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Generic Name: Metronidazole
Class: Antiprotozoals, Miscellaneous
VA Class: AM900
CAS Number: 443-48-1

Warning(s)

Introduction

Antibacterial and antiprotozoal;.152 197 430 494 495 nitroimidazole derivative.494

Uses for Flagyl

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).152 197 495

Endocarditis

Treatment of endocarditis caused by Bacteroides (including the B. fragilis group).152 197 495

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.152 197 495

Treatment of acute pelvic inflammatory disease (PID); used in conjunction with other anti-infectives.199 341 496 Metronidazole is included in PID regimens to provide coverage against anaerobes.341

When a parenteral regimen is indicated for PID, an initial regimen of IV cefoxitin and IV or oral doxycycline is recommended followed by oral doxycycline; if tubo-ovarian abscess is present, some experts recommend that the oral follow-up regimen include metronidazole (or clindamycin) in addition to doxycycline.341

When an oral regimen is indicated for PID, an single IM dose of ceftriaxone, cefoxitin (with oral probenecid), or cefotaxime is recommended in conjunction with oral doxycycline (with or without oral metronidazole).199 341 496 Alternatively, if a parenteral cephalosporin is not feasible and the community prevalence and individual risk for gonorrhea is low, a regimen of oral levofloxacin or oral ofloxacin (with or without oral metronidazole) may be considered.496

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.152 197 495

Meningitis and Other CNS Infections

Treatment of CNS infections (including meningitis, brain abscess) caused by Bacteroides (including the B. fragilis group).152 197 495

Respiratory Tract Infections

Treatment of respiratory tract infections (including pneumonia) caused by Bacteroides (including the B. fragilis group).152 197 495

Septicemia

Treatment of septicemia caused by Bacteroides (including the B. fragilis group) or Clostridium.152 197 495

Skin and Skin Structure Infections

Treatment of skin and skin structure infections caused by Bacteroides (including the B. fragilis group), Clostridium, Fusobacterium, P. niger, or Peptostreptococcus.152 197 495

Amebiasis

Treatment of acute intestinal amebiasis and amebic liver abscess caused by Entamoeba histolytica.100 152 153 197 364 368 370 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.100 153 364 368 370

Bacterial Vaginosis

Treatment of bacterial vaginosis (formerly called Haemophilus vaginitis, Gardnerella vaginitis, nonspecific vaginitis, Corynebacterium vaginitis, or anaerobic vaginosis) in pregnant or nonpregnant women.199 292 297 298 302 341 365 366 430

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CDC recommends treatment of bacterial vaginosis in all symptomatic women (including pregnant women).341 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.341

Treatment recommendations for bacterial vaginosis in HIV-infected women are the same as those for women without HIV infection.341

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;341 alternative regimens are a 7-day regimen of oral clindamycin or 3-day regimen of intravaginal clindamycin suppositories.341 The preferred regimens for pregnant women are a 7-day regimen of oral metronidazole or a 7-day regimen of oral clindamycin.341

Regardless of regimen used, relapse or recurrence is common;287 295 297 298 300 302 307 341 365 an alternative regimen (e.g., topical therapy when oral therapy was used initially) may be used in such situations.297 341

Routine treatment of asymptomatic male sexual contacts of women who have relapsing or recurrent bacterial vaginosis not recommended.341

Balantidiasis

Alternative to tetracycline for treatment of balantidiasis caused by Balantidium coli.100 153

Blastocystis hominis Infections

Treatment of infections caused by Blastocystis hominis.100 153 368 371 372 May be effective, but metronidazole resistance may be common.153

Clinical importance of B. hominis as a cause of GI pathology is controversial;100 153 368 371 372 unclear when treatment is indicated.100 368 371 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.100 368

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).100 125 126 127 128 129 131 132 312 313 314 315 316 344 345 443 444 445 446 447

Drugs of choice are metronidazole and vancomycin; 100 312 313 314 315 316 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.100 126 127 312 313 314 315 316 322 323 406 443 444 445 446 447 448

Crohn’s Disease

Mangement of Crohn’s disease as an adjunct to conventional therapies.101 102 103 104

Has been used with467 468 471 475 476 477 485 or without ciprofloxacin;101 102 103 104 105 469 470 471 472 473 474 478 479 484 485 486 for induction of remission of mildly to moderately active Crohn’s disease.101 102 103 104 105 467 468 469 471 472 473 474 475 476 477 478 479 484

