46067 30 AHFS Essentials ASHPI BATCH LEFT top of rh base of rh Metronidazole Bacterial Vaginosis Metronidazole (Systemic) Antibacterial and antiprotozoal; nitroimidazole derivative. Class: Antiprotozoals, Miscellaneous 8:30.92 (AHFS primary); AP100 (VA primary) Brands: Flagyl I.V.; Flagyl; Flagyl ER; Flagyl I.V. RTU; Helidac Therapy; also available generically Boxed Warning • • Carcinogenic in mice and rats. Avoid unnecessary use; reserve for use in approved indications. (See Uses.) Uses cap height base of text Treatment of bacterial vaginosis (formerly called Haemophilus vaginitis, Gardnerella vaginitis, nonspeciﬁc vaginitis, Corynebacterium vaginitis, or anaerobic vaginosis) in pregnant or nonpregnant women. CDC recommends treatment of bacterial vaginosis in all symptomatic nonpregnant women, in symptomatic pregnant women, and asymptomatic pregnant women at high risk for complications of pregnancy. Treatment recommendations for bacterial vaginosis in HIV-infected women are the same as those for women without HIV infection. Regimens of choice in nonpregnant women are a 7-day regimen of oral metronidazole; a 5-day regimen of intravaginal metronidazole; or a 7-day regimen of intravaginal clindamycin; alternative regimens are a single oral dose of metronidazole; 7-day regimen of oral clindamycin; or 3- to 7-day regimen of intravaginal clindamycin. The preferred regimens for symptomatic or asymptomatic pregnant women at high risk are a 7-day regimen of oral metronidazole or a 7-day regimen of oral clindamycin. Regardless of regimen used, relapse or recurrence is common; an alternative regimen (e.g., topical therapy when oral therapy was used initially) may be used in such situations. Long-term maintenance therapy does not appear to be beneﬁcial in women with recurrent or relapsing disease and is not recommended. Balantidiasis Alternative to tetracycline for treatment of balantidiasis† caused by Balantidium coli. Bone and Joint Infections Adjunct for treatment of bone and joint infections caused by Bacteroides, including the B. fragilis group (B. fragilis, B. distasonis, B. ovatus, B. thetaiotaomicron, B. vulgatus). Endocarditis Treatment of endocarditis caused by Bacteroides (including the B. fragilis group). Gynecologic Infections Treatment of gynecologic infections (including endometritis, endomyometritis, tubo-ovarian abscess, postsurgical vaginal cuff infection) caused by Bacteroides (including the B. fragilis group), Clostridium, Peptococcus niger, or Peptostreptococcus. Treatment of acute pelvic inﬂammatory disease (PID); used in conjunction with other anti-infectives. Metronidazole is included in PID regimens to provide coverage against anaerobes. When a parenteral regimen is indicated for PID and tubo-ovarian abscess is present, a regimen of metronidazole (or clindamycin) and doxycycline has been recommended. An alternative parenteral regimen is IV oﬂoxacin (or IV levoﬂoxacin) given with or without IV metronidazole. When an oral regimen is indicated for PID, oral oﬂoxacin (or oral levoﬂoxacin) with or without oral metronidazole is one of several regimens recommended by CDC and others. Intra-abdominal Infections Treatment of intra-abdominal infections (including peritonitis, intra-abdominal abscess, liver abscess) caused by susceptible Bacteroides (including the B. fragilis group), Clostrium, Eubacterium, P. niger, or Peptostreptococcus. Blastocystis hominis Infections Treatment of infections caused by Blastocystis hominis†. May be effective, but metronidazole resistance may be common. Clinical importance of B. hominis as a cause of GI pathology is controversial; unclear when treatment is indicated. Some clinicians suggest treatment be reserved for certain individuals (e.g., immunocompromised patients) when symptoms persist and no other pathogen or process is found to explain their GI symptoms. Clostridium difﬁcile-associated Diarrhea and Colitis Treatment of Clostridium difﬁcile-associated diarrhea and colitis† (CDAD; also known as antibiotic-associated diarrhea and colitis, C. difﬁcile diarrhea, C. difﬁcile colitis, and pseudomembranous colitis). Drugs of choice are metronidazole and vancomycin; metronidazole generally preferred and vancomycin reserved for those with severe or potentially life-threatening colitis, patients in whom metronidazole-resistant C. difﬁcile is suspected, patients in whom metronidazole is contraindicated or not tolerated, or those who do not respond to metronidazole. Crohn’s Disease Mangement of Crohn’s disease† as an adjunct to conventional therapies. Has