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  • CLASSES

    Agents for Amoebiasis and Other Protozoal Diseases
    Anaerobicides
    Antiinfectives for Treatment of Acne
    Bulk Agents for Compounding
    Compounding Kits Miscellaneous
    Gynecological Antibiotics and Sulfonamides
    Imidazole Derivative Antibiotics
    Topical Rosacea Agents

    BOXED WARNING

    New primary malignancy

    Metronidazole, when given systemically, has been reported to be carcinogenic in mice and rats. Similar studies in the hamster gave negative results. Also, metronidazole has shown mutagenic activity in a number of in vitro assay systems, but studies in mammals (in vivo) failed to demonstrate a potential for genetic damage. Human data are not available to describe the risk of a new primary malignancy secondary to use. The boxed warning states that systemic metronidazole use should be reserved for conditions where the drug is clearly needed; avoid unnecessary use. Vaginal and topical forms of metronidazole do not carry the boxed warning regarding carcinogenicity.

    DEA CLASS

    Rx

    DESCRIPTION

    Oral/parenteral/topical synthetic nitroimidazole; antibacterial and antiprotozoal; effective against protozoa such as Trichomonas vaginalis, amebiasis, and giardiasis; highly effective drug for anaerobic bacterial infections; also useful for Crohn's disease, antibiotic-associated diarrhea, rosacea, and in combination regimens for H. pylori eradication.

    COMMON BRAND NAMES

    First-Metronidazole 100, First-Metronidazole 50, Flagyl, Flagyl ER, Flagyl RTU, MetroCream, MetroGel, MetroGel Vaginal, MetroGel-Vaginal, MetroLotion, Noritate, NUVESSA, Nydamax, Rosadan, Vandazole, Vitazol

    HOW SUPPLIED

    First-Metronidazole 100/First-Metronidazole 50 Oral Pwd F/Recon: 7.5g, 15g
    Flagyl ER Oral Tab ER: 750mg
    Flagyl RTU/Metronidazole Intravenous Inj Sol: 1mL, 5mg
    Flagyl/Metronidazole Oral Cap: 375mg
    Flagyl/Metronidazole Oral Tab: 250mg, 500mg
    MetroCream/Metronidazole/Noritate/Rosadan/Vitazol Topical Cream: 0.75%, 1%
    MetroGel/MetroGel Vaginal/MetroGel-Vaginal/Metronidazole/NUVESSA/Vandazole Vaginal Gel: 0.75%, 1.3%
    MetroGel/Metronidazole/Nydamax Topical Gel: 0.75%, 1%
    MetroLotion/Metronidazole Topical Lotion: 0.75%

    DOSAGE & INDICATIONS

    For the treatment of trichomoniasis.
    Oral dosage
    Adults

    2 g PO as a single dose, or alternatively, 500 mg PO twice daily for 7 days is recommended by the CDC. HIV-infected patients should receive the 7-day course. The FDA-approved dosage is 375 mg PO twice daily or 250 mg PO 3 times daily for 7 days. The CDC states that the 2 g dose is safe during all stages of pregnancy although the FDA-approved labeling recommends against use in the first trimester. If repeat courses are necessary, the FDA-approved labeling recommends an interval of 4 to 6 weeks between courses and that appropriate laboratory tests reconfirm presence of infection. If treatment failure occurs with the single 2 g dose, the CDC recommends retreatment with 500 mg PO twice daily for 7 days. If this regimen fails, consider treatment with 2 g PO for 7 days. For male partners of women with treatment failures, use the same treatment regimen as the patient.

    Adolescents†

    2 g PO as a single dose is recommended by the CDC and American Academy of Pediatrics (AAP), or alternatively, 500 mg PO twice daily for 7 days is recommended by the CDC. HIV-infected patients should receive the 7-day course. The CDC states that the 2 g dose is safe during all stages of pregnancy although the FDA-approved labeling recommends against use in the first trimester. If treatment failure occurs with the single 2 g dose, the CDC recommends retreatment with 500 mg PO twice daily for 7 days. If this regimen fails, consider treatment with 2 g PO for 7 days. For male partners of women with treatment failures, use the same treatment regimen as the patient.

    Children weighing 45 kg or more†

    2 g PO as a single dose is recommended by the CDC and American Academy of Pediatrics (AAP). Alternatively, 500 mg PO twice daily for 7 days is recommended by the CDC. HIV-infected patients should receive the 7-day course. If treatment failure occurs with the single 2 g dose, the CDC recommends retreatment with 500 mg PO twice daily for 7 days. If this regimen fails, consider treatment with 2 g PO for 7 days. For male partners of women with treatment failures, use the same treatment regimen as the patient.

    Children weighing less than 45 kg†

    45 mg/kg/day PO in 3 divided doses for 7 days is recommended by the American Academy of Pediatrics (AAP).

    For the treatment of bacterial vaginosis.
    Vaginal dosage (0.75% gel)
    Adult females

    1 applicatorful (5 g of 0.75% metronidazole gel) intravaginally once daily for 5 days as an option is recommended by the CDC. The FDA-approved dosage is 1 applicatorful intravaginally 1 to 2 times daily for 5 days, depending on the product used. For once daily dosing, administer at bedtime. In patients with multiple recurrences, metronidazole gel administered twice weekly for 4 to 6 months has been shown to reduce recurrences, but the benefit may not persist when therapy is stopped. Limited data suggest that an oral nitroimidazole followed by intravaginal boric acid with suppressive metronidazole gel may be an option for recurrent bacterial vaginosis.

    Female Adolescent (post-menarchal)

    1 applicatorful (5 g of 0.75% metronidazole gel) intravaginally once daily for 5 days; administer at bedtime. In patients with multiple recurrences, metronidazole gel administered twice weekly for 4 to 6 months has been shown to reduce recurrences, but the benefit may not persist when therapy is stopped. Limited data suggest that an oral nitroimidazole followed by intravaginal boric acid with suppressive metronidazole gel may be an option for recurrent bacterial vaginosis.

    Vaginal dosage (1.3% gel)
    Adult females

    1 applicatorful (5 g of 1.3% gel containing 65 mg of metronidazole) intravaginally as a single dose at bedtime. Only approved for use in non-pregnant women.

    Oral dosage (regular-release)†
    Adult females

    500 mg PO twice daily for 7 days is recommended by the CDC. For patients with multiple recurrences, limited data suggest that an oral nitroimidazole, such as metronidazole 500 mg PO twice daily for 7 days followed by intravaginal boric acid with suppressive metronidazole gel may be an option. Monthly oral metronidazole 2 g PO with fluconazole has been evaluated as suppressive therapy.

    Female Children weighing 45 kg or more and Adolescent females

    500 mg PO twice daily for 7 days is recommended by the CDC and American Academy of Pediatrics (AAP). For patients with multiple recurrences, limited data suggest that an oral nitroimidazole, such as metronidazole 500 mg PO twice daily for 7 days, followed by intravaginal boric acid with suppressive metronidazole gel may be an option. Monthly oral metronidazole 2 g PO with fluconazole has been evaluated as suppressive therapy.

    Female Children weighing less than 45 kg

    45 mg/kg/day in 3 divided doses for 7 days is recommended by the American Academy of Pediatrics (AAP).

    Oral dosage (extended-release tablet)
    Adult females

    750 mg PO once daily for 7 days. The CDC recommends the extended-release as an alternative regimen.

    For the treatment of pelvic inflammatory disease (PID), including tubo-ovarian abscess.
    Oral dosage
    Adults females

    500 mg PO twice daily in combination with doxycycline for 14 days and either single dose ceftriaxone IM, cefoxitin IM plus probenecid, or other parenteral third generation cephalosporin is recommended by the CDC for patients with mild-to-moderate PID. Patients who do not respond to oral therapy within 72 hours should be switched to parenteral therapy. If tubo-ovarian abscess is present, oral metronidazole should be used with oral doxycycline as part of a 14-day course of stepdown therapy following IV therapy. For patients with cephalosporin allergy, if the community prevalence and individual risk of gonorrhea are low, and if follow-up is assured, metronidazole in combination with a fluoroquinolone for 14 days may be considered.

    Adolescent females†

    500 mg PO twice daily in combination with doxycycline for 14 days and either single dose ceftriaxone IM, cefoxitin IM plus probenecid, or other parenteral third generation cephalosporin is recommended by the CDC for patients with mild-to-moderate PID. Patients who do not respond to oral therapy within 72 hours should be switched to parenteral therapy. If tubo-ovarian abscess is present, oral metronidazole should be used with oral doxycycline as part of a 14-day course of stepdown therapy following IV therapy. For patients with cephalosporin allergy, if the community prevalence and individual risk of gonorrhea are low, and if follow-up is assured, metronidazole in combination with a fluoroquinolone for 14 days may be considered.

    For the treatment of amebiasis (amebic dysentery) and amebic hepatic abscess.
    Oral dosage
    Adults

    500 or 750 mg PO every 8 hours for 5 to 10 days.

    Infants, Children, and Adolescents

    35 to 50 mg/kg/day (Max: 2,250 mg/day) PO divided every 8 hours for 7 to 10 days.

    Intravenous dosage†
    Adults

    750 mg IV every 8 hours for 7 to 10 days for severe intestinal or extraintestinal disease.

    Infants, Children, and Adolescents

    35 to 50 mg/kg/day (Max: 2,250 mg/day) IV divided every 8 hours for 7 to 10 days for severe intestinal or extraintestinal disease.

    For the treatment of serious anaerobic infections (e.g., skin and skin structure infections [e.g. diabetic foot ulcer], CNS infection including meningitis and brain abscess, bone and joint infections, endocarditis, bacteremia, and gynecologic infections [e.g. endometritis, endomyometritis]).
    Intravenous dosage
    Adults

    15 mg/kg IV loading dose, then 7.5 mg/kg/dose IV every 6 hours (Max: 4 g/day). Although metronidazole has traditionally been dosed as multiple-daily dosing, pharmacokinetic and clinical studies in adults have demonstrated that once daily dosing (1 to 1.5 g every 24 hours) is similar in efficacy to multiple-daily dosing and offers an advantageous dosing strategy. It has been suggested that metronidazole displays concentration-dependent killing, and the goal of dosing regimens for these agents is to maximize the concentration (peak/MIC or peak/AUC ratios), which once-daily dosing does.

    Infants†, Children†, and Adolescents†

    22.5 to 40 mg/kg/day IV divided every 8 hours (Usual Max: 500 mg/dose). The maximum recommended dose in adults is 4 g/day.Although metronidazole has traditionally been dosed as multiple-daily dosing, pharmacokinetic and clinical studies in adults have demonstrated that once daily dosing (1 to 1.5 g every 24 hours) is similar in efficacy to multiple-daily dosing and offers an advantageous dosing strategy. It has been suggested that metronidazole displays concentration-dependent killing, and the goal of dosing regimens for these agents is to maximize the concentration (peak/MIC or peak/AUC ratios), which once-daily dosing does.

    Neonates more than 40 weeks postmenstrual age†

    15 mg/kg IV loading dose, then 7.5 mg/kg/dose IV every 6 hours.

    Neonates 34 to 40 weeks postmenstrual age†

    15 mg/kg IV loading dose, then 7.5 mg/kg/dose IV every 8 hours.

    Neonates 28 to 33 weeks postmenstrual age†

    15 mg/kg IV loading dose, then 7.5 mg/kg/dose IV every 12 hours.

    Neonates 26 to 27 weeks postmenstrual age†

    15 mg/kg IV loading dose, then 10 mg/kg/dose IV every 24 hours.

    Neonates 24 to 25 weeks postmenstrual age†

    15 mg/kg IV loading dose, then 7.5 mg/kg/dose IV every 24 hours.

    Oral dosage
    Adults

    7.5 mg/kg PO every 6 hours (Max: 4 g/day). Duration of therapy is usually 7 to 10 days; however, bone and joint and endocardium infections may require longer treatment.

    Infants†, Children†, and Adolescents†

    30 to 50 mg/kg/day PO divided every 6 to 8 hours (Usual adult dose: 750 to 2,250 mg/day). The maximum recommended dose in adults in 4 g/day.

    Neonates more than 40 weeks postmenstrual age†

    7.5 mg/kg/dose PO every 6 hours. Although PO dosing is not specified in the guidelines for neonates, oral absorption of metronidazole is nearly complete and the same dose that is given IV is given orally. Only use oral metronidazole when the clinical situation is appropriate.

    Neonates 34 to 40 weeks postmenstrual age†

    7.5 mg/kg/dose PO every 8 hours. Although PO dosing is not specified in the guidelines for neonates, oral absorption of metronidazole is nearly complete and the same dose that is given IV is given orally. Only use oral metronidazole when the clinical situation is appropriate.

    Neonates 28 to 33 weeks postmenstrual age†

    7.5 mg/kg/dose PO every 12 hours. Although PO dosing is not specified in the guidelines for neonates, oral absorption of metronidazole is nearly complete and the same dose that is given IV is given orally. Only use oral metronidazole when the clinical situation is appropriate.

    Neonates 26 to 27 weeks postmenstrual age†

    10 mg/kg/dose PO every 24 hours. Although PO dosing is not specified in the guidelines for neonates, oral absorption of metronidazole is nearly complete and the same dose that is given IV is given orally. Only use oral metronidazole when the clinical situation is appropriate.

    Neonates 24 to 25 weeks postmenstrual age†

    7.5 mg/kg/dose PO every 24 hours. Although PO dosing is not specified in the guidelines for neonates, oral absorption of metronidazole is nearly complete and the same dose that is given IV is given orally. Only use oral metronidazole when the clinical situation is appropriate.

    For the treatment of acne rosacea.
    Topical dosage (0.75% Gel, Cream, or Lotion)
    Adults

    Apply thin film of 0.75% metronidazole topical cream, gel, or lotion to the cleansed, affected areas twice daily in the morning and evening. Once response occurs, adjust frequency and duration of therapy according to severity of disease.

    Topical dosage (1% Gel or Cream)
    Adults

    Apply and rub in a thin film of 1% metronidazole gel or cream once daily to the cleansed, affected area(s).

    For the treatment of serious anaerobic intraabdominal infections, including intraabdominal abscess, peritonitis, perforated appendicitis, necrotizing enterocolitis, and biliary tract infections such as cholangitis and cholecystitis.
    For the treatment of perforated appendicitis† in pediatric patients.
    Intravenous dosage
    Infants†, Children†, and Adolescents†

    30 mg/kg/dose IV every 24 hours in combination with ceftriaxone for 5 days. Some studies have used a maximum dose of 1,000 mg for metronidazole while others have used 1,500 mg. Single daily dosing of metronidazole and ceftriaxone was as effective as standard triple antibiotic therapy (ampicillin, gentamicin, and clindamycin) in a prospective randomized trial in 100 children with perforated appendicitis. No difference in wound infections or abscess rate was noted between the 2 groups. In another retrospective study in 123 children with perforated appendicitis, there was no statistically significant difference in postoperative length of stay (5.7 vs. 5.8 days; p = 0.83), abscess rate (8% vs. 4%; p = 0.57), wound infection rate (5% vs. 2%; p = 0.73), and 30-day readmissions (3% vs. 11%; p = 0.19) in patients who received once daily metronidazole and ceftriaxone compared with other standard antibiotic regimens.

    Intravenous dosage
    Adults

    500 mg IV every 8 to 12 hours or 1,500 mg IV every 24 hours as part of combination therapy for 4 to 7 days is recommended by clinical practice guidelines. The FDA-labeled dose is 15 mg/kg IV once as a loading dose, then 7.5 mg/kg IV every 6 hours (Max: 4 g/day). Depending on origin of infection and pathogens, regimens could include a cephalosporin, fluoroquinolone, piperacillin; tazobactam, or carbapenem.