Has been used for refractory perianal Crohn’s disease.102 104 105 470 471 474 478 479 485 486

Dientamoeba fragilis Infections

Treatment of infections caused by Dientamoeba fragilis.153 Drugs of choice are iodoquinol, paromomycin, tetracycline, or metronidazole.153

Dracunculiasis

Treatment of dracunculiasis caused by Dracunculus medinensis (guinea worm disease).153

Treatment of choice is slow extraction of worm combined with wound care.153 Metronidazole is not curative, but decreases inflammation and facilitates worm removal.153

Giardiasis

Treatment of giardiasis.100 153 367 452 Drugs of choice are metronidazole, tinidazole, or nitazoxanide;100 153 367 452 alternatives are paromomycin, furazolidone (no longer commercially available in the US), or quinacrine (not commercially available in the US).100 153 367

Treatment of asymptomatic carriers of giardiasis.100 367 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.100

Helicobacter pylori Infection and Duodenal Ulcer Disease

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.455 If initial 14-day regimen does not eradicate H. pylori, a retreatment regimen that does not include metronidazole should be used.455

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).341

Oral metronidazole or oral tinidazole used in conjunction with oral azithromycin (if azithromycin was not used in the initial regimen) 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.341

Rosacea

Treatment of inflammatory lesions (papules and pustules) and erythema associated with rosacea (acne rosacea).137 139 145 146 148 168 180 181 Topical metronidazole may be preferred to oral metronidazole.137 181

Tetanus

Adjunct in treatment of tetanus caused by C. tetani.100 489

Trichomoniasis

Treatment of symptomatic and asymptomatic trichomoniasis when Trichomonas vaginalis has been demonstrated by an appropriate diagnostic procedure (e.g., wet smear and/or culture, OSOM Trichomonas Rapid Test, Affirm VP III).100 152 153 197 199 297 298 302 337 338 339 341

Drug of choice is metronidazole or tinidazole.100 153 199 297 302 337 338 339 341 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.153 199 297 302 339 341

If treatment failure occurs with initial metronidazole treatment and reinfection is excluded, alternative regimens using metronidazole or tinidazole can be used.153 199 341 If retreatment is ineffective, consultation with an expert (available through CDC) is recommended.341

Perioperative Prophylaxis

Perioperative prophylaxis to reduce the incidence of postoperative anaerobic bacterial infections in patients undergoing colorectal surgery.109 110 111 112 156 495 Preferred regimens are IV cefoxitin alone; IV cefazolin and IV metronidazole; oral erythromycin and oral neomycin; or oral metronidazole and oral neomycin.110 112 490

Perioperative prophylaxis in patients undergoing appendectomy;109 111 110 112 113 used in conjunction with cefazolin.110 Preferred regimens for appendectomy (nonperforated) are IV cefoxitin alone or IV cefazolin and IV metronidazole.110

Prophylaxis in Sexual Assault Victims

Empiric anti-infective prophylaxis in sexual assault victims; used in conjunction with IM ceftriaxone and oral azithromycin or doxycycline.199 341

Flagyl Dosage and Administration

Administration

Administer orally152 197 430 or by continuous or intermittent IV infusion.156 495 Do not administer by rapid IV injection because of the low pH of the reconstituted product.156 495

In the treatment of serious anaerobic infections, parenteral route usually is used initially and oral metronidazole substituted when warranted by patient’s condition.152 197

Oral Administration

Administer extended-release tablets at least 1 hour before or 2 hours after meals.430

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.156 495

Metronidazole hydrochloride powder for injection must by reconstituted, diluted, and then neutralized prior to IV administration.156

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.156 The reconstituted solution contains approximately 100 mg of metronidazole/mL and has a pH of 0.5–2.156

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 ≤8 mg/mL.156

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.156 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.156

Rate of Administration

IV infusions usually are infused over 1 hour.156 495

Dosage

Available as metronidazole152 156 197 430 495 and metronidazole hydrochloride;156 dosage expressed in terms of metronidazole.156

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 kg, 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.100

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.100

General Dosage in Children ≥1 Month of Age
Oral

15–35 mg/kg daily in 3 divided doses.100 AAP states oral route inappropriate for severe infections.100

Amebiasis
Entamoeba histolytica Infections
Oral

35–50 mg/kg daily in 3 divided doses given for 7–10 (usually 10) days;152 153 197 370 follow-up with a luminal amebicide (e.g., iodoquinol, paromomycin).153