been used with or without ciproﬂoxacin; for induction of remission of mildly to moderately active Crohn’s disease†. Has been used for refractory perianal Crohn’s disease†. Dientamoeba fragilis Infections Treatment of infections caused by Dientamoeba fragilis†. Drugs of choice are iodoquinol, paromomycin, tetracycline, or metronidazole. Meningitis and Other CNS Infections Dracunculiasis Treatment of CNS infections (including meningitis, brain abscess) caused by Bac- Treatment of dracunculiasis† caused by Dracunculus medinensis (guinea worm teroides (including the B. fragilis group). Respiratory Tract Infections Treatment of respiratory tract infections (including pneumonia) caused by Bacteroides (including the B. fragilis group). Septicemia Treatment of septicemia caused by Bacteroides (including the B. fragilis group) or Clostridium. Skin and Skin Structure Infections Treatment of skin and skin structure infections caused by Bacteroides (including disease). Treatment of choice is slow extraction of worm combined with wound care. Metronidazole is not curative, but decreases inﬂammation and facilitates worm removal. Giardiasis Treatment of giardiasis†. Drugs of choice are metronidazole, tinidazole, or nitazoxanide; alternatives are paromomycin, furazolidone (no longer commercially available in the US), or quinacrine (not commercially available in the US). Treatment of asymptomatic carriers of giardiasis†. Treatment of such carriers not generally recommended, except possibly in patients with hypogammaglobulinemia or cystic ﬁbrosis or in an attempt to prevent household transmission of the disease from toddlers to pregnant women. the B. fragilis group), Clostridium, Fusobacterium, P. niger, or Peptostreptococcus. Helicobacter pylori Infection and Duodenal Ulcer Disease Amebiasis Treatment of acute intestinal amebiasis and amebic liver abscess caused by Entamoeba histolytica. Oral metronidazole or oral tinidazole followed by a luminal amebicide (iodoquinol, paromomycin) is the regimen of choice for mild to moderate or severe intestinal disease and for amebic hepatic abscess. Treatment of Helicobacter pylori infection and duodenal ulcer disease (active or a history of duodenal ulcer); eradication of H. pylori has been shown to reduce the risk of duodenal ulcer recurrence. Used in a multiple-drug regimen that includes metronidazole, tetracycline, and bismuth subsalicylate and a histamine H2-receptor antagonist. If initial 14-day regi- short stand 46067 AHFS Essentials ASHPI BATCH RIGHT Metronidazole men does not eradicate H. pylori, a retreatment regimen that does not include metronidazole should be used. Nongonococcal Urethritis Treatment of recurrent and persistent urethritis† in patients with nongonococcal urethritis who have already been treated with a recommended regimen (i.e., azithromycin, doxycycline, erythromycin, oﬂoxacin or levoﬂoxacin). Metronidazole used in conjunction with erythromycin is the regimen recommended by CDC for recurrent and persistent urethritis in patients who were compliant with their initial regimen and have not been re-exposed. Available as metronidazole and metronidazole hydrochloride; dosage expressed in terms of metronidazole. Pediatric Patients General Dosage in Neonates† Oral or IV: Neonates ⬍1 week of age: AAP recommends 7.5 mg/kg every 24– 48 hours in those weighing ⬍1.2 g, 7.5 mg/kg every 24 hours in those weighing 1.2– 2 kg, or 7.5 mg/kg every 12 hours in those weighing ⬎2 kg. Neonates 1– 4 weeks of age: AAP recommends 7.5 mg/kg every 24– 48 hours in those weighing ⬍1.2 kg, 7.5 mg/kg every 12 hours in those weighing 1.2– 2 kg, and 15 mg/kg every 12 hours in those weighing ⬎2 kg. Treatment of inﬂammatory lesions (papules and pustules) and erythema associ- Tetanus Adjunct in treatment of tetanus caused by C. tetani. Trichomoniasis Treatment of symptomatic and asymptomatic trichomoniasis when Trichomonas vaginalis has been demonstrated by wet smear and/or culture. Drug of choice is metronidazole or tinidazole. Goal of treatment is to provide symptomatic relief, achieve microbiologic cure, and reduce transmission; to achieve this goal, both the index patient and sexual (particularly steady) partner(s) should be treated. Resistant infections may respond to higher metronidazole dosage or to tinidazole. Perioperative Prophylaxis Perioperative prophylaxis to reduce the incidence of postoperative anaerobic bacterial infections in patients undergoing colorectal surgery. Preferred regimens are IV cefotetan or IV cefoxitin; IV cefazolin used in conjunction with