative dose must be completely infused approximately 1 hour prior
to surgery to ensure adequate serum and tissue concentrations of metronidazole at the time of incision. Prophylactic use of metronidazole should
be limited to the day of surgery and should not be continued for more
than 12 hours after surgery.
Bacterial Vaginosis
⬎Nonpregnant Women
Oral: Conventional tablets: 500 mg twice daily given for 7 days. Alternatively, a single 2-g dose.
Extended-release tablets: 750 mg once daily given for 7 days.
⬎Pregnant Women
Oral: 250 mg 3 times daily given for 7 days.
Prophylaxis in Sexual Assault Victims†
Oral: A single 2-g dose given in conjunction with IM ceftriaxone and either oral azithromycin or oral doxycycline.
Contraindicated during first trimester of pregnancy. In addition, single-dose
regimens not recommended in pregnant women because of the slightly
higher serum concentrations attained, which may reach fetal circulation.
Balantidiasis†
Oral: 750 mg 3 times daily given for 5 days.
Special Populations
Hepatic Impairment
Blastocystis hominis Infections†
Oral: 750 mg 3 times daily given for 10 days may improve symptoms in
some patients.
Crohn’s Disease†
Oral: 400 mg twice daily or 1 g daily has been effective for treatment of
active Crohn’s disease†. For treatment of refractory perineal disease, 20
mg/kg (1– 1.5 g) given in 3– 5 divided doses daily has been employed.
Decrease dosage in patients with severe hepatic impairment and monitor
plasma concentrations of the drug.
Geriatric Patients
Select dosage with caution because of age-related decreases in hepatic function.
Clostridium difficile-associated Diarrhea and Colitis†
Oral: 750 mg to 2 g daily in 3 or 4 divided doses given for 7– 14 days.
Dose-ranging studies to determine comparative efficacy have not been
performed; most commonly employed regimens are 250 mg 4 times daily
or 500 mg 3 times daily given for 10 days.
IV: 500– 750 mg every 6– 8 hours; use when oral therapy is not feasible.
Dientamoeba fragilis Infections†
Oral: 500– 750 mg 3 times daily given for 10 days.
Dracunculiasis†
Oral: 250 mg 3 times daily given for 10 days. Is not curative, but may
decrease inflammation and facilitate worm removal.
Giardiasis†
Oral: 250 mg 3 times daily given for 5– 7 days.
Helicobacter pylori Infection and Duodenal Ulcer Disease
Oral: 250 mg in conjunction with tetracycline (500 mg) and bismuth subsalicylate (525 mg) 4 times daily (at meals and at bedtime) for 14 days;
these drugs should be given concomitantly with an H2-receptor antagonist
in recommended dosage.
Nongonococcal Urethritis†
Oral: A single 2-g dose given in conjunction with a 7-day regimen of oral
erythromycin.
Tetanus†
IV: 500 mg every 6 hours given for 7– 10 days.
Trichomoniasis
⬎Initial Treatment
Oral: 2 g as a single dose or in 2 divided doses. Alternatively, 500 mg
twice daily given for 7 days or 375 mg twice daily given for 7 days. Manufacturer also recommends 250 mg 3 times daily given for 7 days.
⬎Retreatment
Oral: 500 mg twice daily given for 7 days. If repeated failure occurs, CDC
recommends 2 g once daily given for 3– 5 days. Others recommend retreatment with 2– 4 g daily for 7– 14 days if metronidazole-resistant
strains are involved.
Do not administer repeat courses of treatment unless presence of T. vagi-
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Cautions
Contraindications
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Hypersensitivity to metronidazole or other nitroimidazole derivatives. Cautious desensitization has been used in some situations when use of metronidazole was
considered necessary. (See Hypersensitivity Reactions and Desensitization under
Cautions.)
First trimester of pregnancy.
Helidac Therapy (kit containing tetracycline, metronidazole, bismuth subsalicylate)
contraindicated in pregnant or nursing women, pediatric patients, patients with
hepatic or renal impairment, patients with known allergy to aspirin or salicylates,
and those with known hypersensitivity to any component of the kit.