Bacterial Vaginosis
Oral

Children weighing <45 kg: 15 mg/kg daily (up to 1 g) in 2 divided doses given for 7 days.100

Adolescents: 500 mg twice daily for 7 days.100

Balantidiasis
Oral

35–50 mg/kg daily in 3 divided doses given for 5 days.153

Blastocystis hominis Infections
Oral

20–35 mg/kg daily in 3 divided doses given for 10 days may improve symptoms in some patients.100

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.487

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).100 445 446

Dientamoeba fragilis Infections
Oral

20–40 mg/kg daily in 3 divided doses given for 10 days.153

Dracunculiasis
Oral

25 mg/kg daily (up to 750 mg) in 3 divided doses given for 10 days.153 Is not curative, but may decrease inflammation and facilitate worm removal.153

Giardiasis
Oral

15 mg/kg daily in 3 divided doses given for 5–7 days.153 367 452

Nongonococcal Urethritis
Oral

Recurrent or persistent urethritis in adolescents: A single 2-g dose given in conjunction with a single 1-g dose of oral azithromycin (if azithromycin not used in the initial regimen).341

Tetanus
Oral

30 mg/kg daily (up to 4 g daily) in 4 doses given for 10–14 days.100

IV

30 mg/kg daily (up to 4 g daily) in 4 doses given for 10–14 days.100

Trichomoniasis
Oral

Prepubertal children weighing <45 kg: 15 mg/kg daily in 3 divided doses (up to 2 g daily) given for 7 days.100 153

Adolescents: A single 2-g dose or 500 mg twice daily for 7 days.100

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.100 341

Adolescents and preadolescent children weighing ≥45 kg: A single 2-g dose given in conjunction with IM ceftriaxone and either oral azithromycin or oral doxycycline.100 341

Adults

Anaerobic Bacterial Infections
Serious Infections
Oral

7.5 mg/kg every 6 hours (up to 4 g daily).152 156 197

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.156 495 After clinical improvement occurs, switch to oral metronidazole (7.5 mg/kg every 6 hours).156 495

Total duration of treatment usually is 7–10 days, but infections of bone and joints, lower respiratory tract, or endocardium may require longer treatment.156 495

Gynecologic Infections
Pelvic Inflammatory Disease
Oral

500 mg twice daily given for 14 days; used in conjunction with a single IM dose of ceftriaxone (250 mg), cefoxitin (2 g with oral probenecid 1 g), or another parenteral cephalosporin (e.g., cefotaxime) and 14-day regimen of oral doxycycline (100 mg twice daily).341 496

Alternatively, 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).199 341 496 Regimens containing a fluoroquinolone should only be considered when a parenteral cephalosporin is not feasible and the community prevalence and individual risk of gonorrhea is low.496

Amebiasis
Entamoeba histolytica Infections
Oral

750 mg 3 times daily given for 5–10 (usually 10) days for intestinal amebiasis152 153 197 364 368 370 or 500–750 mg 3 times daily given for 5–10 (usually 10) days for amebic liver abscess.152 197 364 368 370 Alternatively, amebic liver abscess has been treated with 2.4 g once daily given for 1 or 2 days.364

Follow-up with a luminal amebicide (e.g., iodoquinol, paromomycin) after metronidazole.153 364 368 370

IV

500 mg every 6 hours for 10 days.364

Bacterial Vaginosis
Nonpregnant Women
Oral

Conventional tablets: 500 mg twice daily given for 7 days.100 199 286 297 298 300 301 302 341 366 A single 2-g dose has been used (e.g., for patients who may be noncompliant with the multiple-dose regimen),120 122 199 292 297 but appears to be less effective than other regimens and is no longer recommended by CDC.341

Extended-release tablets: 750 mg once daily given for 7 days.199 341 416 417 430

Pregnant Women
Oral

Conventional tablets: 500 mg twice daily or 250 mg 3 times daily given for 7 days.341 416 417

Contraindicated during first trimester of pregnancy.152 197 430 In addition, single-dose regimens not recommended in pregnant women because of the slightly higher serum concentrations attained, which may reach fetal circulation.152

Balantidiasis
Oral

750 mg 3 times daily given for 5 days.153

Blastocystis hominis Infections
Oral

750 mg 3 times daily given for 10 days may improve symptoms in some patients.100 153