IV metronidazole; or oral erythromycin and oral neomycin. Perioperative prophylaxis in patients undergoing appendectomy†; used in conjunction with gentamicin. The preferred regimen for appendectomy (nonperforated) is IV cefotetan or IV cefoxitin. Prophylaxis in Sexual Assault Victims Empiric anti-infective prophylaxis in sexual assault victims†; used in conjunction with IM ceftriaxone and oral azithromycin or doxycycline. Dosage and Administration Administration Administer orally or by continuous or intermittent IV infusion. Do not administer by rapid IV injection because of the low pH of the reconstituted product. In the treatment of serious anaerobic infections, parenteral route usually is used initially and oral metronidazole substituted when warranted by patient’s condition. Oral Administration Administer extended-release tablets at least 1 hour before or 2 hours after meals. General Dosage in Children ⱖ1 Month of Age† Oral: 15– 35 mg/kg daily in 3 divided doses. AAP states oral route inappropriate for severe infections. Amebiasis ⬎Entamoeba histolytica Infections Oral: 35– 50 mg/kg daily in 3 divided doses given for 7– 10 (usually 10) days; follow-up with a luminal amebicide (e.g., iodoquinol, paromomycin). Bacterial Vaginosis† Oral: Children weighing ⬍45 kg: 15 mg/kg daily (up to 1 g) in 2 divided doses given for 7 days. Adolescents: 500 mg twice daily for 7 days. Balantidiasis† Oral: 35– 50 mg/kg daily in 3 divided doses given for 5 days. Blastocystis hominis Infections† Oral: 20– 35 mg/kg daily in 3 divided doses given for 10 days may improve symptoms in some patients. Crohn’s Disease† Oral: 10– 20 mg/kg daily (up to 1 g daily) has been recommended for children with mild perianal Crohn’s disease† or those intolerant to sulfasalazine or mesalamine. Clostridium difficile-associated Diarrhea and Colitis† Oral: 30– 50 mg/kg daily in 3 or 4 equally divided doses given for 7– 10 days (not to exceed adult dosage). Dientamoeba fragilis Infections† Oral: 20– 40 mg/kg daily in 3 divided doses given for 10 days. Dracunculiasis† Oral: 25 mg/kg daily (up to 750 mg) in 3 divided doses given for 10 days. Is not curative, but may decrease inﬂammation and facilitate worm removal. Giardiasis† Oral: 15 mg/kg daily in 3 divided doses given for 5– 7 days. Nongonococcal Urethritis† Oral: Adolescents: A single 2-g dose given in conjunction with a 7-day regimen of oral erythromycin. Tetanus† Oral: 30 mg/kg daily (up to 4 g daily) in 4 doses given for 10– 14 days. IV Infusion For solution and drug compatibility information, see Compatibility under Stability. Commercially available metronidazole injection for IV infusion does not need to be diluted or neutralized prior to IV administration. Metronidazole hydrochloride powder for injection must by reconstituted, diluted, and then neutralized prior to IV administration. Reconstitution and Dilution Reconstitute metronidazole hydrochloride powder for injection by adding 4.4 mL of sterile or bacteriostatic water for injection, 0.9% sodium chloride injection, or bacteriostatic sodium chloride injection to the vial containing 500 mg of metronidazole. The reconstituted solution contains approximately 100 mg of metronidazole/mL and has a pH of 0.5– 2. The reconstituted metronidazole hydrochloride solution must be further diluted with 0.9% sodium chloride injection, 5% dextrose injection, or lactated Ringer’s injection to a concentration of ⱕ8 mg/mL. The reconstituted and diluted metronidazole hydrochloride solution must then be neutralized by adding approximately 5 mEq of sodium bicarbonate injection for each 500 mg of metronidazole. The addition of sodium bicarbonate to the metronidazole hydrochloride solution may generate carbon dioxide gas and it may be necessary to relieve gas pressure in the container. Rate of Administration IV infusions usually are infused over 1 hour. top of rh base of rh cap height base of text Dosage Rosacea ated with rosacea† (acne rosacea). Topical metronidazole may be preferred to oral metronidazole. 