    Infants†, Children†, and Adolescents†

    30 to 40 mg/kg/day IV divided every 8 hours (Usual Max: 500 mg/dose) for 4 to 7 days as part of broad-spectrum combination therapy for complicated intraabdominal infections. Depending on origin of infection and pathogens, regimens could include an advanced-generation cephalosporin, fluoroquinolone, or an aminoglycoside with or without ampicillin.

    Neonates more than 40 weeks postmenstrual age†

    15 mg/kg IV loading dose, then 7.5 mg/kg/dose IV every 6 hours. Clinical practice guidelines suggest as part of broad-spectrum combination therapy for necrotizing enterocolitis. Regimens could include ampicillin or vancomycin plus gentamicin or ampicillin or vancomycin plus cefotaxime.

    Neonates 34 to 40 weeks postmenstrual age†

    15 mg/kg IV loading dose, then 7.5 mg/kg/dose IV every 8 hours. Clinical practice guidelines suggest as part of broad-spectrum combination therapy for necrotizing enterocolitis. Regimens could include ampicillin or vancomycin plus gentamicin or ampicillin or vancomycin plus cefotaxime.

    Neonates 28 to 33 weeks postmenstrual age†

    15 mg/kg IV loading dose, then 7.5 mg/kg/dose IV every 12 hours. Clinical practice guidelines suggest as part of broad-spectrum combination therapy for necrotizing enterocolitis. Regimens could include ampicillin or vancomycin plus gentamicin or ampicillin or vancomycin plus cefotaxime.

    Neonates 26 to 27 weeks postmenstrual age†

    15 mg/kg IV loading dose, then 10 mg/kg/dose IV every 24 hours. Clinical practice guidelines suggest as part of broad-spectrum combination therapy for necrotizing enterocolitis. Regimens could include ampicillin or vancomycin plus gentamicin or ampicillin or vancomycin plus cefotaxime.

    Neonates 24 to 25 weeks postmenstrual age†

    15 mg/kg IV loading dose, then 7.5 mg/kg/dose IV every 24 hours. Clinical practice guidelines suggest as part of broad-spectrum combination therapy for necrotizing enterocolitis. Regimens could include ampicillin or vancomycin plus gentamicin or ampicillin or vancomycin plus cefotaxime.

    Oral dosage
    Adults

    7.5 mg/kg PO every 6 hours (Max: 4 g/day). Clinical practice guidelines suggest as part of combination step-down oral therapy with a second- or third-generation cephalosporin or a fluoroquinolone.

    Infants†, Children†, and Adolescents†

    30 to 50 mg/kg/day PO divided every 6 to 8 hours (Usual adult dose: 750 to 2,250 mg/day). Clinical practice guidelines suggest as part of combination step-down oral therapy with a second- or third-generation cephalosporin or a fluoroquinolone.

    Neonates more than 40 weeks postmenstrual age†

    7.5 mg/kg/dose PO every 6 hours. Although oral dosing is not specified in the guidelines for neonates, oral absorption of metronidazole is nearly complete, and the same dose that is given IV is given orally. Only use oral metronidazole for appropriate clinical situations.

    Neonates 34 to 40 weeks postmenstrual age†

    7.5 mg/kg/dose PO every 8 hours. Although oral dosing is not specified in the guidelines for neonates, oral absorption of metronidazole is nearly complete, and the same dose that is given IV is given orally. Only use oral metronidazole for appropriate clinical situations.

    Neonates 28 to 33 weeks postmenstrual age†

    7.5 mg/kg/dose PO every 12 hours. Although oral dosing is not specified in the guidelines for neonates, oral absorption of metronidazole is nearly complete, and the same dose that is given IV is given orally. Only use oral metronidazole for appropriate clinical situations.

    Neonates 26 to 27 weeks postmenstrual age†

    10 mg/kg/dose PO every 24 hours. Although oral dosing is not specified in the guidelines for neonates, oral absorption of metronidazole is nearly complete, and the same dose that is given IV is given orally. Only use oral metronidazole for appropriate clinical situations.

    Neonates 24 to 25 weeks postmenstrual age†

    7.5 mg/kg/dose PO every 24 hours. Although oral dosing is not specified in the guidelines for neonates, oral absorption of metronidazole is nearly complete, and the same dose that is given IV is given orally. Only use oral metronidazole for appropriate clinical situations.

    For the treatment of serious anaerobic lower respiratory tract infections, including pleural empyema, pneumonia, and lung abscess.
    Intravenous dosage
    Adults

    15 mg/kg IV loading dose, then 7.5 mg/kg IV every 6 hours (Max: 4 g/day). Use metronidazole in combination with a second- or third-generation cephalosporin for community-acquired empyema or with vancomycin and cefepime for hospital-acquired or postprocedural empyema. Treat for a minimum of 2 weeks after drainage and defervescence. Although metronidazole has traditionally been dosed as multiple-daily dosing, pharmacokinetic and clinical studies in adults have demonstrated that once daily dosing (1 to 1.5 g every 24 hours) is similar in efficacy to multiple-daily dosing and offers an advantageous dosing strategy. It has been suggested that metronidazole displays concentration-dependent killing, and the goal of dosing regimens for these agents is to maximize the concentration (peak/MIC or peak/AUC ratios), which once-daily dosing does.

    Infants†, Children†, and Adolescents†

    22.5 to 40 mg/kg/day IV divided every 8 hours (Usual Max: 500 mg/dose). The maximum recommended dose in adults is 4 g/day.Although metronidazole has traditionally been dosed as multiple-daily dosing, pharmacokinetic and clinical studies in adults have demonstrated that once daily dosing (1 to 1.5 g every 24 hours) is similar in efficacy to multiple-daily dosing and offers an advantageous dosing strategy. It has been suggested that metronidazole displays concentration-dependent killing, and the goal of dosing regimens for these agents is to maximize the concentration (peak/MIC or peak/AUC ratios), which once-daily dosing does.

    Neonates more than 40 weeks postmenstrual age†

    15 mg/kg IV loading dose, then 7.5 mg/kg/dose IV every 6 hours.

    Neonates 34 to 40 weeks postmenstrual age†

    15 mg/kg IV loading dose, then 7.5 mg/kg/dose IV every 8 hours.

    Neonates 28 to 33 weeks postmenstrual age†

    15 mg/kg IV loading dose, then 7.5 mg/kg/dose IV every 12 hours.

    Neonates 26 to 27 weeks postmenstrual age†

    15 mg/kg IV loading dose, then 10 mg/kg/dose IV every 24 hours.

    Neonates 24 to 25 weeks postmenstrual age†

    15 mg/kg IV loading dose, then 7.5 mg/kg/dose IV every 24 hours.

    Oral dosage
    Adults

    7.5 mg/kg PO every 6 hours (Max: 4 g/day). Use metronidazole in combination with a second- or third-generation cephalosporin for community-acquired empyema or with vancomycin and cefepime for hospital-acquired or postprocedural empyema. Treatment for a minimum of 2 weeks after drainage and defervescence.

    Infants†, Children†, and Adolescents†

    30 to 50 mg/kg/day PO divided every 6 to 8 hours (Usual adult dose: 750 to 2,250 mg/day). The maximum recommended dose in adults in 4 g/day.

    Neonates more than 40 weeks postmenstrual age†

    7.5 mg/kg/dose PO every 6 hours. Although oral dosing is not specified in the guidelines for neonates, oral absorption of metronidazole is nearly complete, and the same dose that is given IV is given orally. Only use oral metronidazole for appropriate clinical situations.

    Neonates 34 to 40 weeks postmenstrual age†

    7.5 mg/kg/dose PO every 8 hours. Although oral dosing is not specified in the guidelines for neonates, oral absorption of metronidazole is nearly complete, and the same dose that is given IV is given orally. Only use oral metronidazole for appropriate clinical situations.

    Neonates 28 to 33 weeks postmenstrual age†

    7.5 mg/kg/dose PO every 12 hours. Although oral dosing is not specified in the guidelines for neonates, oral absorption of metronidazole is nearly complete, and the same dose that is given IV is given orally. Only use oral metronidazole for appropriate clinical situations.

    Neonates 26 to 27 weeks postmenstrual age†

    10 mg/kg/dose PO every 24 hours. Although oral dosing is not specified in the guidelines for neonates, oral absorption of metronidazole is nearly complete, and the same dose that is given IV is given orally. Only use oral metronidazole for appropriate clinical situations.

    Neonates 24 to 25 weeks postmenstrual age†

    7.5 mg/kg/dose PO every 24 hours. Although oral dosing is not specified in the guidelines for neonates, oral absorption of metronidazole is nearly complete, and the same dose that is given IV is given orally. Only use oral metronidazole for appropriate clinical situations.

    For bacterial vaginosis prophylaxis† or trichomoniasis prophylaxis† in victims of sexual assault.
    Oral dosage
    Adults

    2 g PO as a single dose in combination with ceftriaxone plus azithromycin (for gonorrhea and chlamydia prophylaxis) is recommended by the CDC.

    Adolescents

    2 g PO as a single dose in combination with ceftriaxone plus azithromycin (for gonorrhea and chlamydia prophylaxis) is recommended by the CDC.

    For the treatment of recurrent and persistent non-gonococcal urethritis (NGU)†.
    Oral dosage
    Adults

    2 g PO as a single dose for men who have sex with women in areas where T. vaginalis is prevalent is recommended by the CDC.

    For the treatment of dental infection† or dentoalveolar infection†, including periodontitis†.
    Oral dosage
    Adults

    250 mg PO 3 or 4 times daily for 10 days or 500 mg PO 3 times daily for 8 days has been recommended. For severe periodontitis, 250 mg PO 3 times daily with amoxicillin for 7 to 10 days has been used. For refractory disease in patients with beta-lactam allergy, 500 mg PO twice daily with ciprofloxacin for 8 days.

    Adolescents 16 years and older

    250 mg PO 3 or 4 times daily for 10 days or 500 mg PO 3 times daily for 8 days has been recommended. For severe periodontitis, 250 mg PO 3 times daily with amoxicillin for 7 to 10 days has been used.

    For surgical infection prophylaxis, including bowel preparation† in patients undergoing colorectal surgery.
    For bowel preparation† in patients undergoing colorectal surgery.
    Oral dosage
    Adults

    1 g PO in combination with neomycin for 3 doses given over 10 hours beginning the afternoon and evening prior to the surgery. Intravenous antibmicrobial prophylaxis should also be given prior to the surgical incision.

    Infants, Children, and Adolescents

    15 mg/kg/dose (Max: 1 g/dose) PO in combination with neomycin for 3 doses given over 10 hours beginning the afternoon and evening prior to the surgery. Intravenous antibmicrobial prophylaxis should also be given prior to the surgical incision.

    Intravenous dosage
    Adults

    500 mg IV or alternately, 15 mg/kg IV, as a single dose within 60 minutes prior to the surgical incision, then 7.5 mg/kg IV every 6 hours for 2 doses. No intraoperative redosing and a duration of prophylaxis less than 24 hours for most procedures are recommended by clinical practice guidelines. Metronidazole is FDA-approved for elective, contaminated or potentially contaminated colorectal surgery. Clinical practice guidelines recommend metronidazole in combination with cefazolin for uncomplicated appendectomy, obstructed small intestine, and clean-contaminated head and neck or urologic procedures or in combination with cefazolin or ceftriaxone for colorectal procedures. Metronidazole is also recommended in combination with an aminoglycoside or fluoroquinolone as alternate therapy in patients with beta-lactam allergy for biliary tract, uncomplicated appendectomy, obstructed small intestine, colorectal, hysterectomy, or clean-contaminated urologic procedures.

    Neonates weighing more than 1,200 g†, Infants†, Children†, and Adolescents†

    15 mg/kg IV as a single dose (Max: 500 mg/dose) within 60 minutes prior to the surgical incision. No intraoperative redosing and a duration of prophylaxis less than 24 hours for most procedures are recommended by clinical practice guidelines. Clinical practice guidelines recommend metronidazole in combination with cefazolin for uncomplicated appendectomy, obstructed small intestine, and clean-contaminated head and neck or urologic procedures or in combination with cefazolin or ceftriaxone for colorectal procedures. Metronidazole is also recommended in combination with an aminoglycoside or fluoroquinolone as alternate therapy in patients with beta-lactam allergy for biliary tract, uncomplicated appendectomy, obstructed small intestine, colorectal, or clean-contaminated urologic procedures.

    Premature Neonates weighing less than 1,200 g†

    7.5 mg/kg IV as a single dose within 60 minutes prior to the surgical incision. No intraoperative redosing and a duration of prophylaxis less than 24 hours for most procedures are recommended by clinical practice guidelines. Clinical practice guidelines recommend metronidazole in combination with cefazolin for uncomplicated appendectomy, obstructed small intestine, and clean-contaminated head and neck or urologic procedures or in combination with cefazolin or ceftriaxone for colorectal procedures. Metronidazole is also recommended in combination with an aminoglycoside or fluoroquinolone as alternate therapy in patients with beta-lactam allergy for biliary tract, uncomplicated appendectomy, obstructed small intestine, colorectal, or clean-contaminated urologic procedures.

    Oral dosage†
    Adults

    500 mg PO twice daily for 5 days for induced abortion/dilation and evacuation procedures.

    For the treatment of antibiotic-associated pseudomembranous colitis† due to Clostridium difficile.
    For the treatment of antibiotic-associated pseudomembranous colitis† due to Clostridium difficile in adults.
    Oral dosage
    Adults

    500 mg PO 3 times daily for 10 days is recommended by clinical practice guidelines as an alternative for nonsevere initial cases when oral vancomycin and fidaxomicin are not available. Avoid repeated or prolonged courses due to risk of cumulative and potentially irreversible neurotoxicity.

    Intravenous dosage
    Adults

    500 mg IV every 8 hours in combination with oral and rectal vancomycin, particularly if ileus is present, is recommended by clinical practice guidelines for fulminant cases.

    For the treatment of antibiotic-associated pseudomembranous colitis† due to Clostridium difficile in pediatric patients.
    Oral dosage
    Infants, Children, and Adolescents

    7.5 mg/kg/dose (Max: 500 mg/dose) PO every 6 to 8 hours for 10 days. Clinical practice guidelines recommend oral metronidazole as a first line therapy option for nonsevere initial episodes or first recurrence.

    Intravenous dosage
    Infants, Children, and Adolescents

    7.5 mg/kg/dose (Max: 500 mg/dose) IV every 6 to 8 hours for 10 days. Clinical practice guidelines recommend intravenous metronidazole in combination with oral vancomycin for initial severe or fulminant cases.

    For the treatment of Crohn's disease† associated with colonic and/or perianal involvement.
    Oral dosage
    Adults

    1,000 to 1,500 mg/day PO in 2 to 4 divided doses. In some patients, higher doses (up to 20 mg/kg/day) may be needed for the treatment of perianal disease.

    Children and Adolescents

    15 to 20 mg/kg/day PO in 2 to 3 divided doses based on limited data in pediatric patients. In adult studies of patients with Crohn's disease, usual doses have ranged from 1,000 to 1,500 mg/day in 2 to 4 divided doses. Metronidazole, in combination with ciprofloxacin or azithromycin, has been shown to improve the clinical symptoms of Crohn's disease and may be effective in inducing remission in patients with active Crohn's disease.