Crohn’s Disease
Oral

400 mg twice daily101 103 105 or 1 g daily has been effective for treatment of active Crohn’s disease.467 472 473 475 476 482 For treatment of refractory perineal disease, 20 mg/kg (1–1.5 g) given in 3–5 divided doses daily has been employed.102 103 104 105 478 486

Clostridium difficile-associated Diarrhea and Colitis
Oral

750 mg to 2 g daily in 3 or 4 divided doses given for 7–14 days.125 126 129 131 132 133 313 314

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.443 444 445 446

IV

500–750 mg every 6–8 hours; use when oral therapy is not feasible.134 161 162 313 342 343 445

Dientamoeba fragilis Infections
Oral

500–750 mg 3 times daily given for 10 days.153

Dracunculiasis
Oral

250 mg 3 times daily given for 10 days.153 Is not curative, but may decrease inflammation and facilitate worm removal.153

Giardiasis
Oral

250 mg 3 times daily given for 5–7 days.153 367 452

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.455

Nongonococcal Urethritis
Oral

Recurrent or persistent urethritis: A single 2-g dose given in conjunction with a single 1-g dose of oral azithromycin (if azithromycin not used in the initial regimen).341

Tetanus
IV

500 mg every 6 hours given for 7–10 days.489

Trichomoniasis
Initial Treatment
Oral

2 g as a single dose152 153 199 341 or in 2 divided doses.152 Alternatively, 500 mg twice daily given for 7 days153 199 341 or 375 mg twice daily given for 7 days.199 197 Manufacturer also recommends 250 mg 3 times daily given for 7 days.152

Retreatment
Oral

500 mg twice daily given for 7 days.297 341 If repeated failure occurs, CDC recommends 2 g once daily given for 5 days.297 341 Others recommend retreatment with 2–4 g daily for 7–14 days if metronidazole-resistant strains are involved.153 199

Do not administer repeat courses of treatment unless presence of T. vaginalis is confirmed by wet smear and/or culture and an interval of 4–6 weeks has passed since the initial course.152 197

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.124 302 338 340 Because strains with high-level resistance are difficult to treat,124 297 302 338 340 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).297 341

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).110

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.156 495 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.156 495 Prophylactic use of metronidazole should be limited to the day of surgery and should not be continued for more than 12 hours after surgery.156 495

Oral

2 g with oral neomycin sulfate (2 g) given at 7 p.m. and 11 p.m. on day before surgery; used in conjunction with appropriate diet and catharsis.110

Prophylaxis in Sexual Assault Victims
Oral

A single 2-g dose given in conjunction with IM ceftriaxone and either oral azithromycin or oral doxycycline.100 341

Special Populations

Hepatic Impairment

Decrease dosage in patients with severe hepatic impairment and monitor plasma concentrations of the drug.152 156 160 197 430 495

Geriatric Patients

Select dosage with caution because of age-related decreases in hepatic function.152 197 430

Cautions for Flagyl

Contraindications

  • Hypersensitivity to metronidazole or other nitroimidazole derivatives.152 156 197 430 495 Cautious desensitization has been used in some situations when use of metronidazole was considered necessary.341 436 (See Hypersensitivity Reactions and Desensitization under Cautions.)

  • First trimester of pregnancy.152 197 430

  • 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.455

Warnings/Precautions

Warnings

Seizures and Peripheral Neuropathy

Seizures and peripheral neuropathy (characterized by numbness or paresthesia of an extremity) reported with metronidazole.152 156 197 430 495

Persistent peripheral neuropathy reported in some patients receiving prolonged therapy.430 If abnormal neurologic signs develop, promptly discontinue drug..152 156 197 430

Use with caution in those with CNS diseases.152 197 430

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.152 156 197 430 495

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.341 The possibility that desensitization may be hazardous should be considered435 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.435 Pretreatment (e.g., with an antihistamine and/or corticosteroid) also should be considered.435

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.435 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.435 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.435 For trichomoniasis, desensitization dosing can be stopped after the 2-g dose.435 Patient should be monitored for ≥4 hours after the last dose (24 hours if there was any evidence of a reaction).435

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.152 197 430 495

When selecting or modifying anti-infective therapy, use results of culture and in vitro susceptibility testing.152 197 430 495 In the absence of such data, consider local epidemiology and susceptibility patterns when selecting anti-infectives for empiric therapy.152 197 430 495

Surgical procedures should be performed in conjunction with metronidazole therapy when indicated.152 156 197 430 495