31 IV: 30 mg/kg daily in 4 doses given for 10– 14 days. Trichomoniasis† Oral: Prepubertal children weighing ⬍45 kg: 15 mg/kg daily in 3 divided doses (up to 2 g daily) given for 7 days. Adolescents: A single 2-g dose or 500 mg twice daily for 7 days. Prophylaxis in Sexual Assault Victims† Oral: Preadolescent children weighing ⬍45 kg: 15 mg/kg daily given in 3 divided doses for 7 days given in conjunction with IM ceftriaxone and either oral azithromycin or oral erythromycin. Adolescents and preadolescent children weighing ⱖ45 kg: A single 2-g dose given in conjunction with IM ceftriaxone and either oral azithromycin or oral doxycycline. Adults Anaerobic Bacterial Infections ⬎Serious Infections Oral: 7.5 mg/kg every 6 hours. Maximum of 4 g daily. IV, then Oral: An initial IV loading dose of 15 mg/kg followed by IV maintenance doses of 7.5 mg/kg every 6 hours. After clinical improvement occurs, switch to oral metronidazole (7.5 mg/kg every 6 hours). Total duration of treatment usually is 7– 10 days, but infections of bone short stand 46067 32 AHFS Essentials ASHPI BATCH LEFT top of rh base of rh Metronidazole and joints, lower respiratory tract, or endocardium may require longer treatment. nalis is conﬁrmed by wet smear and/or culture and an interval of 4– 6 weeks has passed since the initial course. If treatment of resistant infection is guided by in vitro susceptibility testing under aerobic conditions, some clinicians recommend that T. vaginalis strains exhibiting low-level resistance (minimum lethal concentration [MLC] ⬍100 mcg/mL) be treated with 2 g daily for 3– 5 days, those with moderate (intermediate) resistance (MLC 100– 200 mcg/mL) be treated with 2– 2.5 g daily for 7– 10 days, and those with high-level resistance (MLC ⬎200 mcg/mL) be treated with 3– 3.5 g daily for 14– 21 days. Because strains with high-level resistance are difﬁcult to treat, CDC recommends that patients with culture-documented infection who do not respond to repeat regimens at dosages up to 2 g daily for 3– 5 days and in whom the possibility of reinfection has been excluded should be managed in consultation with an expert (available through CDC). Gynecologic Infections ⬎Pelvic Inﬂammatory Disease Oral: 500 mg twice daily given for 14 days; used in conjunction with a 14-day regimen of oral oﬂoxacin (400 mg twice daily) or levoﬂoxacin (500 mg once daily). IV: 500 mg every 8 hours; used in conjunction with IV oﬂoxacin (400 mg every 12 hours) or IV levoﬂoxacin (500 mg once daily). Amebiasis ⬎Entamoeba histolytic Infections Oral: 750 mg 3 times daily given for 5– 10 (usually 10) days for intestinal amebiasis or 500– 750 mg 3 times daily given for 5– 10 (usually 10) days for amebic liver abscess. Alternatively, amebic liver abscess has been treated with 2.4 g once daily given for 1 or 2 days. Perioperative Prophylaxis ⬎Colorectal Surgery IV: 0.5 g given at induction of anesthesia (within 0.5– 1 hour prior to incision); used in conjunction with IV cefazolin (1– 2 g). Follow-up with a luminal amebicide (e.g., iodoquinol, paromomycin) after metronidazole. IV: 500 mg every 6 hours for 10 days. Manufacturer recommends 15 mg/kg by IV infusion over 30– 60 minutes 1 hour prior to the procedure and, if necessary, 7.5 mg/kg by IV infusion over 30– 60 minutes at 6 and 12 hours after the initial dose. The initial preoperative dose must be completely infused approximately 1 hour prior to surgery to ensure adequate serum and tissue concentrations of metronidazole at the time of incision. Prophylactic use of metronidazole should be limited to the day of surgery and should not be continued for more than 12 hours after surgery. Bacterial Vaginosis ⬎Nonpregnant Women Oral: Conventional tablets: 500 mg twice daily given for 7 days. Alternatively, a single 2-g dose. Extended-release tablets: 750 mg once daily given for 7 days. ⬎Pregnant Women Oral: 250 mg 3 times daily given for 7 days. Prophylaxis in Sexual Assault Victims† Oral: A single 2-g dose given in conjunction with IM ceftriaxone and either oral azithromycin or oral doxycycline. Contraindicated during ﬁrst trimester of pregnancy. In addition, single-dose regimens not recommended in pregnant women because of the slightly higher serum concentrations attained, which may reach fetal circulation. Balantidiasis† Oral: 750 mg 3 times daily given for 5 days. Special Populations Hepatic Impairment Blastocystis hominis Infections† Oral: 750 mg 3 times daily given for 10 days may improve symptoms in some patients. Crohn’s Disease† Oral: 400 mg twice daily or 1 g daily has been effective for treatment of active Crohn’s disease†. For treatment of refractory perineal disease, 20 mg/kg (1– 1.5 g) given in 3– 5 divided doses daily has been employed. Decrease dosage in patients with severe hepatic impairment and monitor plasma concentrations of the drug. Geriatric Patients Select dosage with caution because of age-related decreases in hepatic function. Clostridium difficile-associated Diarrhea and Colitis† Oral: 750 mg to 2 g daily in 3 or 4 divided doses given for 7– 14 days. Dose-ranging studies to determine comparative