Warnings/Precautions
Warnings
Seizures and Peripheral Neuropathy
Seizures and peripheral neuropathy (characterized by numbness or paresthesia of
an extremity) reported with metronidazole.
Persistent peripheral neuropathy reported in some patients receiving prolonged
therapy. If abnormal neurologic signs develop, promptly discontinue drug.
Use with caution in those with CNS diseases.
Sensitivity Reactions
Hypersensitivity Reactions and Desensitization
Hypersensitivity reactions, including urticaria, pruritus, erythematous rash, flushing,
nasal congestion, fever, and fleeting joint pains sometimes resembling serum sickness, have been reported with metronidazole.
Because there are no effective alternatives to metronidazole in the US for treatment of trichomoniasis, CDC states that desensitization can be attempted in patients
with metronidazole hypersensitivity. The possibility that desensitization may be hazardous should be considered and adequate procedures (e.g., established IV access, BP
monitoring) and therapies (e.g., epinephrine, corticosteroids, antihistamines, oxygen)
for management of an acute hypersensitivity reaction should be readily available. Pretreatment (e.g., with an antihistamine and/or corticosteroid) also should be considered.
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Desensitization has been performed by administering increasing doses of IV metronidazole incrementally until a therapeutic dose was achieved, at which time oral dosing was initiated. In this regimen, an initial 5-mcg dose of IV metronidazole was given
and the dose increased at 15- to 20-minute intervals to 15, 50, 150, and 500 mcg
and then to 1.5, 5, 15, 30, 60, and 125 mg. After the 125-mg IV dose, dosing was
switched to oral metronidazole and doses of 250, 500, and 2 g were given at 1-hour
intervals. For trichomoniasis, desensitization dosing can be stopped after the 2-g
dose. Patient should be monitored for ⱖ4 hours after the last dose (24 hours if there
was any evidence of a reaction).
General Precautions
Selection and Use of Anti-infectives
To reduce development of drug-resistant bacteria and maintain effectiveness of
metronidazole and other antibacterials, use only for treatment or prevention of infections proven or strongly suspected to be caused by susceptible bacteria.
When selecting or modifying anti-infective therapy, use results of culture and in
vitro susceptibility testing. In the absence of such data, consider local epidemiology
and susceptibility patterns when selecting anti-infectives for empiric therapy.
Surgical procedures should be performed in conjunction with metronidazole therapy when indicated.
In mixed aerobic and anaerobic infections, anti-infectives appropriate for treatment
of aerobic bacteria should be used in conjunction with metronidazole.
History of Blood Dyscrasia
Use with caution in patients with evidence or history of blood dyscrasias.
Mild leukopenia has been reported, but persistent hematologic abnormalities do
not occur.
Perform total and differential leukocyte counts before and after metronidazole
treatment, especially when repeated courses are necessary.
Sodium Content
Metronidazole injection contains approximately 28 mEq of sodium per g of metronidazole. Use with caution in patients receiving corticosteroids and in those predisposed to edema.
Candidiasis
Known or previously unrecognized candidiasis may present more prominent symptoms during metronidazole therapy; treatment with an appropriate antifungal is required.
Helidac Therapy
When the kit containing tetracycline, metronidazole, and bismuth subsalicylate
(Helidac Therapy) is used for the treatment of H. pylori infection and duodenal ulcer
disease, the cautions, precautions, and contraindications associated with tetracycline
and bismuth subsalicylate must be considered in addition to those associated with
metronidazole.
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Common Adverse Effects
Nausea, headache, anorexia, dry mouth, unpleasant metallic taste.