In mixed aerobic and anaerobic infections, anti-infectives appropriate for treatment of aerobic bacteria should be used in conjunction with metronidazole.152 156 197 430 495

History of Blood Dyscrasia

Use with caution in patients with evidence or history of blood dyscrasias.152 156 197 430 495

Mild leukopenia has been reported, but persistent hematologic abnormalities do not occur.152 156 197 430 495

Perform total and differential leukocyte counts before and after metronidazole treatment, especially when repeated courses are necessary.152 156 197 430 495

Sodium Content

Metronidazole injection contains approximately 28 mEq of sodium per g of metronidazole.156 495 Use with caution in patients receiving corticosteroids and in those predisposed to edema.156 495

Candidiasis

Known or previously unrecognized candidiasis may present more prominent symptoms during metronidazole therapy; treatment with an appropriate antifungal is required.152 156 197 430 495

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.455

Specific Populations

Pregnancy

Category B.152 156 197 430 495 Contraindicated during the first trimester of pregnancy.100 152 197 341 430 442

Lactation

Distributed into milk;152 156 197 430 495 discontinue nursing or the drug.152 156 197 430 495

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.100

Pediatric Use

Except for oral treatment of amebiasis, safety and efficacy not established in pediatric patients.152 156 197 430 495

Metronidazole has been used and is recommended for use in pediatric patients for various indications other than amebiasis (e.g., trichomoniasis, giardiasis).100 153 Unusual adverse effects have not been reported in pediatric patients.100

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.455

Geriatric Use

Because of age-related decreases in hepatic function, monitor serum metronidazole concentrations and adjust dosage accordingly.152 197 430

Insufficient experience in those ≥65 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.455 Age-related decreases in hepatic, renal, and/or cardiac function and concomitant disease and drug therapy should be considered.455

Hepatic Impairment

Patients with severe hepatic impairment metabolize metronidazole more slowly, and increased concentrations of the drug and metabolites may occur.152 156 197 430 495

Use with caution, monitor plasma metronidazole concentrations, and reduce dosage in patients with severe hepatic impairment.152 156 197 430 495

Common Adverse Effects

Nausea, headache, anorexia, dry mouth, unpleasant metallic taste.152 156 197 430 495

Interactions for Flagyl

Specific Drugs

Drug

Interaction

Comments

Alcohol

Mild disulfiram-like reactions (flushing, headache, nausea, vomiting, abdominal cramps, sweating) may occur if alcohol is ingested while receiving metronidazole139 152 156 157 187 196 197 430 495

Alcohol should not be consumed during or for at least 1 day following completion of metronidazole therapy (at least 3 days after oral capsules or extended-release tablets)152 156 197 430 495

Anticoagulants, oral (warfarin)

Prolonged PT152 156 191 192 193 194 195 197 430 495

Monitor PT and adjust anticoagulant dosage as needed191 192 193 194 195

Cimetidine

Possible prolonged half-life and decreased clearance of metronidazole106 152 156 197 430 495

If used concomitantly, consider possibility of increased metronidazole adverse effects106

Disulfiram

Acute psychoses and confusion with concomitant use152 156 197 430 495

Avoid concomitant use; do not initiate metronidazole therapy until 2 weeks after discontinuance of disulfiram152 156 197 430 495

Lithium

Increased lithium concentrations resulting in lithium toxicity;151 152 155 197 430 495 renal toxicity (elevated serum creatinine, hypernatremia, abnormally dilute urine) reported151

Use concomitantly with caution; monitor serum lithium and creatinine concentrations during concomitant use151 152 155 197 430 495

Phenobarbital

Decreased serum half-life and increased metabolism of metronidazole116 117 152 197 430 495

Phenytoin

Decrased serum concentration and increased metabolism of metronidazole; decreased clearance of phenytoin152 156 197 430 495

Flagyl Pharmacokinetics

Absorption

Bioavailability

≥80% of an oral dose is absorbed from the GI tract.g Following oral administration of conventional tablets or capsules, peak plasma concentrations of unchanged drug and active metabolites attained within 1–3 hours.g

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.430

Food

Conventional tablets or capsules: Food decreases the rate of absorption and peak plasma concentrations; total amount of drug not affected.g

Extended-release tablets: Food increases rate of absorption and peak plasma concentrations.430