efﬁcacy have not been performed; most commonly employed regimens are 250 mg 4 times daily or 500 mg 3 times daily given for 10 days. IV: 500– 750 mg every 6– 8 hours; use when oral therapy is not feasible. Dientamoeba fragilis Infections† Oral: 500– 750 mg 3 times daily given for 10 days. Dracunculiasis† Oral: 250 mg 3 times daily given for 10 days. Is not curative, but may decrease inﬂammation and facilitate worm removal. Giardiasis† Oral: 250 mg 3 times daily given for 5– 7 days. Helicobacter pylori Infection and Duodenal Ulcer Disease Oral: 250 mg in conjunction with tetracycline (500 mg) and bismuth subsalicylate (525 mg) 4 times daily (at meals and at bedtime) for 14 days; these drugs should be given concomitantly with an H2-receptor antagonist in recommended dosage. Nongonococcal Urethritis† Oral: A single 2-g dose given in conjunction with a 7-day regimen of oral erythromycin. Tetanus† IV: 500 mg every 6 hours given for 7– 10 days. Trichomoniasis ⬎Initial Treatment Oral: 2 g as a single dose or in 2 divided doses. Alternatively, 500 mg twice daily given for 7 days or 375 mg twice daily given for 7 days. Manufacturer also recommends 250 mg 3 times daily given for 7 days. ⬎Retreatment Oral: 500 mg twice daily given for 7 days. If repeated failure occurs, CDC recommends 2 g once daily given for 3– 5 days. Others recommend retreatment with 2– 4 g daily for 7– 14 days if metronidazole-resistant strains are involved. Do not administer repeat courses of treatment unless presence of T. vagi- cap height base of text Cautions Contraindications • • • Hypersensitivity to metronidazole or other nitroimidazole derivatives. Cautious desensitization has been used in some situations when use of metronidazole was considered necessary. (See Hypersensitivity Reactions and Desensitization under Cautions.) First trimester of pregnancy. Helidac Therapy (kit containing tetracycline, metronidazole, bismuth subsalicylate) contraindicated in pregnant or nursing women, pediatric patients, patients with hepatic or renal impairment, patients with known allergy to aspirin or salicylates, and those with known hypersensitivity to any component of the kit. Warnings/Precautions Warnings Seizures and Peripheral Neuropathy Seizures and peripheral neuropathy (characterized by numbness or paresthesia of an extremity) reported with metronidazole. Persistent peripheral neuropathy reported in some patients receiving prolonged therapy. If abnormal neurologic signs develop, promptly discontinue drug. Use with caution in those with CNS diseases. Sensitivity Reactions Hypersensitivity Reactions and Desensitization Hypersensitivity reactions, including urticaria, pruritus, erythematous rash, ﬂushing, nasal congestion, fever, and ﬂeeting joint pains sometimes resembling serum sickness, have been reported with metronidazole. Because there are no effective alternatives to metronidazole in the US for treatment of trichomoniasis, CDC states that desensitization can be attempted in patients with metronidazole hypersensitivity. The possibility that desensitization may be hazardous should be considered and adequate procedures (e.g., established IV access, BP monitoring) and therapies (e.g., epinephrine, corticosteroids, antihistamines, oxygen) for management of an acute hypersensitivity reaction should be readily available. Pretreatment (e.g., with an antihistamine and/or corticosteroid) also should be considered. short stand 46067 AHFS Essentials ASHPI BATCH RIGHT Metronidazole Desensitization has been performed by administering increasing doses of IV metronidazole incrementally until a therapeutic dose was achieved, at which time oral dosing was initiated. In this regimen, an initial 5-mcg dose of IV metronidazole was given and the dose increased at 15- to 20-minute intervals to 15, 50, 150, and 500 mcg and then to 1.5, 5, 15, 30, 60, and 125 mg. After the 125-mg IV dose, dosing was switched to oral metronidazole and doses of 250, 500, and 2 g were given at 1-hour intervals. For trichomoniasis, desensitization dosing can be stopped after the 2-g dose. Patient should be monitored for ⱖ4 hours after the last dose (24 hours if there was any evidence of a reaction). General Precautions Selection and Use of Anti-infectives To reduce development of drug-resistant bacteria and maintain effectiveness of metronidazole and other antibacterials, use only for treatment or prevention of infections proven or strongly suspected to be caused by susceptible bacteria. When selecting or modifying anti-infective therapy, use results of culture and in