    For Helicobacter pylori (H. pylori) eradication† in the treatment of patients with duodenal ulcer† disease (active or a history of duodenal ulcer), gastric ulcer†, dyspepsia†, or gastric mucosa associated lymphoid tissue (MALT) lymphoma†.
    NOTE: The American College of Gastroenterology (ACG) recommends 10 to 14 days of a triple-drug regimen containing a proton pump inhibitor (PPI), clarithromycin, and either amoxicillin or metronidazole. Although 10 to 14 days is recommended, ACG also indicates that giving therapy for 2 weeks may be preferred; a meta-analysis of more than 900 patients found that, as compared to a 7-day regimen, the rate of H. pylori eradication was significantly higher in patients taking triple therapy for 14 days (odds ratio 0.62, 95% CI 0.45 to 0.84). Although not significant, there was a trend towards improved eradication rates with 10 days of therapy vs. 7 days of therapy. The same combination for 14 days continues to be recommended as first line therapy in the 2006 global updates from the Maastricht III Consensus Report.
    NOTE: Metronidazole-resistant strains of H. pylori are prevalent in the US (approximately 25%), and primarily occur in patients previously treated with metronidazole. Therapy with at least two antimicrobials is necessary to limit the development of metronidazole resistance. Patients who have persistence of H. pylori following therapy may have metronidazole-resistant H. pylori infection.
    NOTE: In populations where H. pylori infection is common (10% or more), patients presenting with non-ulcer dyspepsia should be tested for H. pylori; those found to be H. pylori positive should be started on combination eradication therapy (also see Prevpac monograph).
    NOTE: A large body of data exists to support the importance of H. pylori eradication as the first line treatment of gastric MALT lymphoma. Following H. pylori eradication, long term tumor regression is observed in 60% to 90% of patients.
    In combination with bismuth subsalicylate and tetracycline and acid-suppressive therapy in adults (see also Helidac monograph).
    Oral dosage
    Adults

    250 mg PO with bismuth subsalicylate (525 mg PO) and tetracycline hydrochloride (500 mg PO) 4 times daily (with meals and at bedtime) for 10 to 14 days, in conjunction with acid-suppressive therapy. The FDA-approved regimen with an H2-blocker is a quadruple regimen recommended by the ACG. Alternatively, ACG recommends using a proton pump inhibitor (PPI) in combination with bismuth subsalicylate (525 mg 4 times daily), metronidazole (250 mg 4 times daily), and tetracycline (500 mg 4 times daily) to achieve higher H. pylori eradication rates. Higher metronidazole doses (1,500 mg/day vs. 1,000 mg/day) may increase the response rate in areas where metronidazole resistance is prevalent.

    In combination with clarithromycin and a proton pump inhibitor (PPI) in adults.
    Oral dosage
    Adults

    500 mg PO with clarithromycin (500 mg PO) given twice daily, in conjunction with a PPI (e.g., omeprazole 20 mg PO twice daily or lansoprazole 30 mg PO twice daily) for 10 to 14 days. This is one of several triple-drug regimens recommended by the ACG guidelines for managing H. pylori infection.

    In combination with amoxicillin and a proton pump inhibitor (PPI) in pediatric patients.
    Oral dosage
    Children and Adolescents

    10 mg/kg/dose PO twice daily (Max: 500 mg/dose) with amoxicillin (25 mg/kg/dose PO twice daily [Max: 1 g/dose]) and a proton pump inhibitor (PPI; 1 to 2 mg/kg/day PO divided every 12 hours) for 1 to 2 weeks.

    As part of a sequential therapy regimen in pediatric patients.
    Oral dosage
    Children and Adolescents

    10 mg/kg/dose PO twice daily [Max: 500 mg/dose]) with clarithromycin (10 mg/kg/dose PO twice daily [Max: 500 mg/dose]) and a proton pump inhibitor (PPI; 1 to 2 mg/kg/day PO divided every 12 hours) for 5 days, after initial treatment with amoxicillin (25 mg/kg/dose PO twice daily [Max: 1 g/dose]) and a PPI for 5 days.

    For the treatment of giardiasis†.
    Oral dosage
    Adults

    250 mg PO 3 times daily for 5 to 7 days.

    Infants, Children, and Adolescents

    15 mg/kg/day PO divided every 8 hours for 5 to 10 days.

    †Indicates off-label use

    MAXIMUM DOSAGE

    Adults

    4 g/day PO or IV.

    Geriatric

    4 g/day PO or IV.

    Adolescents

    50 mg/kg/day PO. Safety and efficacy of IV have not been established; however, doses up to 40 mg/kg/day IV have been used off-label (Max: 4 g/day PO or IV per the manufacturer, although a Max: of 2,250 mg has been suggested by others).

    Children

    50 mg/kg/day PO. Safety and efficacy of IV have not been established; however, doses up to 40 mg/kg/day IV have been used off-label (Max: 4 g/day PO or IV per the manufacturer, although a Max: of 2,250 mg has been suggested by others).

    Infants

    50 mg/kg/day PO. Safety and efficacy of IV have not been established; however, doses up to 40 mg/kg/day IV have been used off-label.

    Neonates

    Postmenstrual age (PMA) more than 40 weeks: Safety and efficacy have not been established; however, doses up to 30 mg/kg/day IV have been used off-label.
    PMA 34 to 40 weeks: Safety and efficacy have not been established; however, doses up to 22.5 mg/kg/day IV have been used off-label.
    PMA 28 to 33 weeks: Safety and efficacy have not been established; however, doses up to 15 mg/kg/day IV have been used off-label.
    PMA 26 to 27 weeks: Safety and efficacy have not been established; however, doses up to 10 mg/kg/day IV have been recommended.
    PMA 24 to 25 weeks: Safety and efficacy have not been established; however, doses up to 7.5 mg/kg/day IV have been recommended.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Reduce the dose of systemic metronidazole by 50% in patients with severe hepatic impairment (Child-Pugh C). Single systemic doses may not need to be adjusted.

    Renal Impairment

    No dosage adjustment needed in adult patients. Metabolites will likely accumulate in patients with a CrCl less than 10 mL/minute. In pediatric patients with a CrCl less than 10 mL/minute/1.73 m2, a dose of 4 mg/kg/dose IV/PO every 6 hours is recommended (based on usual dose of 15 to 30 mg/kg/day divided every 6 to 8 hours).
     
    Intermittent hemodialysis
    No dosage adjustment is necessary in adult patients; however, administer systemic doses after hemodialysis. Systemically administered metronidazole is significantly removed (up to 65% of a dose) during a standard hemodialysis session. In pediatric patients, a dose of 4 mg/kg/dose IV/PO every 6 hours is recommended (based on usual dose of 15 to 30 mg/kg/day divided every 6 to 8 hours).
     
    Peritoneal dialysis
    No dosage adjustment is necessary in adult patients. The pharmacokinetic disposition of metronidazole is not significantly altered in patients undergoing CAPD. In pediatric patients, a dose of 4 mg/kg/dose IV/PO every 6 hours is recommended (based on usual dose of 15 to 30 mg/kg/day divided every 6 to 8 hours).
     
    Chronic renal replacement therapy (CRRT)
    No dosage adjustment is necessary.

    ADMINISTRATION

    Oral Administration

    Oral absorption is nearly complete; therefore, parenteral administration is often unnecessary unless patients cannot take PO.

    Oral Solid Formulations

    Regular-release tablets or capsules: Administer without regard to meals.
    Extended-release tablets: Swallow whole; do not crush, break, or chew. Administer on an empty stomach, at least 1 hour before or 2 hours after meals.

    Oral Liquid Formulations

    Reconstitution for powder for oral suspension
    Available as a compounding kit containing 1 bottle of metronidazole powder and 1 bottle of grape-flavored diluent.
    Various bottle sizes are available that when reconstituted produce either a 50 mg/mL or 100 mg/mL metronidazole oral suspension. Select the appropriate bottle size and concentration for the individual patient.
    Tap the bottom edges of the bottle containing the metronidazole powder on a hard surface to loosen the powder.
    Remove the cap from the bottle containing the metronidazole powder. Tap the top of the induction seal to loosen any powder which may have adhered to the seal. Slowly peel back the foil seal.
    Shake the diluent bottle for a few seconds prior to removing the cap.
    Open the diluent bottle and pour about half of the diluent into the metronidazole powder bottle.
    Replace the cap and shake the mixture bottle vigorously for approximately 60 seconds.
    Empty the remaining diluent into the metronidazole powder bottle. Allow remaining diluent to drain into the powder bottle for 10 seconds.
    Replace the cap and shake the mixture bottle vigorously for approximately 60 seconds.
    Wait at least 1 hour before administering the first dose.
    Storage: Store reconstituted solution at room temperature (15 to 30 degrees C; 59 to 86 degrees F); Do not freeze. Keep container tightly closed and protect from light. Discard any unused solution after 30 days.
     
    Administration for oral suspension
    Shake bottle vigorously prior to each administration.
    Measure dosage with calibrated spoon, cup, or oral syringe.

    Extemporaneous Compounding-Oral

    NOTE: Extemporaneously prepared suspensions are not FDA-approved.
     
    Extemporaneous preparation of 50 mg/mL metronidazole oral suspension:
    Using a mortar and pestle, grind 24 x 250 mg metronidazole tablets to a fine powder.
    To make the base solution: In a separate container, mix 1 of the following combinations: 1) 60 mL of Ora-Sweet with 60 mL of Ora-Plus; or 2) 60 mL of Ora-Sweet SF with 60 mL of Ora-Plus; or 3) 120 mL cherry syrup (cherry syrup concentrate diluted 1:4 with simple syrup).
    Add a small amount of the base solution to the fine powder and mix into a uniform paste. Add geometric amounts of the base solution and mix well after each addition.
    Transfer to a graduated cylinder and add additional base solution to make a total of 120 mL. Mix well.
    Place in amber plastic bottles. Shake well before each use.
    Storage: This oral suspension is stable for at least 60 days when stored at room temperature or refrigerated.
     
    Extemporaneous preparation of 10 mg/mL metronidazole oral suspension:
    Using a mortar and pestle, grind 5 x 250 mg metronidazole tablets to a fine powder.
    To make the base solution: In a separate container, mix 62.5 mL of Ora-Sweet with 62.5 mL of Ora-Plus and shake well.
    Add a small amount of the base solution to the fine powder and mix into a uniform paste. Add geometric amounts of the base solution and mix well after each addition.
    Transfer to a graduated cylinder and add additional base solution to make a total of 125 mL. Mix well.
    Place in amber plastic bottles. Shake well before each use.
    Storage: This oral suspension is stable for at least 90 days when stored at room temperature.

    Injectable Administration

    Administer by slow IV infusion only, either as a continuous or intermittent infusion.
    Do not admix with other drugs. If used with a primary intravenous fluid system, the primary solution should be discontinued during metronidazole infusion.
    Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.

    Intravenous Administration

    Preparation of Intravenous Infusion
    Supplied as 5 mg/mL ready to use single-use infusion bags. No dilution required prior to administration.
    Do not refrigerate.
     
    Intermittent Intravenous Infusion
    Remove from foil wrapping just prior to administration.
    Infuse by slow intermittent IV infusion over 30 to 60 minutes.
    Do not use in series connections; air embolism may occur.
    Do not use equipment containing aluminum (e.g., needles, cannulae) that would come in contact with the drug solution during administration as precipitates may form.

    Topical Administration

    Topical products differ in pH from vaginal products; therefore, topical cream, gel, and lotion are for topical application to the skin only. Do not use topical products orally or vaginally.
    Avoid contact with the eyes.
    Prior to administration, cleanse area with a mild, nonirritating cleanser.

    Cream/Ointment/Lotion Formulations

    Cream/Gel application: A thin layer should be rubbed into the affected areas. Cosmetics, sunscreens, and/or moisturizers may be used after applying cream, if needed.
    Lotion application: Apply a thin layer to entire affected areas. Cosmetics, sunscreens, and/or moisturizers may be applied after the lotion has dried and 5 minutes have passed.

    Intravaginal Administration

    Vaginal and topical products differ in pH, therefore, vaginal gel is for vaginal use only; do not use vaginal products orally or topically.
    Instruct patient on proper use.
    Use special applicator supplied by the manufacturer.

    STORAGE

    Generic:
    - Avoid excessive heat (above 104 degrees F)
    - Protect from freezing
    - Protect from light
    - Store at 77 degrees F; brief exposure up to 104 degrees F does not adversely affect product
    First-Metronidazole 100 :
    - After compounding, store at controlled room temperature (between 59 to 86 degrees F)
    - Protect from freezing
    - Protect from light
    - Store at room temperature (between 59 to 86 degrees F)
    First-Metronidazole 50:
    - After compounding, store at controlled room temperature (between 59 to 86 degrees F)
    - Protect from freezing
    - Protect from light
    - Store at room temperature (between 59 to 86 degrees F)
    Flagyl:
    - Protect from light
    - Store at controlled room temperature (between 68 and 77 degrees F)
    Flagyl ER:
    - Store at 77 degrees F; excursions permitted to 59-86 degrees F
    - Store in a dry place
    Flagyl RTU:
    - Discard product if it contains particulate matter, is cloudy, or discolored
    - Discard unused portion. Do not store for later use.
    - Do not refrigerate
    - Protect from light
    - Store at 77 degrees F
    - Store in moisture barrier overwrap until time of use
    MetroCream:
    - Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F
    MetroGel:
    - Store at controlled room temperature (between 68 and 77 degrees F)
    MetroGel Vaginal:
    - Protect from freezing
    - Store at room temperature (between 59 to 86 degrees F)
    MetroGel-Vaginal:
    - Protect from freezing
    - Store at room temperature (between 59 to 86 degrees F)
    MetroLotion:
    - Protect from freezing
    - Store at controlled room temperature (between 68 and 77 degrees F)
    Noritate:
    - Store at controlled room temperature (between 68 and 77 degrees F)
    NUVESSA:
    - Do not refrigerate
    - Protect from freezing
    - Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F
    Nydamax:
    - Store at controlled room temperature (between 68 and 77 degrees F)
    Rosadan:
    - Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F
    Vandazole:
    - Protect from freezing
    - Store at room temperature (between 59 to 86 degrees F)
    Vitazol :
    - Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F

    CONTRAINDICATIONS / PRECAUTIONS

    Hematological disease

    Metronidazole is contraindicated in patients with a prior history of hypersensitivity to metronidazole or other nitroimidazole derivatives. Systemic metronidazole should be used with care in patients with evidence of or history of hematological disease; monitor complete blood count (CBC) in these patients. Agranulocytosis, leukopenia, and neutropenia have been associated with systemic metronidazole administration.

    Dialysis, renal failure, renal impairment

    Systemic metronidazole and its metabolites may accumulate significantly in patients with severe renal impairment or end stage renal disease (renal failure), including in patients receiving peritoneal dialysis, due to reduced urinary excretion. Monitor for metronidazole-associated adverse events.

    Bradycardia, cardiac arrhythmias, cardiac disease, coronary artery disease, diabetes mellitus, females, heart failure, hypertension, hypocalcemia, hypokalemia, hypomagnesemia, long QT syndrome, malnutrition, myocardial infarction, QT prolongation, thyroid disease

    Use metronidazole injection with caution in patients with cardiac disease or heart failure, or in those otherwise predisposed to edema, because it contains 28 mEq of sodium per gram of metronidazole. This large amount of sodium can promote sodium retention and exacerbate peripheral edema or congestive heart failure. Additionally, QT prolongation has been reported with metronidazole use. Use metronidazole with caution in patients with conditions that may increase the risk of QT prolongation including cardiac arrhythmias, congenital long QT syndrome, heart failure, bradycardia, myocardial infarction, hypertension, coronary artery disease, hypomagnesemia, hypokalemia, hypocalcemia, or in patients receiving medications known to prolong the QT interval or cause electrolyte imbalances. Females, elderly patients, patients with diabetes mellitus, thyroid disease, malnutrition, alcohol dependency, or liver disease may also be at increased risk for QT prolongation.