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.g

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.g

Readily crosses the placenta and is distributed into milk.g

Plasma Protein Binding

<20%.g

Elimination

Metabolism

Approximately 30–60% of an oral or IV dose is metabolized in the liver by hydroxylation, side-chain oxidation, and glucuronide conjugation.g The major metabolite, 2-hydroxy metronidazole, has some antibacterial and antiprotozoal activity.g

Elimination Route

Metronidazole and its metabolites are excreted principally in urine (60–80%) and to a lesser extent in feces (6–15%).152 197 430 g

Half-life

Adults with normal renal and hepatic function: 6–8 hours.430 g

Special Populations

Half-life may be prolonged in patients with impaired hepatic function.g In adults with alcoholic liver disease and impaired hepatic function, half-life averages 18.3 hours.160

Pharmacokinetics not affected by renal impairment.430 g

Stability

Storage

Oral

Capsules

15–25°C.197 Dispense in well-closed container with child-resistant closure.197

Tablets

Conventional tablets: <25°C.152

Extended-release tablets: 25°C (may be exposed to 15–30°C).430 Dispense in well-closed container with child-resistant closure.430

Metronidazole Combinations

Kit containing tetracycline, metronidazole, and bismuth subsalicylate: 20–25°C.455

Parenteral

Injection for IV infusion

15–30°C; protect from light.156 495 Do not refrigerate.156

Powder for IV infusion

<25°C; protect from light.156 After reconstitution, dilution, and neutralization, use within 24 hours; do not refrigerate.156

Compatibility

For information on systemic interactions resulting from concomitant use, see Interactions.

Drug Compatibility (Metronidazole)

Admixture Compatibilitya

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

Amoxicillin sodium–clavulanate potassium

Aztreonam

Variable

Ampicillin sodium

Cefepime HCl

Cefoxitin sodium

Hydrocortisone sodium succinate

Penicillin G potassium

Y-Site Compatibilitya

Compatible

Acyclovir sodium

Allopurinol sodium

Amifostine

Bivalirudin

Cefepime HCl

Cisatracurium besylate

Clarithromycin

Cyclophosphamide

Dexmedetomidine HCl

Diltiazem HCl

Dimenhydrinate

Docetaxel

Dopamine HCl

Doxapram HCl

Doxorubicin HCl liposome injection

Enalaprilat

Esmolol HCl

Etoposide phosphate

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

Incompatible

Amphotericin B cholesteryl sulfate complex

Aztreonam

Drotrecogin alfa (activated)

Filgrastim

Lansoprazole

Pantoprazole sodium

Pemetrexed disodium

Metronidazole HCla

Solution Compatibility

Incompatible

Amino acids 10%

Drug Compatibility (Metronidazole HCl)
Admixture Compatibilitya

Compatible

Amikacin sulfate

Aminophylline

Cefazolin sodium

Cefotaxime sodium

Cefoxitin sodium

Chloramphenicol sodium succinate

Clindamycin phosphate

Disopyramide phosphate

Gentamicin sulfate

Heparin sodium

Hydrocortisone sodium succinate

Multielectrolyte concentrate

Multivitamins

Penicillin G potassium

Tobramycin sulfate

Incompatible

Ciprofloxacin

Dopamine HCl

Meropenem

Variable

Ampicillin sodium

Cefepime HCl

Ceftriaxone sodium

Y-Site Compatibilitya

Compatible

Amiodarone HCl

Diltiazem HCl

Incompatible

Meropenem

Warfarin sodium

Actions and Spectrum

  • Bactericidal, amebicidal, and trichomonacidal in action.g

  • Un-ionized at physiologic pH and readily taken up by anaerobic organisms or cells.g 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).g

  • Has direct anti-inflammatory effects137 139 148 166 167 and effects on neutrophil motility, lymphocyte transformation, and some aspects of cell-mediated immunity.148 168 169 170 171 172

  • Spectrum of activity includes most obligately anaerobic bacteria and many protozoa.g Inactive against fungi and viruses and most aerobic or facultatively anaerobic bacteria.g

  • Gram-positive anaerobes: Clostridium,148 152 156 164 174 176 C. difficile,175 176 C. perfringens,164 176 Eubacterium,148 152 156 164 174 175 Peptococcus,148 152 156 164 174 175 176 and Peptostreptococcus.148 152 156 164 174 176 177 275 278