Interactions
Specific Drugs
Drug
Interaction
Alcohol
Mild disulfiram-like reactions Alcohol should not be con(flushing, headache, nausumed during or for at
sea, vomiting, abdominal
least 1 day following comcramps, sweating) may
pletion of metronidazole
occur if alcohol is intherapy (at least 3 days
gested while receiving
after oral capsules or exmetronidazole
tended-release tablets)
Anticoagulants, oral (war- Prolonged PT
farin)
Comments
Monitor PT and adjust anticoagulant dosage as
needed
Cimetidine
Possible prolonged half-life
and decreased clearance
of metronidazole
If used concomitantly, consider possibility of increased metronidazole adverse effects
Disulfiram
Acute psychoses and confusion with concomitant use
Avoid concomitant use; do
not initiate metronidazole
therapy until 2 weeks after
discontinuance of disulfiram
Lithium
Increased lithium concentra- Use concomitantly with cautions resulting in lithium
tion; monitor serum lithtoxicity; renal toxicity (elium and creatinine conevated serum creatinine,
centrations during
hypernatremia, abnormally
concomitant use
dilute urine) reported
Phenobarbital
Decreased serum half-life
and increased metabolism
of metronidazole
Phenytoin
Decrased serum concentration and increased metabolism of metronidazole;
decreased clearance of
phenytoin
Specific Populations
Pregnancy
Category B. Contraindicated during the first trimester of pregnancy.
Lactation
Distributed into milk; discontinue nursing or the drug.
If a single 2-g dose of metronidazole is indicated in the mother, AAP states that
breast-feeding should be interrupted for 12– 24 hours following the dose; if a multipledose regimen is indicated in the mother, breast-feeding should be discontinued during
treatment.
Pediatric Use
Except for oral treatment of amebiasis, safety and efficacy not established in pediatric patients.
Metronidazole has been used and is recommended for use in pediatric patients for
various indications other than amebiasis (e.g., trichomoniasis, giardiasis). Unusual adverse effects have not been reported in pediatric patients.
Safety and efficacy of the kit containing metronidazole, tetracycline, and bismuth
subsalicylate (Helidac Therapy) for treatment of H. pylori infection and duodenal ulcer disease have not been established in pediatric patients.
Geriatric Use
Because of age-related decreases in hepatic function, monitor serum metronidazole concentrations and adjust dosage accordingly.
Insufficient experience in those ⱖ65 years of age to determine whether they respond differently than younger adults to concomitant use of metronidazole, tetracycline, and bismuth subsalicylate (Helidac Therapy) for treatment of H. pylori infection
and duodenal ulcer disease. Age-related decreases in hepatic, renal, and/or cardiac
function and concomitant disease and drug therapy should be considered.
Hepatic Impairment
Patients with severe hepatic impairment metabolize metronidazole more slowly,
and increased concentrations of the drug and metabolites may occur.
Use with caution, monitor plasma metronidazole concentrations, and reduce dosage in patients with severe hepatic impairment.
Pharmacokinetics
Absorption
Bioavailability
ⱖ80% of an oral dose is absorbed from the GI tract. Following oral administration
of conventional tablets or capsules, peak plasma concentrations of unchanged drug
and active metabolites attained within 1– 3 hours.
Following oral administration of metronidazole extended-release tablets for 7 consecutive days under fasting conditions, steady-state peak plasma concentrations attained an average of 6.8 hours after the dose.
Food
Conventional tablets or capsules: Food decreases the rate of absorption and peak
plasma concentrations; total amount of drug not affected.
Extended-release tablets: Food increases rate of absorption and peak plasma concentrations.
Distribution
Extent
Widely distributed into most body tissues and fluids, including bone, bile, saliva,
pleural fluid, peritoneal fluid, vaginal secretions, seminal fluid, and cerebral and hepatic abscesses.
Distributed into CSF; CSF concentrations are 43% of concurrent plasma concentrations in patients with uninflamed meninges and equal to or greater than concurrent
plasma concentrations in patients with inflamed meninges.
Readily crosses the placenta and is distributed into milk.
Plasma Protein Binding
⬍20%.
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Elimination
Metabolism
Approximately 30– 60% of an oral or IV dose is metabolized in the liver by hydroxylation, side-chain oxidation, and glucuronide conjugation. The major metabolite, 2-hydroxy metronidazole, has some antibacterial and antiprotozoal activity.