    New primary malignancy

    Metronidazole, when given systemically, has been reported to be carcinogenic in mice and rats. Similar studies in the hamster gave negative results. Also, metronidazole has shown mutagenic activity in a number of in vitro assay systems, but studies in mammals (in vivo) failed to demonstrate a potential for genetic damage. Human data are not available to describe the risk of a new primary malignancy secondary to use. The boxed warning states that systemic metronidazole use should be reserved for conditions where the drug is clearly needed; avoid unnecessary use. Vaginal and topical forms of metronidazole do not carry the boxed warning regarding carcinogenicity.

    Pregnancy

    According to the manufacturer, oral metronidazole is contraindicated during the first trimester of pregnancy in patients with trichomoniasis. However, the CDC states that metronidazole can be used for trichomoniasis at any stage of pregnancy as studies have not demonstrated an association between metronidazole and teratogenic effects. For indications other than trichomoniasis, avoid metronidazole during pregnancy whenever possible, with use occurring only after careful assessment of the potential risk to benefit ratio. While not an animal teratogen, systemically absorbed metronidazole readily crosses the placenta and enters the fetal circulation. Reports in humans are conflicting, and the effects of metronidazole on human fetal organogenesis are not known. In a large population-based cohort study (n = 139,938 live births) assessing antibiotic exposure during the first trimester of pregnancy (n = 15,469 exposures) and the risk of major birth defects, metronidazole use was not associated with an increased risk of major congenital malformations (MCMs) or organ specific MCMs. However, in a nested, case-control study (n = 87,020 controls; 8,702 cases) within the Quebec Pregnancy Cohort, metronidazole use during early pregnancy was associated with an increased risk of spontaneous abortion (adjusted odds ratio (aOR) 1.7; 95% CI: 1.27 to 2.26; 53 exposed cases); residual confounding by severity of infection may be a potential limitation of this study.

    Breast-feeding

    Metronidazole is excreted into breast milk. Breast-feeding is not recommended during treatment with systemic products. While there is some systemic absorption from topical and vaginal products, plasma concentrations would be lower than demonstrated with systemic formulations; however, caution is still advised. Metronidazole is a mutagen in vitro and has been shown to be carcinogenic in animal studies. In general, increased oral and rectal Candida colonization and loose stools have been reported in infants exposed to metronidazole via breast milk. The CDC recommends a single 2 g oral dose for the treatment of trichomoniasis during breast-feeding. Previous American Academy of Pediatrics (AAP) recommendations stated that if a single 2 g oral dose is given for trichomoniasis, then breast-feeding may be resumed in 12 to 24 hours. Otherwise, if other dosage regimens are used, breast-feeding may be resumed within 24 to 48 hours after the last dose of treatment is completed. In a study of 3 patients that received a single 2 g oral dose, peak milk concentrations ranged between 50 to 60 mcg/mL at 2 to 4 hours after the dose. If breast-feeding were to continue, the estimated infant exposure during the next 48 hours would be 25.3 mg; if breast-feeding was interrupted for 12 hours, the estimated 48 hour exposure would be 9.8 mg, and if breast-feeding was interrupted for 24 hours, the estimated 48 hour exposure would be 3.5 mg. In studies of women receiving 600 mg/day, metronidazole milk concentrations ranged from 1.1 to 15.2 mcg/mL and in patients receiving 1200 mg/day concentrations ranged from 9.02 to 15.52 mcg/mL. The mean milk:plasma ratio in both groups was approximately 1, and the mean plasma concentrations in the exposed infants were approximately 20% of the maternal plasma concentration. Depending on the indication, oral vancomycin, amoxicillin; clavulanate, ampicillin; sulbactam, or clindamycin (systemic or intravaginal) may be potential alternatives to consider during breast-feeding. Site of infection, patient factors, local susceptibility patterns, and specific microbial susceptibility should be assessed before choosing an alternative agent. Vancomycin is excreted in breast milk; however, absorption from the GI tract of any ingested vancomycin would be minimal. Alternative antimicrobials that previous AAP recommendations considered as usually compatible with breast-feeding include clindamycin and penicillins.

    Alcoholism, ethanol ingestion, ethanol intoxication

    Oral, injectable, and intravaginal dosage forms of metronidazole should be used with caution in patients with alcoholism or ethanol intoxication. Metronidazole may interfere with the metabolism of ethanol, resulting in disulfiram-like effects. Patients should try to avoid ethanol ingestion to avoid the risk of undesirable side effects. It is recommended that alcoholic beverages or medicines not be used concurrently with metronidazole or for at least 3 days following the discontinuation of the drug. Psychotic reactions have been reported in alcoholic patients on metronidazole and disulfiram therapy. Additionally, QT prolongation has been reported in a limited number of case reports with metronidazole; therefore, use it with caution in patients with other conditions that may increase the risk of QT prolongation including alcoholism.

    Fungal infection

    Metronidazole use may result in candidal overgrowth. Known or previously unrecognized candida fungal infection may present more prominent symptoms during therapy with metronidazole and requires treatment with an appropriate antifungal agent.

    Crohn's disease

    Crohn's disease patients are known to have an increased incidence of gastrointestinal and certain extraintestinal cancers. There have been some reports in the medical literature of breast and colon cancer in Crohn's disease patients who have been treated with metronidazole at high doses for extended periods of time. A cause and effect relationship has not been established.

    Ocular exposure

    Topical metronidazole gels or creams contain ingredients that may cause burning and irritation of the eye. In the event of accidental ocular exposure, rinse the eye with copious amounts of cool tap water.

    Geriatric

    Use metronidazole with caution in geriatric patients as they may also be at increased risk for QT prolongation. Additionally, geriatric patients may be likely to have hepatic impairment or renal impairment and the hepatic metabolism and/or renal clearance of metronidazole may be reduced. Therefore, monitoring of clinical response may be necessary to adjust the metronidazole dosage accordingly. No overall differences have been reported in safety and effectiveness between younger and older adult patients, but greater sensitivity of some older patients cannot be ruled out. The federal Omnibus Budget Reconciliation Act (OBRA) regulates medication use in residents of long-term care facilities (LTCFs). According to OBRA, use of antibiotics should be limited to confirmed or suspected bacterial infections. Antibiotics are non-selective and may result in the eradication of beneficial microorganisms while promoting the emergence of undesired ones, causing secondary infections such as oral thrush, colitis, or vaginitis. Any antibiotic may cause diarrhea, nausea, vomiting, anorexia, and hypersensitivity reactions.

    Sexually transmitted disease

    Metronidazole may be used to treat certain sexually transmitted diseases (STD). All patients with a diagnosed or suspected STD should be tested for other STDs, which may include HIV, syphilis, chlamydia, and gonorrhea, at the time of diagnosis. Initiate appropriate therapy and perform follow-up testing as recommended based upon sexually transmitted disease diagnosis.

    Hepatic disease, hepatic encephalopathy

    Reduce metronidazole dose in patients with severe hepatic disease or impairment (Child-Pugh C) or hepatic encephalopathy due to slowed metabolism and accumulation in plasma, which may cause exacerbations of CNS adverse events in patients with hepatic encephalopathy. Monitor patients with mild to moderate hepatic impairment for metronidazole-associated adverse effects.

    Cockayne syndrome

    Use metronidazole in patients with Cockayne syndrome only if no alternative treatment is available. Cases of severe hepatotoxicity and acute hepatic failure, including a fatal outcome with very rapid onset after treatment initiation with systemic metronidazole, have been reported in these patients. Obtain liver function tests prior to the start of therapy, within the first 2 to 3 days after initiation of therapy, frequently during therapy, and after the end of treatment. Discontinue metronidazole if there is an elevation of liver function tests, and monitor until baseline values are reached. Advise patients with Cockayne syndrome to stop taking metronidazole immediately and contact their healthcare provider if they experience any symptoms of potential hepatic injury, such as abdominal pain, nausea, change in stool color, or jaundice.

    Corticosteroid therapy, edema, sodium restriction

    Use intravenous formulations of metronidazole with caution in patients that require sodium restriction, those on corticosteroid therapy, and those predisposed to edema. Certain formulations of intravenous metronidazole may contain sodium.

    Laboratory test interference

    Systemic metronidazole therapy may cause laboratory test interference with certain laboratory measurements, such as AST, ALT, LDH, triglycerides, and hexokinase glucose; values of zero may be noted. All of the assays in which interference has been observed use enzymatic coupling of the assay to oxidation reduction of nicotinamide adenine dinucleotide. Interference is due to the similarity in the absorbance peaks of NADH (340 nm) and metronidazole (322 nm) at a pH of 7. Metronidazole causes an increase in ultraviolet absorbance at 340 nm resulting in falsely decreased values. Antimicrobials are also known to suppress H. pylori; thus, ingestion of these agents within 4 weeks of performing diagnostic tests for H. pylori may lead to false negative results. At a minimum, instruct the patient to avoid the use of metronidazole in the 4 weeks prior to the test.

    ADVERSE REACTIONS

    Severe

    aseptic meningitis / Delayed / Incidence not known
    seizures / Delayed / Incidence not known
    agranulocytosis / Delayed / Incidence not known
    anaphylactoid reactions / Rapid / Incidence not known
    angioedema / Rapid / Incidence not known
    Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) / Delayed / Incidence not known
    Stevens-Johnson syndrome / Delayed / Incidence not known
    toxic epidermal necrolysis / Delayed / Incidence not known
    pancreatitis / Delayed / Incidence not known
    new primary malignancy / Delayed / Incidence not known
    serum sickness / Delayed / Incidence not known
    hepatic failure / Delayed / Incidence not known
    hepatotoxicity / Delayed / Incidence not known

    Moderate

    vaginitis / Delayed / 0-15.0
    candidiasis / Delayed / 0.2-12.0
    hypertension / Early / 1.1-1.1
    constipation / Delayed / 0-1.0
    depression / Delayed / 0-1.0
    dysuria / Early / 0-1.0
    ataxia / Delayed / Incidence not known
    neurotoxicity / Early / Incidence not known
    dysarthria / Delayed / Incidence not known
    peripheral neuropathy / Delayed / Incidence not known
    nystagmus / Delayed / Incidence not known
    encephalopathy / Delayed / Incidence not known
    confusion / Early / Incidence not known
    psychosis / Early / Incidence not known
    neutropenia / Delayed / Incidence not known
    eosinophilia / Delayed / Incidence not known
    thrombocytopenia / Delayed / Incidence not known
    leukopenia / Delayed / Incidence not known
    erythema / Early / Incidence not known
    contact dermatitis / Delayed / Incidence not known
    phlebitis / Rapid / Incidence not known
    urinary incontinence / Early / Incidence not known
    cystitis / Delayed / Incidence not known
    stomatitis / Delayed / Incidence not known
    superinfection / Delayed / Incidence not known
    glossitis / Early / Incidence not known
    proctitis / Delayed / Incidence not known
    dyspareunia / Delayed / Incidence not known
    dyspnea / Early / Incidence not known
    sinus tachycardia / Rapid / Incidence not known
    QT prolongation / Rapid / Incidence not known
    palpitations / Early / Incidence not known
    ST-T wave changes / Rapid / Incidence not known
    chest pain (unspecified) / Early / Incidence not known
    peripheral edema / Delayed / Incidence not known
    elevated hepatic enzymes / Delayed / Incidence not known

    Mild

    headache / Early / 2.2-18.0
    vaginal discharge / Delayed / 12.0-12.0
    nausea / Early / 1.6-10.0
    metallic taste / Early / 2.0-9.0
    dysgeusia / Early / 2.0-9.0
    infection / Delayed / 0-7.0
    pruritus / Rapid / 1.6-6.0
    influenza / Delayed / 0-6.0
    abdominal pain / Early / 4.0-5.0
    pruritus ani / Early / 5.0-5.0
    diarrhea / Early / 1.0-4.0
    vomiting / Early / 0-4.0
    dizziness / Early / 0-4.0
    rhinitis / Early / 0-4.0
    pharyngitis / Delayed / 2.0-3.1
    dysmenorrhea / Delayed / 1.2-3.0
    sinusitis / Delayed / 1.4-3.0
    xerostomia / Early / 2.0-2.0
    nasal congestion / Early / 1.1-1.1
    flatulence / Early / 0-1.0
    anorexia / Delayed / 0-1.0
    dyspepsia / Early / 0-1.0
    gingivitis / Delayed / 0-1.0
    insomnia / Early / 0-1.0
    diaphoresis / Early / 0-1.0
    acne vulgaris / Delayed / 0-1.0
    urticaria / Rapid / 0-1.0
    rash / Early / 1.0-1.0
    increased urinary frequency / Early / 0-1.0
    breast enlargement / Delayed / 0-1.0
    leukorrhea / Delayed / 0-1.0
    menorrhagia / Delayed / 0-1.0
    back pain / Delayed / 0-1.0
    vaginal irritation / Early / 9.0
    asthenia / Delayed / Incidence not known
    vertigo / Early / Incidence not known
    drowsiness / Early / Incidence not known
    syncope / Early / Incidence not known
    weakness / Early / Incidence not known
    irritability / Delayed / Incidence not known
    paresthesias / Delayed / Incidence not known
    hypoesthesia / Delayed / Incidence not known
    skin irritation / Early / Incidence not known
    hyperhidrosis / Delayed / Incidence not known
    fever / Early / Incidence not known
    flushing / Rapid / Incidence not known
    ocular irritation / Rapid / Incidence not known
    xerosis / Delayed / Incidence not known
    injection site reaction / Rapid / Incidence not known
    polyuria / Early / Incidence not known
    urine discoloration / Early / Incidence not known
    libido decrease / Delayed / Incidence not known
    myalgia / Early / Incidence not known
    arthralgia / Delayed / Incidence not known
    muscle cramps / Delayed / Incidence not known
    hiccups / Early / Incidence not known
    fatigue / Early / Incidence not known
    chills / Rapid / Incidence not known
    malaise / Early / Incidence not known