  • Gram-negative anaerobes: Active against Bacteroides fragilis,148 152 156 164 173 174 175 176 275 277 280 B. distasonis,152 156 175 176 275 B. ovatus,152 156 176 275 B. thetaiotaomicron,152 156 175 176 275 B. vulgatus,152 156 175 176 275 B. ureolyticus,275 277 Fusobacterium,148 152 156 164 174 176 177 Prevotella bivia,174 275 277 278 279 P. buccae,494 P. disiens,175 278 P. intermedia,177 275 P. melaninogenica,164 175 275 277 278 279 P. oralis,175 275 277 279 Porphyromonas,177 275 494 and Veillonella.175 176 177

  • Active against Helicobacter pylori,164 Entamoeba histolytica, Trichomonas vaginalis, Giardia lamblia, and Balantidium coli.g Acts principally against the trophozoite forms of E. histolytica and has limited activity against the encysted form.g

  • Resistance has been reported in some Bacteroides and T. vaginalis.g

Advice to Patients

  • 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).152 197 430

  • Importance of completing full course of therapy, even if feeling better after a few days.152 197 430

  • 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.152 197 430

  • Metronidazole extended-release tablets should be taken at least 1 hour before or 2 hours after meals; optimum absorption occurs under fasting conditions.430

  • Advise patients to avoid alcohol during and for at least 1 day after conventional tablets152 or at least 3 days after receiving metronidazole capsules or extended-release tablets.197 430

  • Advise patients to promptly discontinue metronidazole and contact clinician if abnormal neurologic signs occur.152 197 430

  • Importance of informing clinicians of existing or contemplated therapy, including prescription and OTC drugs.152 197 430

  • Importance of women informing clinician if they are or plan to become pregnant or plan to breast-feed.152 197 430

  • Importance of advising patients of other important precautionary information.152 197 430 (See Cautions.)

Preparations

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

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

Metronidazole

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Capsules

375 mg

Flagyl 375

Pfizer

Tablets

250 mg*

Metronidazole Tablets

Mutual, Teva

500 mg*

Metronidazole Tablets

Mutual, Teva

Tablets, extended-release, film-coated

750 mg

Flagyl ER

Pfizer

Tablets, film-coated

250 mg*

Flagyl

Pfizer

500 mg*

Flagyl

Pfizer

Parenteral

Injection, for IV infusion only

5 mg/mL*

Flagyl I.V. RTU (Viaflex [Baxter])

SCS Pharmaceuticals

Metronidazole Injection (PAB [Braun])

Various Manufacturers

Metronidazole Injection (available in LifeCare and glass containers)

Abbott

Metronidazole Injection RTU (Viaflex [Baxter])

Various Manufacturers

Metronidazole Combinations

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Kit

4 Capsules, Tetracycline Hydrochloride 500 mg

4 Tablets, Metronidazole 250 mg (with povidone)

8 Tablets, chewable, Bismuth Subsalicylate 262.4 mg (with povidone)

Helidac Therapy (available as 14 blister cards)

Prometheus

Metronidazole Hydrochloride

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Parenteral

For injection, for IV infusion only

500 mg (of metronidazole)

Flagyl I.V. (with mannitol 415 mg)

SCS Pharmaceuticals

Comparative Pricing

This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 02/2014. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.

Flagyl 250MG Tablets (PFIZER U.S.): 30/$112.99 or 90/$295.96

Flagyl 375MG Capsules (PFIZER U.S.): 30/$142.80 or 90/$410.51

Flagyl 500MG Tablets (PFIZER U.S.): 30/$189.00 or 90/$535.49

Flagyl ER 750MG 24-hr Tablets (PFIZER U.S.): 30/$384.28 or 90/$1,119.30

MetroNIDAZOLE 250MG Tablets (TEVA PHARMACEUTICALS USA): 90/$38.99 or 180/$64.97

MetroNIDAZOLE 500MG Tablets (TEVA PHARMACEUTICALS USA): 30/$25.99 or 90/$63.97

AHFS DI Essentials. © Copyright, 2004-2014, Selected Revisions July 1, 2007. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

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

References

Only references cited for selected revisions after 1984 are available electronically.