vitro susceptibility testing. In the absence of such data, consider local epidemiology and susceptibility patterns when selecting anti-infectives for empiric therapy. Surgical procedures should be performed in conjunction with metronidazole therapy when indicated. In mixed aerobic and anaerobic infections, anti-infectives appropriate for treatment of aerobic bacteria should be used in conjunction with metronidazole. History of Blood Dyscrasia Use with caution in patients with evidence or history of blood dyscrasias. Mild leukopenia has been reported, but persistent hematologic abnormalities do not occur. Perform total and differential leukocyte counts before and after metronidazole treatment, especially when repeated courses are necessary. Sodium Content Metronidazole injection contains approximately 28 mEq of sodium per g of metronidazole. Use with caution in patients receiving corticosteroids and in those predisposed to edema. Candidiasis Known or previously unrecognized candidiasis may present more prominent symptoms during metronidazole therapy; treatment with an appropriate antifungal is required. Helidac Therapy When the kit containing tetracycline, metronidazole, and bismuth subsalicylate (Helidac Therapy) is used for the treatment of H. pylori infection and duodenal ulcer disease, the cautions, precautions, and contraindications associated with tetracycline and bismuth subsalicylate must be considered in addition to those associated with metronidazole. 33 top of rh base of rh cap height base of text Common Adverse Effects Nausea, headache, anorexia, dry mouth, unpleasant metallic taste. Interactions Speciﬁc Drugs Drug Interaction Alcohol Mild disulfiram-like reactions Alcohol should not be con(flushing, headache, nausumed during or for at sea, vomiting, abdominal least 1 day following comcramps, sweating) may pletion of metronidazole occur if alcohol is intherapy (at least 3 days gested while receiving after oral capsules or exmetronidazole tended-release tablets) Anticoagulants, oral (war- Prolonged PT farin) Comments Monitor PT and adjust anticoagulant dosage as needed Cimetidine Possible prolonged half-life and decreased clearance of metronidazole If used concomitantly, consider possibility of increased metronidazole adverse effects Disulfiram Acute psychoses and confusion with concomitant use Avoid concomitant use; do not initiate metronidazole therapy until 2 weeks after discontinuance of disulfiram Lithium Increased lithium concentra- Use concomitantly with cautions resulting in lithium tion; monitor serum lithtoxicity; renal toxicity (elium and creatinine conevated serum creatinine, centrations during hypernatremia, abnormally concomitant use dilute urine) reported Phenobarbital Decreased serum half-life and increased metabolism of metronidazole Phenytoin Decrased serum concentration and increased metabolism of metronidazole; decreased clearance of phenytoin Specific Populations Pregnancy Category B. Contraindicated during the ﬁrst trimester of pregnancy. Lactation Distributed into milk; discontinue nursing or the drug. If a single 2-g dose of metronidazole is indicated in the mother, AAP states that breast-feeding should be interrupted for 12– 24 hours following the dose; if a multipledose regimen is indicated in the mother, breast-feeding should be discontinued during treatment. Pediatric Use Except for oral treatment of amebiasis, safety and efﬁcacy not established in pediatric patients. Metronidazole has been used and is recommended for use in pediatric patients for various indications other than amebiasis (e.g., trichomoniasis, giardiasis). Unusual adverse effects have not been reported in pediatric patients. Safety and efﬁcacy of the kit containing metronidazole, tetracycline, and bismuth subsalicylate (Helidac Therapy) for treatment of H. pylori infection and duodenal ulcer disease have not been established in pediatric patients. Geriatric Use Because of age-related decreases in hepatic function, monitor serum metronidazole concentrations and adjust dosage accordingly. Insufﬁcient experience in those ⱖ65 years of age to determine whether they respond differently than younger adults to concomitant use of metronidazole, tetracycline, and bismuth subsalicylate (Helidac Therapy) for treatment of H. pylori infection and duodenal ulcer disease. Age-related decreases in hepatic, renal, and/or cardiac function and concomitant disease and drug therapy should be considered. Hepatic Impairment Patients with severe hepatic impairment metabolize metronidazole more slowly, and