    DRUG INTERACTIONS

    Alfuzosin: (Major) Potential QT prolongation has been reported in limited case reports with metronidazole. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with metronidazole include alfuzosin.
    Amiodarone: (Major) Potential QT prolongation has been reported in limited case reports with metronidazole. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with metronidazole include amiodarone.
    Amitriptyline: (Minor) Coadministration of metronidazole with tricyclic antidepressants (TCAs) may increase the risk for QT prolongation. Potential QT prolongation has been reported in limited case reports with metronidazole. Tricyclic antidepressants share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations).
    Amitriptyline; Chlordiazepoxide: (Minor) Coadministration of metronidazole with tricyclic antidepressants (TCAs) may increase the risk for QT prolongation. Potential QT prolongation has been reported in limited case reports with metronidazole. Tricyclic antidepressants share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations).
    Amoxicillin; Clarithromycin; Lansoprazole: (Major) Potential QT prolongation has been reported in limited case reports with metronidazole. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with metronidazole include clarithromycin.
    Amoxicillin; Clarithromycin; Omeprazole: (Major) Potential QT prolongation has been reported in limited case reports with metronidazole. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with metronidazole include clarithromycin.
    Anagrelide: (Major) Potential QT prolongation has been reported in limited case reports with metronidazole. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously with metronidazole include anagrelide.
    Anthracyclines: (Moderate) Potential QT prolongation has been reported in limited case reports with metronidazole. Acute cardiotoxicity can occur during administration of daunorubicin, doxorubicin, epirubicin, or idarubicin; cumulative, dose-dependent cardiomyopathy may also occur. Acute ECG changes during anthracycline therapy are usually transient and include ST-T wave changes, QT prolongation, and changes in QRS voltage. Sinus tachycardia is the most common arrhythmia, but other arrhythmias such as supraventricular tachycardia (SVT), ventricular tachycardia, heart block, and premature ventricular contractions (PVCs) have been reported.
    Apomorphine: (Major) Potential QT prolongation has been reported in limited case reports with metronidazole. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with metronidazole include apomorphine.
    Aripiprazole: (Moderate) Potential QT prolongation has been reported in limited case reports with metronidazole. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously with metronidazole include aripiprazole.
    Arsenic Trioxide: (Major) Avoid coadministration of metronidazole and arsenic trioxide. Potential QT prolongation has been reported in limited case reports with metronidazole. If possible, drugs that are known to prolong the QT interval should be discontinued prior to initiating arsenic trioxide therapy. If concomitant drug use is unavoidable, frequently monitor electrocardiograms. QT prolongation should be expected with the administration of arsenic trioxide.
    Artemether; Lumefantrine: (Major) Potential QT prolongation has been reported in limited case reports with metronidazole. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with metronidazole include artemether; lumefantrine.
    Asenapine: (Major) Potential QT prolongation has been reported in limited case reports with metronidazole. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with metronidazole include asenapine.
    Atomoxetine: (Moderate) Potential QT prolongation has been reported in limited case reports with metronidazole. Drugs with a possible risk for QT prolongation and torsade de pointes (TdP) that should be used cautiously with metronidazole include atomoxetine. QT prolongation has occurred during therapeutic use of atomoxetine and following overdose. Atomoxetine is considered a drug with a possible risk of TdP.
    Azithromycin: (Major) Due to a possible risk for QT prolongation and torsade de pointes (TdP), azithromycin and metronidazole should be used together cautiously. There have been case reports of QT prolongation and TdP with the use of azithromycin in postmarketing reports. Potential QT prolongation has been reported in limited case reports with metronidazole. Concurrent use may increase the risk of QT prolongation.
    Barbiturates: (Minor) Barbiturates may decrease the half-life and plasma concentrations of metronidazole. The clinical significance of this effect is uncertain.
    Bedaquiline: (Major) Potential QT prolongation has been reported in limited case reports with metronidazole. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with metronidazole include bedaquiline.
    Belladonna Alkaloids; Ergotamine; Phenobarbital: (Major) Coadministration of ergotamine with inhibitors of CYP3A4, such as metronidazole, may potentially increase the risk of ergot toxicity.
    Bortezomib: (Minor) Monitor patients for the development of peripheral neuropathy when receiving bortezomib in combination with other drugs that can cause peripheral neuropathy like metronidazole; the risk of peripheral neuropathy may be additive.
    Bosentan: (Moderate) Bosentan is metabolized by CYP2C9 and CYP3A4 isoenzymes. Metronidazole inhibits CYP2C9 and may theoretically lead to elevated plasma concentrations of bosentan when coadministered.
    Buprenorphine: (Major) Buprenorphine should be used cautiously and with close monitoring with metronidazole. Buprenorphine has been associated with QT prolongation and has a possible risk of torsade de pointes (TdP). FDA-approved labeling for some buprenorphine products recommend avoiding use with Class 1A and Class III antiarrhythmic medications while other labels recommend avoiding use with any drug that has the potential to prolong the QT interval, such as metronidazole. Potential QT prolongation has been reported in limited case reports with metronidazole. If these drugs are used together, consider the potential for additive effects on the QT interval.
    Buprenorphine; Naloxone: (Major) Buprenorphine should be used cautiously and with close monitoring with metronidazole. Buprenorphine has been associated with QT prolongation and has a possible risk of torsade de pointes (TdP). FDA-approved labeling for some buprenorphine products recommend avoiding use with Class 1A and Class III antiarrhythmic medications while other labels recommend avoiding use with any drug that has the potential to prolong the QT interval, such as metronidazole. Potential QT prolongation has been reported in limited case reports with metronidazole. If these drugs are used together, consider the potential for additive effects on the QT interval.
    Busulfan: (Major) Systemic metronidazole should not be administered with busulfan unless the benefit outweighs the risk. If no therapeutic alternatives to metronidazole exist, monitor busulfan concentrations and adjust the busulfan doses as necessary. Metronidazole may increase plasma concentrations of busulfan, which can result in an increased risk for serious busulfan toxicity such as sinusoidal obstruction syndrome, gastrointestinal mucositis, and hepatic veno-occlusive disease.
    Caffeine; Ergotamine: (Major) Coadministration of ergotamine with inhibitors of CYP3A4, such as metronidazole, may potentially increase the risk of ergot toxicity.
    Carbamazepine: (Minor) Monitor serum concentrations of carbamazepine when coadministered with systemic metronidazole. Concomitant use with metronidazole may increase the serum concentrations of carbamazepine; thereby, increasing the risk of side effects.
    Carbidopa: (Major) There was a 5% incidence of generalized polyneuropathy during clinical trial evaluation of carbidopa; levodopa enteral suspension (Duopa). The manufacturer recommends an initial evaluation for signs and symptoms of peripheral neuropathy, and periodic monitoring for peripheral neuropathy during treatment with Duopa, particularly in patients receiving other medications that are associated with neuropathy. Metronidazole has been associated with peripheral neuropathy, with the prevalence and severity of the neuropathy being directly related to the cumulative dose and duration of therapy. Peripheral neuropathy has also been reported in patients treated with other nitroimidazole drugs including tinidazole.
    Carbidopa; Levodopa: (Major) There was a 5% incidence of generalized polyneuropathy during clinical trial evaluation of carbidopa; levodopa enteral suspension (Duopa). The manufacturer recommends an initial evaluation for signs and symptoms of peripheral neuropathy, and periodic monitoring for peripheral neuropathy during treatment with Duopa, particularly in patients receiving other medications that are associated with neuropathy. Metronidazole has been associated with peripheral neuropathy, with the prevalence and severity of the neuropathy being directly related to the cumulative dose and duration of therapy. Peripheral neuropathy has also been reported in patients treated with other nitroimidazole drugs including tinidazole.
    Carbidopa; Levodopa; Entacapone: (Major) There was a 5% incidence of generalized polyneuropathy during clinical trial evaluation of carbidopa; levodopa enteral suspension (Duopa). The manufacturer recommends an initial evaluation for signs and symptoms of peripheral neuropathy, and periodic monitoring for peripheral neuropathy during treatment with Duopa, particularly in patients receiving other medications that are associated with neuropathy. Metronidazole has been associated with peripheral neuropathy, with the prevalence and severity of the neuropathy being directly related to the cumulative dose and duration of therapy. Peripheral neuropathy has also been reported in patients treated with other nitroimidazole drugs including tinidazole.
    Celecoxib: (Minor) Since celecoxib is metabolized by cytochrome P450 2C9, concurrent administration with metronidazole, which can inhibit this enzyme, may result in increased levels of celecoxib. The clinical significance of this interaction has not been established.
    Ceritinib: (Major) Periodically monitor electrolytes and ECGs in patients receiving concomitant treatment with ceritinib and metronidazole; an interruption of ceritinib therapy, dose reduction, or discontinuation of therapy may be necessary if QT prolongation occurs. Ceritinib causes concentration-dependent prolongation of the QT interval. Potential QT prolongation has been reported in limited case reports with metronidazole.
    Chloroquine: (Major) Potential QT prolongation has been reported in limited case reports with metronidazole. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with metronidazole include chloroquine.
    Chlorpromazine: (Major) Potential QT prolongation has been reported in limited case reports with metronidazole. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with metronidazole include chlorpromazine.
    Cholestyramine: (Moderate) The bile-acid sequestrant cholestyramine is well-known to cause drug interactions by binding and decreasing the oral administration of many drugs; to minimize drug interactions, administer other drugs at least 1 hour before or at least 4 to 6 hours after the administration of cholestyramine. The oral bioavailability of metronidazole was reduced by 21% when given with cholestyramine
    Cimetidine: (Moderate) Cimetidine is an enzyme inhibitor that can decrease the hepatic metabolism of metronidazole. As a result, elimination can be delayed and serum metronidazole concentrations can increase. The sequelae of this interaction are unclear, although prolonged administration of metronidazole has been associated with seizures. If possible, cimetidine should not be used during metronidazole therapy.
    Ciprofloxacin: (Moderate) Potential QT prolongation has been reported in limited case reports with metronidazole. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously with metronidazole include ciprofloxacin.
    Cisapride: (Severe) Potential QT prolongation has been reported in limited case reports with metronidazole. Because of the potential for TdP, use of cisapride with metronidazole is contraindicated.
    Citalopram: (Major) Potential QT prolongation has been reported in limited case reports with metronidazole. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with metronidazole include citalopram.
    Clarithromycin: (Major) Potential QT prolongation has been reported in limited case reports with metronidazole. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with metronidazole include clarithromycin.
    Clomipramine: (Minor) Coadministration of metronidazole with tricyclic antidepressants (TCAs) may increase the risk for QT prolongation. Potential QT prolongation has been reported in limited case reports with metronidazole. Tricyclic antidepressants share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations).
    Clozapine: (Major) Potential QT prolongation has been reported in limited case reports with metronidazole. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with metronidazole include clozapine.
    Codeine; Phenylephrine; Promethazine: (Moderate) Promethazine carries a possible risk of QT prolongation. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously with promethazine include metronidazole.
    Codeine; Promethazine: (Moderate) Promethazine carries a possible risk of QT prolongation. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously with promethazine include metronidazole.
    Crizotinib: (Major) Monitor ECGs for QT prolongation and monitor electrolytes in patients receiving crizotinib concomitantly with metronidazole. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib patients if QT prolongation occurs. Crizotinib has been associated with concentration-dependent QT prolongation. Potential QT prolongation has also been reported in limited case reports with metronidazole.
    Cyclobenzaprine: (Moderate) Potential QT prolongation has been reported in limited case reports with metronidazole. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously with metronidazole include cyclobenzaprine.
    Cyclophosphamide: (Moderate) Use caution if cyclophosphamide is used concomitantly with metronidazole, as animal studies found the combination to be associated with an increased risk of cyclophosphamide-related toxicities. Acute encephalopathy has been reported in one patient receiving cyclophosphamide and metronidazole, but the causal association is unclear.
    Cyclosporine: (Major) Monitor serum concentrations of cyclosporine when coadministered with systemic metronidazole. Concomitant use with metronidazole may increase the serum concentrations of cyclosporine; thereby, increasing the risk of side effects. Also, medications with significant alcohol content should not be ingested during therapy with metronidazole and should be avoided for 3 days after metronidazole is discontinued. Cyclosporine parenteral and oral solutions contain ethanol; liquid-filled capsules contain ethanol in lower percentages. Administration of ethanol-containing formulations of cyclosporine to patients receiving or who have recently received metronidazole may result in disulfiram-like reactions. A disulfiram reaction would not be expected to occur with non-ethanol containing formulations.
    Dasabuvir; Ombitasvir; Paritaprevir; Ritonavir: (Major) Medications with significant alcohol content should not be ingested during therapy with metronidazole and should be avoided for 3 days after therapy is discontinued. Oral solutions of ritonavir contain ethanol. Administration of ritonavir oral solution to patients receiving or who have recently received disulfiram or metronidazole may result in disulfiram-like reactions. A disulfiram reaction would not be expected to occur with non-ethanol containing formulations. Addtionally, potential QT prolongation has been reported in limited case reports with metronidazole; therefore, it should be used cautiously and with close monitoring when administered with ritonavir, which has a possible risk for QT prolongation and TdP.
    Dasatinib: (Major) Monitor for evidence of QT prolongation during concurrent use of dasatinib and metronidazole. In vitro studies have shown that dasatinib has the potential to prolong the QT interval. Potential QT prolongation has been reported in limited case reports with metronidazole.
    Daunorubicin: (Moderate) Potential QT prolongation has been reported in limited case reports with metronidazole. Acute cardiotoxicity can occur during administration of daunorubicin, doxorubicin, epirubicin, or idarubicin; cumulative, dose-dependent cardiomyopathy may also occur. Acute ECG changes during anthracycline therapy are usually transient and include ST-T wave changes, QT prolongation, and changes in QRS voltage. Sinus tachycardia is the most common arrhythmia, but other arrhythmias such as supraventricular tachycardia (SVT), ventricular tachycardia, heart block, and premature ventricular contractions (PVCs) have been reported.
    Degarelix: (Major) Potential QT prolongation has been reported in limited case reports with metronidazole. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with metronidazole include degarelix.
    Desflurane: (Major) Potential QT prolongation has been reported in limited case reports with metronidazole. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with metronidazole include halogenated anesthetics.
    Desipramine: (Minor) Coadministration of metronidazole with tricyclic antidepressants (TCAs) may increase the risk for QT prolongation. Potential QT prolongation has been reported in limited case reports with metronidazole. Tricyclic antidepressants share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations).
    Deutetrabenazine: (Moderate) For patients taking a deutetrabenazine dosage more than 24 mg/day with metronidazole, assess the QTc interval before and after increasing the dosage of either medication. Clinically relevant QTc prolongation may occur with deutetrabenazine. Potential QT prolongation has been reported in limited case reports with metronidazole.
    Dextromethorphan; Promethazine: (Moderate) Promethazine carries a possible risk of QT prolongation. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously with promethazine include metronidazole.
    Dextromethorphan; Quinidine: (Major) Potential QT prolongation has been reported in limited case reports with metronidazole. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with metronidazole include quinidine, (including dextromethorphan; quinidine),
    Dienogest; Estradiol valerate: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available.
    Disopyramide: (Major) Potential QT prolongation has been reported in limited case reports with metronidazole. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with metronidazole include disopyramide.
    Disulfiram: (Severe) The combination of systemic metronidazole and disulfiram is contraindicated. Do not administer systemic metronidazole concomitantly or within 2 weeks after the administration of disulfiram because additive CNS toxic effects can occur. Case reports have described the development of CNS toxicity after metronidazole was coadministered with disulfiram, resulting in psychosis and confusion. This toxicity is believed to occur because of combined inhibition of aldehyde dehydrogenase. When metronidazole and disulfiram are combined, symptoms may become evident within 10 to 14 days, and symptoms may remain for 2 to 3 days after the drugs are discontinued.
    Dofetilide: (Severe) Potential QT prolongation has been reported in limited case reports with metronidazole. Because of the potential for TdP, use of dofetilide with metronidazole is contraindicated.
    Dolasetron: (Major) Potential QT prolongation has been reported in limited case reports with metronidazole. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with metronidazole include dolasetron.
    Dolutegravir; Rilpivirine: (Major) Potential QT prolongation has been reported in limited case reports with metronidazole. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with metronidazole include rilpivirine.
    Donepezil: (Major) Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. Donepezil is considered a drug with a known risk of TdP. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with donepezil include metronidazole.
    Donepezil; Memantine: (Major) Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. Donepezil is considered a drug with a known risk of TdP. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with donepezil include metronidazole.
    Doxepin: (Minor) Coadministration of metronidazole with tricyclic antidepressants (TCAs) may increase the risk for QT prolongation. Potential QT prolongation has been reported in limited case reports with metronidazole. Tricyclic antidepressants share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations).
    Doxercalciferol: (Moderate) Cytochrome P450 enzyme inhibitors, such as metronidazole, may inhibit the 25-hydroxylation of doxercalciferol, thereby decreasing the formation of the active metabolite and thus, decreasing efficacy.
    Doxorubicin: (Moderate) Potential QT prolongation has been reported in limited case reports with metronidazole. Acute cardiotoxicity can occur during administration of daunorubicin, doxorubicin, epirubicin, or idarubicin; cumulative, dose-dependent cardiomyopathy may also occur. Acute ECG changes during anthracycline therapy are usually transient and include ST-T wave changes, QT prolongation, and changes in QRS voltage. Sinus tachycardia is the most common arrhythmia, but other arrhythmias such as supraventricular tachycardia (SVT), ventricular tachycardia, heart block, and premature ventricular contractions (PVCs) have been reported.
    Dronabinol, THC: (Major) The use of metronidazole within 14 days of beginning therapy with dronabinol oral solution is contraindicated, due to the risk of a disulfiram-like reaction. Do not administer metronidazole within 7 days of completing therapy with the oral solution. Dronabinol oral solution contains 50% (w/w) dehydrated alcohol and 5% (w/w) propylene glycol, which can produce disulfiram-like reactions (e.g., abdominal cramps, nausea/vomiting, headaches, and flushing) with drugs such as metronidazole. Ethanol competitively inhibits the metabolism of propylene glycol; however, the contribution of propylene glycol to these reactions is unknown. A disulfiram reaction would not be expected to occur with non-ethanol containing formulations (e.g., dronabinol oral capsules).
    Dronedarone: (Severe) Potential QT prolongation has been reported in limited case reports with metronidazole. Because of the potential for TdP, use of dronedarone with metronidazole is contraindicated.
    Droperidol: (Major) Potential QT prolongation has been reported in limited case reports with metronidazole. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with metronidazole include droperidol,
    Drospirenone; Estradiol: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available.
    Drospirenone; Ethinyl Estradiol: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available.
    Drospirenone; Ethinyl Estradiol; Levomefolate: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available.
    Efavirenz: (Major) Although data are limited, coadministration of efavirenz and metronidazole may increase the risk for QT prolongation and torsade de pointes (TdP). QT prolongation has been observed with use of efavirenz. Potential QT prolongation has also been reported in limited case reports with metronidazole.