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230. Talley NJ, Zinsmeister AR, Weaver A et al. Gastric adenocarcinoma and Helicobacter pylori infection. J Natl Cancer Inst. 1991; 83:1734-9. [PubMed 1770552]

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233. Parsonnet J. Helicobacter pylori and gastric cancer. Gastroenterol Clin North Am. 1993; 22:89-104. [PubMed 8449573]

234. Correa P. Is gastric carcinoma an infectious disease? N Engl J Med. 1991; 325:1170-1.

235. Isaacson PG, Spencer J. Is gastric lymphoma an infectious disease? Hum Pathol. 1993; 24:569-70.

236. Oderda G, Forni M, Dell’Olio D et al. Cure of peptic ulcer associated with eradication of Helicobacter pylori. Lancet. 1990; 335:1599.

237. Bianchi Porro G, Parente F, Lazzaroni M. Short and long term outcome of Helicobacter pylori positive resistant duodenal ulcers treated with colloidal bismuth subcitrate plus antibiotics or sucralfate alone. Gut. 1993; 34:466-9. [IDIS 312865] [PubMed 8491391]

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245. Hunt RH. pH and Hp—gastric acid secretion and Helicobacter pylori: implications for ulcer healing and eradication of the organism. Am J Gastroenterol. 1993; 88:481-3. [IDIS 313340] [PubMed 8470623]

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248. Barthel JS, Everett ED. Diagnosis of Campylobacter pylori infections: The “gold standard” and the alternatives. Clin Infect Dis. 1990; 12(Suppl 1):S107-4.

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250. Bell GD. Anti-Helicobacter pylori therapy: clearance, elimination, or eradication? Lancet. 1991; 337:310-1. Letter.

251. Logan RP, Polson RJ, Baron JH et al. Follow-up after anti-Helicobacter pylori treatment. Lancet. 1991; 337:562-3. [PubMed 1671932]

252. Graham DY, Borsch GM. The who’s and when’s of therapy for Helicobacter pylori. Am J Gastroenterol. 1990; 85:1552-5. [PubMed 2252013]

253. Yeung CK, Fu KH, Yuen KY et al. Helicobacter pylori and associated duodenal ulcer. Arch Dis Child. 1990; 65:1212-6. [IDIS 274943] [PubMed 2248531]

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260. Logan RP, Gummett PA, Hegarty BT et al. Clarithromycin and omeprazole for Helicobacter pylori. Lancet. 1992; 25:340:239.

261. Graham DY. Treatment of peptic ulcers caused by Helicobacter pylori. N Engl J Med. 1993; 328:349-50. [IDIS 308865] [PubMed 8419823]

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273. Reviewers’ comments (personal observations).

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291. Anon. Topical treatment for bacterial vaginosis. Med Lett Drugs Ther. 1992 Nov 27; 34:109.

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309. Reviewers’ comments (personal observations).

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345. Fekety R, Shah AB. Diagnosis and treatment of Clostridium difficile colitis. JAMA. 1993; 269:71-5. [IDIS 307078] [PubMed 8416409]

346. Bartlett JG. Antibiotic-associated diarrhea. Clin Infect Dis. 1992; 15:573-81. [IDIS 302937] [PubMed 1420669]

347. Marshall BJ. Helicobacter pylori. Am J Gastroenterol. 1994; 89(Suppl 8):S116-28.

348. Blaser MJ. Helicobacter pylori: its role in disease. Clin Infect Dis. 1992; 15:386-91. [IDIS 301064] [PubMed 1520782]

349. Farrell MK. Dr. Apley meets Helicobacter pylori. J Pediatr Gastroenterol Nutr. 1993; 16:118-9. [PubMed 8450375]

350. Nomura A, Stemmermann GN, Chyou PH et al. Helicobacter pylori infection and gastric carcinoma among Japanese Americans in Hawaii. N Engl J Med. 1991; 325:1132-6. [PubMed 1891021]

351. Parsonnet J, Friedman GD, Vandersteen DP et al. Helicobacter pylori infection and the risk of gastric carcinoma. N Engl J Med. 1991; 352:1127-31.

352. The EUROGAST Study Group. An international association between Helicobacter pylori infection and gastric cancer. Lancet. 1993; 341:1359-62. [PubMed 8098787]

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356. Parsonnet J. Helicobacter pylori and gastric cancer. Gastroenterol Clin North Am. 1993; 22:89-104. [PubMed 8449573]

357. Correa P. Is gastric carcinoma an infectious disease? N Engl J Med. 1991; 325:1170-1.

358. Isaacson PG, Spencer J. Is gastric lymphoma an infectious disease? Hum Pathol. 1993; 24:569-70.

359. Reviewers’ comments (personal observations) on the Aminopenicillins General Statement (Uses: Helicobacter pylori infections).

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