increased concentrations of the drug and metabolites may occur. Use with caution, monitor plasma metronidazole concentrations, and reduce dosage in patients with severe hepatic impairment. Pharmacokinetics Absorption Bioavailability ⱖ80% of an oral dose is absorbed from the GI tract. Following oral administration of conventional tablets or capsules, peak plasma concentrations of unchanged drug and active metabolites attained within 1– 3 hours. Following oral administration of metronidazole extended-release tablets for 7 consecutive days under fasting conditions, steady-state peak plasma concentrations attained an average of 6.8 hours after the dose. Food Conventional tablets or capsules: Food decreases the rate of absorption and peak plasma concentrations; total amount of drug not affected. Extended-release tablets: Food increases rate of absorption and peak plasma concentrations. Distribution Extent Widely distributed into most body tissues and ﬂuids, including bone, bile, saliva, pleural ﬂuid, peritoneal ﬂuid, vaginal secretions, seminal ﬂuid, and cerebral and hepatic abscesses. Distributed into CSF; CSF concentrations are 43% of concurrent plasma concentrations in patients with uninﬂamed meninges and equal to or greater than concurrent plasma concentrations in patients with inﬂamed meninges. Readily crosses the placenta and is distributed into milk. Plasma Protein Binding ⬍20%. short stand 46067 AHFS Essentials 34 ASHPI BATCH LEFT top of rh base of rh Metronidazole Elimination Metabolism Approximately 30– 60% of an oral or IV dose is metabolized in the liver by hydroxylation, side-chain oxidation, and glucuronide conjugation. The major metabolite, 2-hydroxy metronidazole, has some antibacterial and antiprotozoal activity. Elimination Route Metronidazole and its metabolites are excreted principally in urine (60– 80%) and to a lesser extent in feces (6– 15%). Half-life Adults with normal renal and hepatic function: 6– 8 hours. Special Populations Half-life may be prolonged in patients with impaired hepatic function. In adults with alcoholic liver disease and impaired hepatic function, half-life averages 18.3 hours. Pharmacokinetics not affected by renal impairment. Stability Fenoldopam mesylate Fluconazole Foscarnet sodium Gatifloxacin Gemcitabine HCl Granisetron HCl Heparin sodium Hetastarch in lactated electrolyte injection (Hextend) Hydromorphone HCl Labetalol HCl Linezolid Lorazepam Magnesium sulfate Melphalan HCl Meperidine HCl Methylprednisolone sodium succinate Midazolam HCl Milrinone lactate Morphine sulfate Nicardipine HCl Perphenazine Piperacillin sodium– tazobactam sodium Remifentanil HCl Sargramostim Tacrolimus Teniposide Theophylline Thiotepa Vinorelbine tartrate cap height base of text Incompatible Amphotericin B cholesteryl sulfate complex Aztreonam Filgrastim Solution Compatibility (Metronidazole HCl) Incompatible Storage Amino acids 10% Oral Capsules 15– 25C. Dispense in well-closed container with child-resistant closure. Tablets Conventional tablets: ⬍25C. Extended-release tablets: 25C (may be exposed to 15– 30C). Dispense in wellclosed container with child-resistant closure. Metronidazole Combinations Kit containing tetracycline, metronidazole, and bismuth subsalicylate: 20– 25C. Parenteral Injection for IV infusion 15– 25C; protect from light. Do not refrigerate. Drug Compatibility (Metronidazole HCl) ⬎Admixture Compatibility Compatible Amikacin sulfate Aminophylline Cefazolin sodium Cefotaxime sodium Cefoxitin sodium Chloramphenicol sodium succinate Clindamycin phosphate Disopyramide phosphate Powder for IV infusion ⬍25C; protect from light. After reconstitution, dilution, and neutralization, use within 24 hours; do not refrigerate. Incompatible Compatibility Variable For information on systemic interactions resulting from concomitant use, see Interactions. Ampicillin sodium Cefepime HCl Drug Compatibility (Metronidazole) ⬎Admixture Compatibility Compatible Amikacin sulfate Cefazolin sodium Cefotaxime sodium Ceftazidime Ceftizoxime sodium Ceftriaxone sodium Cefuroxime sodium Chloramphenicol sodium succinate Ciprofloxacin Clindamycin phosphate Fluconazole Gentamicin sulfate Midazolam HCl Tobramycin sulfate Incompatible Ciprofloxacin Dopamine HCl Ampicillin sodium Cefepime HCl Cefoxitin sodium Hydrocortisone sodium succinate Penicillin G potassium ⬎Y-Site Compatibility Acyclovir sodium Allopurinol sodium Amifostine Bivalirudin Cefepime HCl Clarithromycin Cyclophosphamide Dexmedetomidine HCl Diltiazem HCl Docetaxel Dopamine HCl Doxapram HCl Doxorubicin HCl liposome