    Efavirenz; Emtricitabine; Tenofovir: (Major) Although data are limited, coadministration of efavirenz and metronidazole may increase the risk for QT prolongation and torsade de pointes (TdP). QT prolongation has been observed with use of efavirenz. Potential QT prolongation has also been reported in limited case reports with metronidazole.
    Efavirenz; Lamivudine; Tenofovir Disoproxil Fumarate: (Major) Although data are limited, coadministration of efavirenz and metronidazole may increase the risk for QT prolongation and torsade de pointes (TdP). QT prolongation has been observed with use of efavirenz. Potential QT prolongation has also been reported in limited case reports with metronidazole.
    Eliglustat: (Major) Eliglustat is predicted to cause PR, QRS, and/or QT prolongation at significantly elevated plasma concentrations. Drugs with a possible risk for QT prolongation and torsade de pointes (TdP) that should be used cautiously and with close monitoring with eliglustat include metronidazole (including bismuth subcitrate potassium; metronidazole; tetracycline and bismuth subsalicylate; metronidazole; tetracycline).
    Emtricitabine; Rilpivirine; Tenofovir alafenamide: (Major) Potential QT prolongation has been reported in limited case reports with metronidazole. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with metronidazole include rilpivirine.
    Emtricitabine; Rilpivirine; Tenofovir disoproxil fumarate: (Major) Potential QT prolongation has been reported in limited case reports with metronidazole. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with metronidazole include rilpivirine.
    Encorafenib: (Major) Avoid coadministration of encorafenib and metronidazole due to the potential for additive QT prolongation. Encorafenib is associated with dose-dependent prolongation of the QT interval. Potential QT prolongation has been reported in limited case reports with metronidazole.
    Enflurane: (Major) Potential QT prolongation has been reported in limited case reports with metronidazole. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with metronidazole include halogenated anesthetics.
    Epirubicin: (Moderate) Potential QT prolongation has been reported in limited case reports with metronidazole. Acute cardiotoxicity can occur during administration of daunorubicin, doxorubicin, epirubicin, or idarubicin; cumulative, dose-dependent cardiomyopathy may also occur. Acute ECG changes during anthracycline therapy are usually transient and include ST-T wave changes, QT prolongation, and changes in QRS voltage. Sinus tachycardia is the most common arrhythmia, but other arrhythmias such as supraventricular tachycardia (SVT), ventricular tachycardia, heart block, and premature ventricular contractions (PVCs) have been reported.
    Ergonovine: (Major) Coadministration of ergonovine with inhibitors of CYP3A4, such as metronidazole, may potentially increase the risk of ergot toxicity.
    Ergotamine: (Major) Coadministration of ergotamine with inhibitors of CYP3A4, such as metronidazole, may potentially increase the risk of ergot toxicity.
    Eribulin: (Major) Potential QT prolongation has been reported in limited case reports with metronidazole. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with metronidazole include eribulin.
    Erythromycin: (Major) Potential QT prolongation has been reported in limited case reports with metronidazole. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with metronidazole include erythromycin.
    Erythromycin; Sulfisoxazole: (Major) Potential QT prolongation has been reported in limited case reports with metronidazole. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with metronidazole include erythromycin.
    Escitalopram: (Moderate) Potential QT prolongation has been reported in limited case reports with metronidazole. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously with metronidazole include escitalopram.
    Estradiol; Levonorgestrel: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available.
    Estradiol; Norethindrone: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available.
    Estradiol; Norgestimate: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available.
    Ethanol: (Severe) Advise patients to discontinue alcoholic beverages and other forms of alcohol (including medicines with significant alcohol content and any products containing propylene glycol) before, during, and up to 3 days after therapy with systemic metronidazole. Disulfiram-like side effects including nausea, vomiting, tachycardia, headache, flushing, and abdominal cramps may occur if used together.
    Ethinyl Estradiol: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available.
    Ethinyl Estradiol; Desogestrel: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available.
    Ethinyl Estradiol; Ethynodiol Diacetate: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available.
    Ethinyl Estradiol; Etonogestrel: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available.
    Ethinyl Estradiol; Levonorgestrel: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available.
    Ethinyl Estradiol; Levonorgestrel; Ferrous bisglycinate: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available.
    Ethinyl Estradiol; Levonorgestrel; Folic Acid; Levomefolate: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available.
    Ethinyl Estradiol; Norelgestromin: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available.
    Ethinyl Estradiol; Norethindrone Acetate: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available.
    Ethinyl Estradiol; Norethindrone Acetate; Ferrous fumarate: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available.
    Ethinyl Estradiol; Norethindrone: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available.
    Ethinyl Estradiol; Norethindrone; Ferrous fumarate: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available.
    Ethinyl Estradiol; Norgestimate: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available.
    Ethinyl Estradiol; Norgestrel: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available.
    Ezogabine: (Major) Potential QT prolongation has been reported in limited case reports with metronidazole. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with metronidazole include ezogabine.
    Fingolimod: (Major) Potential QT prolongation has been reported in limited case reports with metronidazole. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with metronidazole include fingolimod.
    Flecainide: (Major) Potential QT prolongation has been reported in limited case reports with metronidazole. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with metronidazole include flecainide.
    Floxuridine: (Minor) Enhancement of toxicity of fluorouracil, 5-FU, has been reported in a limited number of patients during concurrent treatment with metronidazole. This toxicity occurred without an increase in efficacy of fluorouracil. Toxicity may manifest as granulocytopenia, oral ulceration, anemia, and nausea and vomiting. This interaction is believed to occur through reduced clearance of fluorouracil. Floxuridine is a deoxyribonucleoside derivative of fluorouracil and may interact with metronidazole in a similar manner.
    Fluconazole: (Major) Potential QT prolongation has been reported in limited case reports with metronidazole. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with metronidazole include fluconazole.
    Fluorouracil, 5-FU: (Minor) Caution is warranted with the coadministration of systemic metronidazole and systemic fluorouracil, 5-FU. Concomitant use with metronidazole may increase the serum concentrations of fluorouracil; thereby, increasing the risk of side effects. Toxicity may manifest as granulocytopenia, oral ulceration, anemia, and nausea and vomiting.
    Fluoxetine: (Major) Potential QT prolongation has been reported in limited case reports with metronidazole. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with metronidazole include fluoxetine.
    Fluoxetine; Olanzapine: (Major) Potential QT prolongation has been reported in limited case reports with metronidazole. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with metronidazole include fluoxetine. (Moderate) Potential QT prolongation has been reported in limited case reports with metronidazole. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously with metronidazole include olanzapine.
    Fluphenazine: (Minor) Potential QT prolongation has been reported in limited case reports with metronidazole. Drugs with a possible risk for QT prolongation that should be used cautiously with metronidazole include fluphenazine.
    Fluvoxamine: (Moderate) There may be an increased risk for QT prolongation and torsade de pointes (TdP) during concurrent use of fluvoxamine and metronidazole. Coadminister with caution. Potential QT prolongation has been reported in limited case reports with metronidazole. QT prolongation and TdP have been reported during postmarketing use of fluvoxamine.
    Foscarnet: (Major) When possible, avoid concurrent use of foscarnet with other drugs known to prolong the QT interval, such as metronidazole. Foscarnet has been associated with postmarketing reports of both QT prolongation and torsade de pointes (TdP). Potential QT prolongation has been reported in limited case reports with metronidazole. If these drugs are administered together, obtain an electrocardiogram and electrolyte concentrations before and periodically during treatment.
    Fosphenytoin: (Moderate) Metronidazole can decrease the clearance of phenytoin or fosphenytoin, which can lead to an increase in phenytoin plasma concentrations. Phenytoin levels should be checked regularly when metronidazole therapy is undertaken.
    Gemifloxacin: (Major) Potential QT prolongation has been reported in limited case reports with metronidazole. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with metronidazole include gemifloxacin.
    Gemtuzumab Ozogamicin: (Moderate) Use gemtuzumab ozogamicin and metronidazole together with caution due to the potential for additive QT interval prolongation and risk of torsade de pointes (TdP). If these agents are used together, obtain an ECG and serum electrolytes prior to the start of gemtuzumab and as needed during treatment. Although QT interval prolongation has not been reported with gemtuzumab, it has been reported with other drugs that contain calicheamicin. Potential QT prolongation has been reported in case reports with metronidazole.
    Goserelin: (Moderate) Androgen deprivation therapy (e.g., goserelin) prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously with goserelin include metronidazole.
    Granisetron: (Major) Potential QT prolongation has been reported in limited case reports with metronidazole. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with metronidazole include granisetron.
    Halogenated Anesthetics: (Major) Potential QT prolongation has been reported in limited case reports with metronidazole. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with metronidazole include halogenated anesthetics.
    Haloperidol: (Major) Potential QT prolongation has been reported in limited case reports with metronidazole. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with metronidazole include haloperidol.
    Halothane: (Major) Potential QT prolongation has been reported in limited case reports with metronidazole. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with metronidazole include halogenated anesthetics.
    Histrelin: (Moderate) Consider periodic monitoring of EGCs for QT prolongation and monitor electrolytes if coadministration of histrelin and metronidazole is necessary; correct any electrolyte abnormalities. Androgen deprivation therapy (e.g., histrelin) prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval. Potential QT prolongation has also been reported in limited case reports with metronidazole.
    Hydroxychloroquine: (Major) Avoid coadministration of hydroxychloroquine and metronidazole. Hydroxychloroquine increases the QT interval and should not be administered with other drugs known to prolong the QT interval. Ventricular arrhythmias and torsade de pointes have been reported with the use of hydroxychloroquine. Potential QT prolongation has been reported in limited case reports with metronidazole.
    Hydroxyzine: (Major) Post-marketing data indicate that hydroxyzine causes QT prolongation and Torsade de Pointes (TdP). Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with hydroxyzine include metronidazole.
    Ibutilide: (Major) Potential QT prolongation has been reported in limited case reports with metronidazole. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with metronidazole include ibutilide.
    Idarubicin: (Moderate) Potential QT prolongation has been reported in limited case reports with metronidazole. Acute cardiotoxicity can occur during administration of daunorubicin, doxorubicin, epirubicin, or idarubicin; cumulative, dose-dependent cardiomyopathy may also occur. Acute ECG changes during anthracycline therapy are usually transient and include ST-T wave changes, QT prolongation, and changes in QRS voltage. Sinus tachycardia is the most common arrhythmia, but other arrhythmias such as supraventricular tachycardia (SVT), ventricular tachycardia, heart block, and premature ventricular contractions (PVCs) have been reported.
    Iloperidone: (Major) Potential QT prolongation has been reported in limited case reports with metronidazole. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with metronidazole include iloperidone.
    Imipramine: (Minor) Coadministration of metronidazole with tricyclic antidepressants (TCAs) may increase the risk for QT prolongation. Potential QT prolongation has been reported in limited case reports with metronidazole. Tricyclic antidepressants share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations).
    Inotuzumab Ozogamicin: (Major) Avoid coadministration of inotuzumab ozogamicin with metronidazole due to the potential for additive QT prolongation and risk of torsade de pointes (TdP). If coadministration is unavoidable, obtain an ECG and serum electrolytes prior to the start of treatment, after treatment initiation, and periodically during treatment. Inotuzumab has been associated with QT interval prolongation. Potential QT prolongation has been reported in case reports with metronidazole.
    Isoflurane: (Major) Potential QT prolongation has been reported in limited case reports with metronidazole. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with metronidazole include halogenated anesthetics.
    Itraconazole: (Major) Itraconazole has been associated with prolongation of the QT interval. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with itraconazole include metronidazole. Potential QT prolongation has been reported in limited case reports with metronidazole.
    Ixabepilone: (Severe) Medications with significant alcohol content should not be administered during therapy with metronidazole and should be avoided for 3 days after therapy is discontinued. The supplied diluent that must be used for reconstitution of ixabepilone has a high concentration of dehydrated alcohol (39.8% w/v). Administration of ixabepilone to patients receiving or who have recently received metronidazole may result in disulfiram-like reactions.
    Ketoconazole: (Major) Ketoconazole has been associated with prolongation of the QT interval. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with ketoconazole include metronidazole. Potential QT prolongation has been reported in limited case reports with metronidazole.
    Lapatinib: (Major) Potential QT prolongation has been reported in limited case reports with metronidazole. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with metronidazole include lapatinib.
    Lenvatinib: (Major) Potential QT prolongation has been reported in limited case reports with metronidazole. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with metronidazole include lenvatinib. QT prolongation was reported in patients with radioactive iodine-refractory differentiated thyroid cancer (RAI-refractory DTC) in a double-blind, randomized, placebo-controlled clinical trial after receiving lenvatinib daily at the recommended dose; the QT/QTc interval was not prolonged, however, after a single 32 mg dose (1.3 times the recommended daily dose) in healthy subjects.
    Leuprolide; Norethindrone: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available.
    Levofloxacin: (Major) Potential QT prolongation has been reported in limited case reports with metronidazole. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with metronidazole include levofloxacin.
    Levonorgestrel: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available.
    Lithium: (Moderate) Monitor serum lithium concentrations and serum creatinine with the concomitant use of systemic metronidazole and lithium. In patients stabilized on relatively high doses of lithium, short-term metronidazole use has been associated with elevation of serum lithium concentrations and, in a few cases, signs of lithium toxicity. Lithium toxicity may lead to renal damage. Additionally, lithium has been associated with QT prolongation and should be used cautiously and with close monitoring with other drugs with the potential to prolong the QT interval such as metronidazole.
    Lofexidine: (Moderate) Monitor ECG if lofexidine is coadministered with metronidazole due to the potential for additive QT prolongation. Lofexidine prolongs the QT interval. In addition, there are postmarketing reports of torsade de pointes. Potential QT prolongation has been reported in limited case reports with metronidazole.
    Long-acting beta-agonists: (Moderate) Potential QT prolongation has been reported in limited case reports with metronidazole. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously with metronidazole include beta-agonists.
    Loperamide: (Moderate) Loperamide should be used cautiously and with close monitoring with metronidazole. Potential QT prolongation has been reported in limited case reports with metronidazole and high doses of loperamide have been associated with serious cardiac toxicities, including syncope, ventricular tachycardia, QT prolongation, torsade de pointes (TdP), and cardiac arrest. Coadministration may further increase the risk of QT prolongation and TdP.
    Loperamide; Simethicone: (Moderate) Loperamide should be used cautiously and with close monitoring with metronidazole. Potential QT prolongation has been reported in limited case reports with metronidazole and high doses of loperamide have been associated with serious cardiac toxicities, including syncope, ventricular tachycardia, QT prolongation, torsade de pointes (TdP), and cardiac arrest. Coadministration may further increase the risk of QT prolongation and TdP.
    Lopinavir; Ritonavir: (Major) Medications with significant alcohol content should not be ingested during therapy with metronidazole and should be avoided for 3 days after therapy is discontinued. Oral solutions of ritonavir contain ethanol. Administration of ritonavir oral solution to patients receiving or who have recently received disulfiram or metronidazole may result in disulfiram-like reactions. A disulfiram reaction would not be expected to occur with non-ethanol containing formulations. Addtionally, potential QT prolongation has been reported in limited case reports with metronidazole; therefore, it should be used cautiously and with close monitoring when administered with ritonavir, which has a possible risk for QT prolongation and TdP. (Major) QT prolongation has been reported with metronidazole therapy; therefore, it should be used cautiously and with close monitoring when administered with lopinavir; ritonavir, which also has a possible risk for QT prolongation. Additionally, oral solutions of lopinavir; ritonavir contain ethanol. Medications with significant alcohol content should not be ingested during therapy with metronidazole and should be avoided for 3 days after metronidazole is discontinued. Administration of lopinavir; ritonavir oral solution to patients receiving or who have recently received metronidazole may result in disulfiram-like reactions. A disulfiram reaction would not be expected to occur with non-ethanol containing formulations of lopinavir; ritonavir.
    Maprotiline: (Major) Potential QT prolongation has been reported in limited case reports with metronidazole. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with metronidazole include maprotiline.
    Mebendazole: (Major) Avoid the concomitant use of mebendazole and metronidazole. Serious skin reactions, such as Stevens-Johnson syndrome and toxic epidermal necrolysis, have been reported with coadministration.
    Mefloquine: (Major) Potential QT prolongation has been reported in limited case reports with metronidazole. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with metronidazole include mefloquine.
    Meperidine; Promethazine: (Moderate) Promethazine carries a possible risk of QT prolongation. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously with promethazine include metronidazole.
    Mestranol; Norethindrone: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available.
    Methadone: (Major) Potential QT prolongation has been reported in limited case reports with metronidazole. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with metronidazole include methadone.
    Methylergonovine: (Major) Coadministration of certain ergot alkaloids with inhibitors of CYP3A4, such as metronidazole, may potentially increase the risk of ergot toxicity presenting as severe peripheral vasospasm with possible ischemia, potentially leading to gangrene, cyanosis, stroke, numbness of the extremities and/or other serious effects.
    Methysergide: (Major) Methysergide may be metabolized via CYP3A4. The risk of ergot toxicity is potentially increased by the use of CYP3A4 inhibitors including metronidazole.
    Midostaurin: (Major) The concomitant use of midostaurin and metronidazole may lead to additive QT interval prolongation. If these drugs are used together, consider electrocardiogram monitoring. In clinical trials, QT prolongation has been reported in patients who received midostaurin as single-agent therapy or in combination with cytarabine and daunorubicin. QT prolongation has been reported in a limited number of case reports with metronidazole use.
    Mifepristone: (Moderate) Potential QT prolongation has been reported in limited case reports with metronidazole. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously with metronidazole include mifepristone.
    Mirtazapine: (Moderate) There may be an increased risk for QT prolongation and torsade de pointes (TdP) during concurrent use of mirtazapine and metronidazole. Coadminister with caution. Potential QT prolongation has been reported in limited case reports with metronidazole. Cases of QT prolongation, TdP, ventricular tachycardia, and sudden death have been reported during postmarketing use of mirtazapine, primarily following overdose or in patients with other risk factors for QT prolongation, including concomitant use of other medications associated with QT prolongation.
    Moxifloxacin: (Major) Potential QT prolongation has been reported in limited case reports with metronidazole. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with metronidazole include moxifloxacin.