Elimination Route
Metronidazole and its metabolites are excreted principally in urine (60– 80%) and
to a lesser extent in feces (6– 15%).
Half-life
Adults with normal renal and hepatic function: 6– 8 hours.
Special Populations
Half-life may be prolonged in patients with impaired hepatic function. In adults
with alcoholic liver disease and impaired hepatic function, half-life averages 18.3
hours.
Pharmacokinetics not affected by renal impairment.
Stability
Fenoldopam mesylate
Fluconazole
Foscarnet sodium
Gatifloxacin
Gemcitabine HCl
Granisetron HCl
Heparin sodium
Hetastarch in lactated electrolyte injection
(Hextend)
Hydromorphone HCl
Labetalol HCl
Linezolid
Lorazepam
Magnesium sulfate
Melphalan HCl
Meperidine HCl
Methylprednisolone sodium succinate
Midazolam HCl
Milrinone lactate
Morphine sulfate
Nicardipine HCl
Perphenazine
Piperacillin sodium– tazobactam sodium
Remifentanil HCl
Sargramostim
Tacrolimus
Teniposide
Theophylline
Thiotepa
Vinorelbine tartrate
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Incompatible
Amphotericin B cholesteryl sulfate complex
Aztreonam
Filgrastim
Solution Compatibility (Metronidazole HCl)
Incompatible
Storage
Amino acids 10%
Oral
Capsules
15– 25C. Dispense in well-closed container with child-resistant closure.
Tablets
Conventional tablets: ⬍25C.
Extended-release tablets: 25C (may be exposed to 15– 30C). Dispense in wellclosed container with child-resistant closure.
Metronidazole Combinations
Kit containing tetracycline, metronidazole, and bismuth subsalicylate: 20– 25C.
Parenteral
Injection for IV infusion
15– 25C; protect from light. Do not refrigerate.
Drug Compatibility (Metronidazole HCl)
⬎Admixture Compatibility
Compatible
Amikacin sulfate
Aminophylline
Cefazolin sodium
Cefotaxime sodium
Cefoxitin sodium
Chloramphenicol sodium succinate
Clindamycin phosphate
Disopyramide phosphate
Powder for IV infusion
⬍25C; protect from light. After reconstitution, dilution, and neutralization, use
within 24 hours; do not refrigerate.
Incompatible
Compatibility
Variable
For information on systemic interactions resulting from concomitant use, see Interactions.
Ampicillin sodium
Cefepime HCl
Drug Compatibility (Metronidazole)
⬎Admixture Compatibility
Compatible
Amikacin sulfate
Cefazolin sodium
Cefotaxime sodium
Ceftazidime
Ceftizoxime sodium
Ceftriaxone sodium
Cefuroxime sodium
Chloramphenicol sodium succinate
Ciprofloxacin
Clindamycin phosphate
Fluconazole
Gentamicin sulfate
Midazolam HCl
Tobramycin sulfate
Incompatible
Ciprofloxacin
Dopamine HCl
Ampicillin sodium
Cefepime HCl
Cefoxitin sodium
Hydrocortisone sodium succinate
Penicillin G potassium
⬎Y-Site Compatibility
Acyclovir sodium
Allopurinol sodium
Amifostine
Bivalirudin
Cefepime HCl
Clarithromycin
Cyclophosphamide
Dexmedetomidine HCl
Diltiazem HCl
Docetaxel
Dopamine HCl
Doxapram HCl
Doxorubicin HCl liposome injection
Enalaprilat
Esmolol HCl
Etoposide phosphate
Ceftriaxone sodium
Diltiazem HCl
Incompatible
Meropenem
Warfarin sodium
Actions and Spectrum
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Compatible
Meropenem
⬎Y-Site Compatibility
Compatible
Amiodarone HCl
Amoxicillin sodium– clavulanate potassium
Aztreonam
Variable
Gentamicin sulfate
Heparin sodium
Hydrocortisone sodium succinate
Multielectrolyte concentrate
Multivitamins
Penicillin G potassium
Tobramycin sulfate
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Bactericidal, amebicidal, and trichomonacidal in action.