injection Enalaprilat Esmolol HCl Etoposide phosphate Ceftriaxone sodium Diltiazem HCl Incompatible Meropenem Warfarin sodium Actions and Spectrum • • • • • Compatible Meropenem ⬎Y-Site Compatibility Compatible Amiodarone HCl Amoxicillin sodium– clavulanate potassium Aztreonam Variable Gentamicin sulfate Heparin sodium Hydrocortisone sodium succinate Multielectrolyte concentrate Multivitamins Penicillin G potassium Tobramycin sulfate • • • Bactericidal, amebicidal, and trichomonacidal in action. Un-ionized at physiologic pH and readily taken up by anaerobic organisms or cells. In susceptible organisms or cells, metronidazole is reduced by low-redox-potential electron transport proteins (e.g., nitroreductases such as ferredoxin); the reduction product(s) apparently are responsible for the cytotoxic and antimicrobial effects of the drug (e.g., disruption of DNA, inhibition of nucleic acid synthesis). Has direct anti-inﬂammatory effects and effects on neutrophil motility, lymphocyte transformation, and some aspects of cell-mediated immunity. Spectrum of activity includes most obligately anaerobic bacteria and many protozoa. Inactive against fungi and viruses and most aerobic or facultatively anaerobic bacteria. Gram-positive anaerobes: Clostridium, C. difﬁcile, C. perfringens, Eubacterium, Peptococcus, and Peptostreptococcus. Gram-negative anaerobes: Active against Bacteroides fragilis, B. distasonis, B. ovatus, B. thetaiotaomicron, B. vulgatus, B. ureolyticus,Fusobacterium, Prevotella bivia, P. buccae, P. disiens, P. intermedia, P. melaninogenica, P. oralis, Porphyromonas, and Veillonella. Active against Helicobacter pylori, Entamoeba histolytica, Trichomonas vaginalis, Giardia lamblia, and Balantidium coli. Acts principally against the trophozoite forms of E. histolytica and has limited activity against the encysted form. Resistance has been reported in some Bacteroides and T. vaginalis. short stand 46067 AHFS Essentials ASHPI BATCH RIGHT Metronidazole 35 top of rh base of rh cap height base of text Advice to Patients • • • • • • • • • Advise patients that antibacterials (including metronidazole) should only be used to treat bacterial infections and not used to treat viral infections (e.g., the common cold). Importance of completing full course of therapy, even if feeling better after a few days. Advise patients that skipping doses or not completing the full course of therapy may decrease effectiveness and increase the likelihood that bacteria will develop resistance and will not be treatable with metronidazole or other antibacterials in the future. Metronidazole extended-release tablets should be taken at least 1 hour before or 2 hours after meals; optimum absorption occurs under fasting conditions. Advise patients to avoid alcohol during and for at least 1 day after conventional tablets or at least 3 days after receiving metronidazole capsules or extended-release tablets. Advise patients to promptly discontinue metronidazole and contact clinician if abnormal neurologic signs occur. Importance of informing clinicians of existing or contemplated therapy, including prescription and OTC drugs. Importance of women informing clinician if they are or plan to become pregnant or plan to breast-feed. Importance of advising patients of other important precautionary information. (See Cautions.) Preparations Metronidazole Oral Capsules Tablets Tablets, extendedrelease, filmcoated Tablets, filmcoated Parenteral Injection, for IV infusion only 375 mg 250 mg* 500 mg* 750 mg Flagyl 375, Pfizer 250 mg* Flagyl, Pfizer 500 mg* Flagyl, Pfizer 5 mg/mL Flagyl I.V. RTU (Viaflex [Baxter]), SCS Pharmaceuticals Flagyl ER, Pfizer Metronidazole Injection (PAB [Braun]), Various Manufacturers Metronidazole Injection (available in LifeCare and glass containers), Abbott Metronidazole Injection RTU (Viaflex [Baxter]), Various Manufacturers *available generically Metronidazole Combinations 4 Capsules, Tetracycline Hydrochloride 500 mg Helidac Therapy (available as 14 blister cards), Prometheus 4 Tablets, Metronidazole, 250 mg, (with povidone) 8 Tablets, chewable, Bismuth Subsalicylate, 262.4 mg, (with povidone) *available generically Metronidazole Hydrochloride Parenteral For injection, for IV infusion only 500 mg (of metronidazole) Flagyl I.V. (with mannitol 415 mg), SCS Pharmaceuticals *available generically †Use is not currently included in the labeling approved by the US Food and Drug Administration Selected Revisions August 2005, Copyright, May 2004, American Society of Health-System Pharmacists, Inc. short stand