    Mycophenolate: (Moderate) Coadministration of mycophenolate mofetil, norfloxacin, and metronidazole is not recommended. Administration of all 3 drugs significantly reduced the systemic exposure of mycophenolic acid. Specifically, as compared with the value obtained with mycophenolate mofetil monotherapy, the mean mycophenolic acid AUC (0 to 48 h) was decreased by 33% when 1 gram of mycophenolate mofetil was administered to healthy patients who had received 4 days of both norfloxacin and metronidazole. The mycophenolic acid systemic exposure was slightly reduced when mycophenolate mofetil was coadministered with either norfloxacin or metronidazole. The mean (+/-SD) mycophenolic acid AUC (0 to 48 h) was 56.2 (+/-24) mcgh/ml after mycophenolate mofetil monotherapy, 48.3 (+/-24) mcgh/ml after coadministration with norfloxacin, and 42.7 (+/-23) mcgh/ml after coadministration with metronidazole. Addtionally, potential QT prolongation has been reported in limited case reports with metronidazole; therefore, it should be used cautiously when adminstered with norfloxacin, which has a possible risk for QT prolongation and TdP.
    Nilotinib: (Major) Avoid the concomitant use of nilotinib and metronidazole; significant prolongation of the QT interval may occur. Sudden death and QT prolongation have been reported in patients who received nilotinib therapy. Potential QT prolongation has been reported with metronidazole use in limited case reports.
    Norethindrone: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available.
    Norgestrel: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available.
    Nortriptyline: (Minor) Coadministration of metronidazole with tricyclic antidepressants (TCAs) may increase the risk for QT prolongation. Potential QT prolongation has been reported in limited case reports with metronidazole. Tricyclic antidepressants share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations).
    Octreotide: (Moderate) Potential QT prolongation has been reported in limited case reports with metronidazole. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously with metronidazole include octreotide.
    Ofloxacin: (Major) Potential QT prolongation has been reported in limited case reports with metronidazole. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with metronidazole include ofloxacin.
    Olanzapine: (Moderate) Potential QT prolongation has been reported in limited case reports with metronidazole. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously with metronidazole include olanzapine.
    Ombitasvir; Paritaprevir; Ritonavir: (Major) Medications with significant alcohol content should not be ingested during therapy with metronidazole and should be avoided for 3 days after therapy is discontinued. Oral solutions of ritonavir contain ethanol. Administration of ritonavir oral solution to patients receiving or who have recently received disulfiram or metronidazole may result in disulfiram-like reactions. A disulfiram reaction would not be expected to occur with non-ethanol containing formulations. Addtionally, potential QT prolongation has been reported in limited case reports with metronidazole; therefore, it should be used cautiously and with close monitoring when administered with ritonavir, which has a possible risk for QT prolongation and TdP.
    Ondansetron: (Major) Potential QT prolongation has been reported in limited case reports with metronidazole. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with metronidazole include ondansetron.
    Oral Contraceptives: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available.
    Osimertinib: (Major) Avoid coadministration of metronidazole with osimertinib if possible due to the risk of QT prolongation and torsade de pointes (TdP). If concomitant use is unavoidable, periodically monitor ECGs for QT prolongation and monitor electrolytes; an interruption of osimertinib therapy with dose reduction or discontinuation of therapy may be necessary if QT prolongation occurs. Concentration-dependent QTc prolongation occurred during clinical trials of osimertinib. Potential QT prolongation has been reported in limited case reports with metronidazole.
    Oxaliplatin: (Major) Monitor electrolytes and ECGs for QT prolongation if coadministration of metronidazole with oxaliplatin is necessary; correct electrolyte abnormalities prior to administration of oxaliplatin. QT prolongation and ventricular arrhythmias including fatal torsade de pointes have been reported with oxaliplatin use in postmarketing experience. Potential QT prolongation has also been reported in limited case reports with metronidazole.
    Paclitaxel: (Major) Medications with significant alcohol content should not be ingested during therapy with metronidazole and should be avoided for 3 days after therapy is discontinued. Some formulations of paclitaxel contain a high level of ethanol. Administration to patients receiving or who have recently received metronidazole may result in disulfiram-like reactions. A disulfiram reaction would not be expected to occur with non-ethanol containing formulations.
    Paliperidone: (Major) Paliperidone has been associated with QT prolongation. According to the manufacturer, since paliperidone may prolong the QT interval, it should be avoided in combination with other agents also known to have this effect. Potential QT prolongation has been reported in limited case reports with metronidazole. If coadministration is necessary and the patient has known risk factors for cardiac disease or arrhythmias, close monitoring is essential.
    Panobinostat: (Major) The co-administration of panobinostat with metronidazole or metronidazole combination products is not recommended; QT prolongation has been reported with panobinostat and metronidazole. Obtain an electrocardiogram at baseline and periodically during treatment. Hold panobinostat if the QTcF increases to >= 480 milliseconds during therapy; permanently discontinue if QT prolongation does not resolve.
    Pasireotide: (Major) Potential QT prolongation has been reported in limited case reports with metronidazole. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with metronidazole include pasireotide.
    Pazopanib: (Major) Potential QT prolongation has been reported in limited case reports with metronidazole. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with metronidazole include pazopanib.
    Pentamidine: (Major) Potential QT prolongation has been reported in limited case reports with metronidazole. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with metronidazole include pentamidine.
    Perphenazine: (Minor) Potential QT prolongation has been reported in limited case reports with metronidazole. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously with metronidazole include perphenazine.
    Perphenazine; Amitriptyline: (Minor) Coadministration of metronidazole with tricyclic antidepressants (TCAs) may increase the risk for QT prolongation. Potential QT prolongation has been reported in limited case reports with metronidazole. Tricyclic antidepressants share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). (Minor) Potential QT prolongation has been reported in limited case reports with metronidazole. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously with metronidazole include perphenazine.
    Phenylephrine; Promethazine: (Moderate) Promethazine carries a possible risk of QT prolongation. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously with promethazine include metronidazole.
    Phenytoin: (Minor) Monitor serum concentrations of phenytoin when coadministered with systemic metronidazole. Concomitant use with metronidazole may increase the serum concentrations of phenytoin; thereby, increasing the risk of side effects.
    Pimavanserin: (Major) Pimavanserin may cause QT prolongation and should generally be avoided in patients receiving other medications known to prolong the QT interval, such as metronidazole. Potential QT prolongation has been reported in limited case reports with metronidazole. Coadministration may increase the risk for QT prolongation.
    Pimozide: (Severe) Potential QT prolongation has been reported in limited case reports with metronidazole. Because of the potential for TdP, use of pimozide with metronidazole is contraindicated.
    Posaconazole: (Major) Potential QT prolongation has been reported in limited case reports with metronidazole. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with metronidazole include posaconazole.
    Primaquine: (Major) Due to the potential for QT interval prolongation with primaquine, caution is advised with other drugs that prolong the QT interval. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with primaquine include metronidazole.
    Procainamide: (Major) Potential QT prolongation has been reported in limited case reports with metronidazole. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with metronidazole include procainamide.
    Prochlorperazine: (Minor) Potential QT prolongation has been reported in limited case reports with metronidazole. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously with metronidazole include prochlorperazine.
    Promethazine: (Moderate) Promethazine carries a possible risk of QT prolongation. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously with promethazine include metronidazole.
    Propafenone: (Major) Potential QT prolongation has been reported in limited case reports with metronidazole. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with metronidazole include propafenone.
    Protriptyline: (Minor) Coadministration of metronidazole with tricyclic antidepressants (TCAs) may increase the risk for QT prolongation. Potential QT prolongation has been reported in limited case reports with metronidazole. Tricyclic antidepressants share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations).
    Quetiapine: (Major) Potential QT prolongation has been reported in limited case reports with metronidazole. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with metronidazole include quetiapine.
    Quinidine: (Major) Potential QT prolongation has been reported in limited case reports with metronidazole. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with metronidazole include quinidine, (including dextromethorphan; quinidine),
    Ramelteon: (Moderate) Coadministration of ramelteon with inhibitors of CYP2C9, such as metronidazole, may lead to increases in the serum concentrations of ramelteon.
    Ranolazine: (Major) Potential QT prolongation has been reported in limited case reports with metronidazole. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with metronidazole include ranolazine.
    Regadenoson: (Moderate) Potential QT prolongation has been reported in limited case reports with metronidazole. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously with metronidazole include regadenoson.
    Ribociclib: (Major) Avoid coadministration of ribociclib with metronidazole due to an increased risk for QT prolongation. Ribociclib has been shown to prolong the QT interval in a concentration-dependent manner. Potential QT prolongation has been reported in limited case reports with metronidazole. Concomitant use may increase the risk for QT prolongation.
    Ribociclib; Letrozole: (Major) Avoid coadministration of ribociclib with metronidazole due to an increased risk for QT prolongation. Ribociclib has been shown to prolong the QT interval in a concentration-dependent manner. Potential QT prolongation has been reported in limited case reports with metronidazole. Concomitant use may increase the risk for QT prolongation.
    Rilpivirine: (Major) Potential QT prolongation has been reported in limited case reports with metronidazole. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with metronidazole include rilpivirine.
    Risperidone: (Major) Potential QT prolongation has been reported in limited case reports with metronidazole. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with metronidazole include risperidone.
    Ritonavir: (Major) Medications with significant alcohol content should not be ingested during therapy with metronidazole and should be avoided for 3 days after therapy is discontinued. Oral solutions of ritonavir contain ethanol. Administration of ritonavir oral solution to patients receiving or who have recently received disulfiram or metronidazole may result in disulfiram-like reactions. A disulfiram reaction would not be expected to occur with non-ethanol containing formulations. Addtionally, potential QT prolongation has been reported in limited case reports with metronidazole; therefore, it should be used cautiously and with close monitoring when administered with ritonavir, which has a possible risk for QT prolongation and TdP.
    Romidepsin: (Major) Potential QT prolongation has been reported in limited case reports with metronidazole. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with metronidazole include romidepsin.
    Saquinavir: (Major) Potential QT prolongation has been reported in limited case reports with metronidazole. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with metronidazole include saquinavir.
    Sertraline: (Major) There have been postmarketing reports of QT prolongation and torsade de pointes (TdP) during treatment with sertraline and the manufacturer of sertraline recommends avoiding concurrent use with drugs known to prolong the QTc interval. Potential QT prolongation has been reported in limited case reports with metronidazole. In addition, medications with alcohol content, such as sertraline oral solution, should not be ingested during therapy with metronidazole and should be avoided for 3 days after therapy is discontinued. Oral solutions of sertraline contain a high-percentage of alcohol and although infrequent, may cause disulfiram-like reactions in patients taking metronidazole concurrently.
    Sevoflurane: (Major) Potential QT prolongation has been reported in limited case reports with metronidazole. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with metronidazole include halogenated anesthetics.
    Short-acting beta-agonists: (Minor) Potential QT prolongation has been reported in limited case reports with metronidazole. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously with metronidazole include beta-agonists.
    Sirolimus: (Moderate) Although an interaction between metronidazole and sirolimus has not been studied, metronidazole has been reported to interact with tacrolimus. Specifically, a renal transplant patient reportedly had an increase in tacrolimus and cyclosporine serum concentrations when metronidazole was added to the drug regimen. A similar interaction may potentially occur with sirolimus.
    Sodium picosulfate; Magnesium oxide; Anhydrous citric acid: (Major) Prior or concomitant use of antibiotics with sodium picosulfate; magnesium oxide; anhydrous citric acid may reduce efficacy of the bowel preparation as conversion of sodium picosulfate to its active metabolite bis-(p-hydroxy-phenyl)-pyridyl-2-methane (BHPM) is mediated by colonic bacteria. If possible, avoid coadministration. Certain antibiotics (i.e., tetracyclines and quinolones) may chelate with the magnesium in sodium picosulfate; magnesium oxide; anhydrous citric acid solution. Therefore, these antibiotics should be taken at least 2 hours before and not less than 6 hours after the administration of sodium picosulfate; magnesium oxide; anhydrous citric acid solution.
    Solifenacin: (Moderate) Potential QT prolongation has been reported in limited case reports with metronidazole. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously with metronidazole include solifenacin.
    Sorafenib: (Major) Potential QT prolongation has been reported in limited case reports with metronidazole. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with metronidazole include sorafenib.
    Sotalol: (Major) Potential QT prolongation has been reported in limited case reports with metronidazole. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with metronidazole include sotalol.
    Sulfamethoxazole; Trimethoprim, SMX-TMP, Cotrimoxazole: (Major) Potential QT prolongation has been reported in limited case reports with metronidazole; therefore, it should be used cautiously when adminstered with sulfamethoxazole; trimethoprim, which has a possible risk for QT prolongation and TdP. Also, medications with significant alcohol content should not be ingested during therapy with metronidazole and should be avoided for 3 days after therapy is discontinued. Intravenous sulfamethoxazole; trimethoprim, SMX-TMP contains ethanol. A disulfiram-like reaction has occurred when metronidazole was used with IV sulfamethoxazole; trimethoprim, SMX-TMP. This reaction would not be expected to occur with oral sulfamethoxazole; trimethoprim, SMX-TMP.
    Sunitinib: (Major) Monitor patients for QT prolongation if coadministration of metronidazole with sunitinib is necessary. Sunitinib can cause dose-dependent QT prolongation, which may increase the risk for ventricular arrhythmias, including torsades de points (TdP). Potential QT prolongation has also been reported in limited case reports with metronidazole.
    Tacrolimus: (Major) Monitor patients for signs and symptoms of QT prolongation with coadministration of systemic metronidazole and tacrolimus. QT prolongation has been associated with the use of both agents; therefore, concomitant use may increase this risk.
    Tamoxifen: (Moderate) Caution is advised with the concomitant use of tamoxifen and metronidazole due to an increased risk of QT prolongation. Tamoxifen has been reported to prolong the QT interval, usually in overdose or when used in high doses. Rare case reports of QT prolongation have also been described when tamoxifen is used at lower doses. Potential QT prolongation has been reported in limited case reports with metronidazole.
    Telavancin: (Major) Potential QT prolongation has been reported in limited case reports with metronidazole. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with metronidazole include telavancin.
    Telithromycin: (Major) Potential QT prolongation has been reported in limited case reports with metronidazole. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with metronidazole include telithromycin.
    Tetrabenazine: (Major) Avoid coadministration of tetrabenazine and metronidazole due to the potential for QT prolongation. Tetrabenazine causes a small increase in the corrected QT interval (QTc). Potential QT prolongation has also been reported in limited case reports with metronidazole.
    Thalidomide: (Moderate) Thalidomide and other agents that cause peripheral neuropathy such as metronidazole should be used cautiously due to the potential for additive effects.
    Thioridazine: (Severe) Potential QT prolongation has been reported in limited case reports with metronidazole. Because of the potential for TdP, use of thioridazine with metronidazole is contraindicated.
    Tipranavir: (Major) Medications with significant alcohol content should not be ingested during therapy with metronidazole and should be avoided for 3 days after therapy is discontinued. The Aptivus brand of tipranavir capsules contain alcohol. Administration of Aptivus capsules to patients receiving or who have recently received metronidazole may result in disulfiram-like reactions. A disulfiram reaction would not be expected to occur with non-ethanol containing formulations.
    Tizanidine: (Moderate) Tizanidine should be used cautiously and with close monitoring with metronidazole. Tizanidine administration may result in QT prolongation. Potential QT prolongation has been reported in limited case reports with metronidazole. Coadministration increases the risk for QT prolongation and torsade de pointes.
    Tolterodine: (Moderate) Potential QT prolongation has been reported in limited case reports with metronidazole. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously with metronidazole include tolterodine.
    Toremifene: (Major) Avoid coadministration of metronidazole with toremifene if possible due to the risk of additive QT prolongation. If concomitant use is unavoidable, closely monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia or hypomagnesemia prior to administration of toremifene. Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner. Potential QT prolongation has been reported in limited case reports with metronidazole.
    Trazodone: (Major) Potential QT prolongation has been reported in limited case reports with metronidazole. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with metronidazole include trazodone.
    Tricyclic antidepressants: (Minor) Coadministration of metronidazole with tricyclic antidepressants (TCAs) may increase the risk for QT prolongation. Potential QT prolongation has been reported in limited case reports with metronidazole. Tricyclic antidepressants share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations).
    Trifluoperazine: (Minor) Potential QT prolongation has been reported in limited case reports with metronidazole. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously with metronidazole include trifluoperazine.
    Trimipramine: (Minor) Coadministration of metronidazole with tricyclic antidepressants (TCAs) may increase the risk for QT prolongation. Potential QT prolongation has been reported in limited case reports with metronidazole. Tricyclic antidepressants share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations).
    Vandetanib: (Major) The manufacturer of vandetanib recommends avoiding coadministration with other drugs that prolong the QT interval due to an increased risk of QT prolongation and torsade de pointes (TdP). Vandetanib can prolong the QT interval in a concentration-dependent manner. TdP and sudden death have been reported in patients receiving vandetanib. Potential QT prolongation has been reported in limited case reports with metronidazole. If coadministration is necessary, an ECG is needed, as well as more frequent monitoring of the QT interval. If QTcF is greater than 500 msec, interrupt vandetanib dosing until the QTcF is less than 450 msec; then, vandetanib may be resumed at a reduced dose.
    Vardenafil: (Major) Potential QT prolongation has been reported in limited case reports with metronidazole. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with metronidazole include vardenafil.
    Vecuronium: (Minor) Caution is warranted with the coadministration of systemic metronidazole and vecuronium. Metronidazole may potentiate the effects of vecuronium.
    Vemurafenib: (Major) Potential QT prolongation has been reported in limited case reports with metronidazole. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with metronidazole include vemurafenib.
    Venlafaxine: (Moderate) Coadministration of metronidazole and venlafaxine may increase the risk for QT prolongation and torsade de pointes (TdP). Potential QT prolongation has been reported in limited case reports with metronidazole. Venlafaxine administration is associated with a possible risk of QT prolongation; torsade de pointes (TdP) has reported with postmarketing use.
    Voriconazole: (Major) Potential QT prolongation has been reported in limited case reports with metronidazole. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with metronidazole include voriconazole.
    Vorinostat: (Moderate) Potential QT prolongation has been reported in limited case reports with metronidazole. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously with metronidazole include vorinostat.
    Warfarin: (Major) Monitor prothrombin time and INR and watch for signs of bleeding with concomitant use of systemic metronidazole and warfarin. Warfarin dose adjustments may be necessary. Metronidazole can potentiate the anticoagulant effect of warfarin, resulting in prolongation of prothrombin time and increased risk of bleeding.
    Zalcitabine, ddC: (Moderate) It is recommended that zalcitabine, ddC not be used in combination with metronidazole due to additive peripheral neuropathy seen with concomitant use.
    Ziprasidone: (Severe) Potential QT prolongation has been reported in limited case reports with metronidazole. Because of the potential for TdP, use of ziprasidone with metronidazole is contraindicated.