Un-ionized at physiologic pH and readily taken up by anaerobic organisms or cells.
In susceptible organisms or cells, metronidazole is reduced by low-redox-potential
electron transport proteins (e.g., nitroreductases such as ferredoxin); the reduction
product(s) apparently are responsible for the cytotoxic and antimicrobial effects of
the drug (e.g., disruption of DNA, inhibition of nucleic acid synthesis).
Has direct anti-inflammatory effects and effects on neutrophil motility, lymphocyte
transformation, and some aspects of cell-mediated immunity.
Spectrum of activity includes most obligately anaerobic bacteria and many protozoa. Inactive against fungi and viruses and most aerobic or facultatively anaerobic
bacteria.
Gram-positive anaerobes: Clostridium, C. difficile, C. perfringens, Eubacterium, Peptococcus, and Peptostreptococcus.
Gram-negative anaerobes: Active against Bacteroides fragilis, B. distasonis, B. ovatus, B. thetaiotaomicron, B. vulgatus, B. ureolyticus,Fusobacterium, Prevotella bivia,
P. buccae, P. disiens, P. intermedia, P. melaninogenica, P. oralis, Porphyromonas,
and Veillonella.
Active against Helicobacter pylori, Entamoeba histolytica, Trichomonas vaginalis,
Giardia lamblia, and Balantidium coli. Acts principally against the trophozoite forms
of E. histolytica and has limited activity against the encysted form.
Resistance has been reported in some Bacteroides and T. vaginalis.
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Advice to Patients
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Advise patients that antibacterials (including metronidazole) should only be used
to treat bacterial infections and not used to treat viral infections (e.g., the common cold).
Importance of completing full course of therapy, even if feeling better after a few
days.
Advise patients that skipping doses or not completing the full course of therapy
may decrease effectiveness and increase the likelihood that bacteria will develop
resistance and will not be treatable with metronidazole or other antibacterials in
the future.
Metronidazole extended-release tablets should be taken at least 1 hour before or 2
hours after meals; optimum absorption occurs under fasting conditions.
Advise patients to avoid alcohol during and for at least 1 day after conventional
tablets or at least 3 days after receiving metronidazole capsules or extended-release tablets.
Advise patients to promptly discontinue metronidazole and contact clinician if abnormal neurologic signs occur.
Importance of informing clinicians of existing or contemplated therapy, including
prescription and OTC drugs.
Importance of women informing clinician if they are or plan to become pregnant
or plan to breast-feed.
Importance of advising patients of other important precautionary information. (See
Cautions.)
Preparations
Metronidazole
Oral
Capsules
Tablets
Tablets, extendedrelease, filmcoated
Tablets, filmcoated
Parenteral
Injection, for IV
infusion only
375 mg
250 mg*
500 mg*
750 mg
Flagyl 375, Pfizer
250 mg*
Flagyl, Pfizer
500 mg*
Flagyl, Pfizer
5 mg/mL
Flagyl I.V. RTU (Viaflex [Baxter]), SCS Pharmaceuticals
Flagyl ER, Pfizer
Metronidazole Injection (PAB
[Braun]), Various Manufacturers
Metronidazole Injection (available in LifeCare and glass containers), Abbott
Metronidazole Injection RTU
(Viaflex [Baxter]), Various Manufacturers
*available generically
Metronidazole Combinations
4 Capsules, Tetracycline
Hydrochloride 500 mg
Helidac Therapy (available as
14 blister cards), Prometheus
4 Tablets, Metronidazole,
250 mg, (with povidone)
8 Tablets, chewable, Bismuth Subsalicylate, 262.4
mg, (with povidone)
*available generically
Metronidazole Hydrochloride
Parenteral
For injection, for
IV infusion only
500 mg (of metronidazole)
Flagyl I.V. (with mannitol 415
mg), SCS Pharmaceuticals
*available generically
†Use is not currently included in the labeling approved by the US Food and Drug Administration
Selected Revisions August 2005, Copyright, May 2004, American Society of Health-System Pharmacists, Inc.
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