    PREGNANCY AND LACTATION

    Pregnancy

    According to the manufacturer, oral metronidazole is contraindicated during the first trimester of pregnancy in patients with trichomoniasis. However, the CDC states that metronidazole can be used for trichomoniasis at any stage of pregnancy as studies have not demonstrated an association between metronidazole and teratogenic effects. For indications other than trichomoniasis, avoid metronidazole during pregnancy whenever possible, with use occurring only after careful assessment of the potential risk to benefit ratio. While not an animal teratogen, systemically absorbed metronidazole readily crosses the placenta and enters the fetal circulation. Reports in humans are conflicting, and the effects of metronidazole on human fetal organogenesis are not known. In a large population-based cohort study (n = 139,938 live births) assessing antibiotic exposure during the first trimester of pregnancy (n = 15,469 exposures) and the risk of major birth defects, metronidazole use was not associated with an increased risk of major congenital malformations (MCMs) or organ specific MCMs. However, in a nested, case-control study (n = 87,020 controls; 8,702 cases) within the Quebec Pregnancy Cohort, metronidazole use during early pregnancy was associated with an increased risk of spontaneous abortion (adjusted odds ratio (aOR) 1.7; 95% CI: 1.27 to 2.26; 53 exposed cases); residual confounding by severity of infection may be a potential limitation of this study.

    Metronidazole is excreted into breast milk. Breast-feeding is not recommended during treatment with systemic products. While there is some systemic absorption from topical and vaginal products, plasma concentrations would be lower than demonstrated with systemic formulations; however, caution is still advised. Metronidazole is a mutagen in vitro and has been shown to be carcinogenic in animal studies. In general, increased oral and rectal Candida colonization and loose stools have been reported in infants exposed to metronidazole via breast milk. The CDC recommends a single 2 g oral dose for the treatment of trichomoniasis during breast-feeding. Previous American Academy of Pediatrics (AAP) recommendations stated that if a single 2 g oral dose is given for trichomoniasis, then breast-feeding may be resumed in 12 to 24 hours. Otherwise, if other dosage regimens are used, breast-feeding may be resumed within 24 to 48 hours after the last dose of treatment is completed. In a study of 3 patients that received a single 2 g oral dose, peak milk concentrations ranged between 50 to 60 mcg/mL at 2 to 4 hours after the dose. If breast-feeding were to continue, the estimated infant exposure during the next 48 hours would be 25.3 mg; if breast-feeding was interrupted for 12 hours, the estimated 48 hour exposure would be 9.8 mg, and if breast-feeding was interrupted for 24 hours, the estimated 48 hour exposure would be 3.5 mg. In studies of women receiving 600 mg/day, metronidazole milk concentrations ranged from 1.1 to 15.2 mcg/mL and in patients receiving 1200 mg/day concentrations ranged from 9.02 to 15.52 mcg/mL. The mean milk:plasma ratio in both groups was approximately 1, and the mean plasma concentrations in the exposed infants were approximately 20% of the maternal plasma concentration. Depending on the indication, oral vancomycin, amoxicillin; clavulanate, ampicillin; sulbactam, or clindamycin (systemic or intravaginal) may be potential alternatives to consider during breast-feeding. Site of infection, patient factors, local susceptibility patterns, and specific microbial susceptibility should be assessed before choosing an alternative agent. Vancomycin is excreted in breast milk; however, absorption from the GI tract of any ingested vancomycin would be minimal. Alternative antimicrobials that previous AAP recommendations considered as usually compatible with breast-feeding include clindamycin and penicillins.

    MECHANISM OF ACTION

    Metronidazole is amebicidal, bactericidal, and trichomonicidal. Unionized metronidazole is readily taken up by passive diffusion and activated in the cytoplasm of susceptible anaerobic organisms and cells. Its selectivity for anaerobic bacteria is a result of the ability of these organisms to reduce metronidazole to its active form intracellularly. This process includes intracellular electron transport proteins such as ferredoxin, transfer of an electron to the nitro group of the metronidazole, and formation of a short-lived nitroso free radical. The electron transport proteins necessary for this reaction are found only in anaerobic bacteria. Due to the alteration of the metronidazole molecule, a concentration gradient is created and maintained which promotes the drug's intracellular transport. Reduced metronidazole and free radicals can interact with DNA, which leads to inhibition of DNA synthesis and DNA degradation. The effects on DNA eventually result in bacterial cell death. Metronidazole is equally effective against dividing and nondividing cells. The precise mechanism of action is unclear.
     
    Metronidazole also has immunosuppressive and antiinflammatory actions, and it has been used in patients with rosacea. The antimicrobial actions of metronidazole alter the bacterial metabolism of bile acids in the GI tract, decreasing pruritus in patients with cholestasis secondary to primary biliary cirrhosis.

    PHARMACOKINETICS

    Metronidazole is administered orally, intravenously, intravaginally, and topically. Protein binding is less than 20%. Metronidazole is widely distributed into various body tissues and fluids including cerebrospinal fluid (CSF), pelvic tissue and peritoneal fluid, pancreas, colorectal tissue, bone, saliva, and gingival fluid. CSF concentrations of metronidazole are similar to plasma concentrations. Bactericidal concentrations of metronidazole have also been detected in pus from hepatic abscesses.
     
    Metronidazole is extensively metabolized in the liver by hydroxylation, oxidation, and glucuronide conjugation. The major metabolite is 2-hydroxymethyl metronidazole, which has some antibacterial and antiprotozoal activity (30% to 65% of metronidazole). The major route of elimination of metronidazole and its metabolites is via the urine (60% to 80% of the dose), with approximately 20% appearing as unchanged metronidazole. Fecal excretion accounts for 6% to 15% of the dose. Metronidazole is cleared by the kidneys at a rate of 10 mL/minute/1.73 m2. The mean elimination half-life is approximately 8 hours.
     
    Affected cytochrome P450 isoenzymes and drug transporters: none
    Although previously reported as an inhibitor of CYP3A4 based on assumptions inferred from isolated case reports, controlled in vitro and in vivo studies show that metronidazole does not significantly inhibit CYP3A4/5 activity. Additionally, a study in humans examined S-warfarin and tolbutamide as probes for the CYP2C9 isoenzyme. Metronidazole interacted with S-warfarin, but not tolbutamide. This lessens the likelihood of a potential CYP2C9 interaction, which was originally postulated. It is unknown whether metronidazole alters transport proteins.

    Oral Route

    Immediate-release formulations
    Metronidazole is well absorbed after oral administration (bioavailability more than 90%). Peak concentrations (Cmax) occur 1 to 2 hours after administration.
     
    Extended-release tablets
    Food increases the rate of absorption. The Cmax occurs approximately 4.6 and 6.8 hours after administration under fed and fasted conditions, respectively.

    Intravenous Route

    After IV administration, the plasma concentrations are proportional to the administered dose. An 8-hour IV infusion of 100 to 4,000 mg of metronidazole showed a linear relationship between dose and peak plasma concentration.

    Topical Route

    Topically applied metronidazole products are only minimally absorbed. Peak concentrations of the lotion are approximately 80 times lower than the peak concentrations of a single 250 mg oral dose. The mean Cmax and AUC are less than 1% of the value reported for a single 250 mg oral dose.

    Other Route(s)

    Intravaginal Route
    Intravaginally administered metronidazole is absorbed systemically; but peak serum concentrations (Cmax) and exposure (AUC) are 2% and 4%, respectively, of the concentrations achieved with 500 mg oral doses. The Cmax is achieved approximately 9.5 hours (range, 4 to 17 hours) after administration.