MetroNIDAZOLE (Systemic)

(met roe NYE da zole)

Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product

Capsule, Oral:

Flagyl: 375 mg

Generic: 375 mg

Solution, Intravenous:

Metro: 500 mg (100 mL)

Generic: 500 mg (100 mL)

Solution, Intravenous [preservative free]:

Generic: 500 mg (100 mL [DSC])

Suspension Reconstituted, Oral:

First-Metronidazole 50: 50 mg/mL (150 mL) [contains saccharin sodium, sodium benzoate]

First-Metronidazole 100: 100 mg/mL (150 mL) [contains saccharin sodium, sodium benzoate]

MetroNIDAZOLE Benzo+SyrSpend: 50 mg/mL (120 mL)

Tablet, Oral:

Flagyl: 250 mg, 500 mg

Generic: 250 mg, 500 mg

Tablet Extended Release 24 Hour, Oral:

Flagyl ER: 750 mg [DSC]

After diffusing into the organism, interacts with DNA to cause a loss of helical DNA structure and strand breakage resulting in inhibition of protein synthesis and cell death in susceptible organisms

Absorption

Oral: Well absorbed

Distribution

To bile, seminal fluid, bone, liver, and liver abscesses, lung and vaginal secretions; crosses blood-brain barrier; saliva and CSF concentrations similar to those in plasma

Metabolism

Hepatic (30% to 60%) to several metabolites including an active hydroxyl metabolite which maintains activity ~30% to 65% of the parent compound (Lamp 1999)

Excretion

Urine (unchanged drug and metabolites: 60% to 80%; ~20% of total as unchanged drug); feces (6% to 15%)

Time to Peak

Serum: Oral: Immediate release: 1-2 hours; Extended release: ~5 hours

Half-Life Elimination

Neonates <7 days (Jager-Roman 1982): Within first week of life, more prolonged than with lower GA:

GA 28 to 30 weeks: 75.3 ± 16.9 hours

GA 32 to 35 weeks: 35.4 ± 1.5 hours

GA 36 to 40 weeks: 24.8 ± 1.6 hours

Neonates ≥7 days: ~22.5 hours (Upadhyaya 1988)

Children and Adolescents: 6 to 10 hours (Lamp 1999)

Adults: ~8 hours

Protein Binding

<20%

Half-life: 18.31 hours (mean) in one study (Lau, 1987)

According to Child-Pugh classification (Muscara, 1995):

Child-Pugh class A: ~10.7 hours

Child-Pugh class B: ~13.5 hours

Child-Pugh class C: ~21.5 hours

Balantidiasis (adults)

Balantidiasis is a worldwide subtropic and tropic parasitic disease due to close contact with swine [Schuster 2008]. Data from a limited number of patients treated with metronidazole (single case report of one immunocompromised patient with pulmonary infection) suggest that metronidazole may be beneficial for the treatment of this condition [Anagyrou 2003]. Additional data may be necessary to further define the role of metronidazole for the treatment of balantidiasis.

Balantidiasis (children/adolescents)

Balantidiasis is a worldwide subtropic and tropic parasitic disease due to close contact with swine [Schuster 2008]. Based on the American Academy of Pediatrics Report of the Committee on Infectious Disease, metronidazole is an effective and recommended alternative treatment for children and adolescents with balantidiasis [AAP [Red Book 2012]].

Bite wounds (animal/human)

Based on the Infectious Diseases Society of America (IDSA) guidelines for the diagnosis and management of skin and soft tissue infections (SSTI), metronidazole, in combination with a second- or third-generation cephalosporin, levofloxacin, or sulfamethoxazole/trimethoprim for animal bites, or in combination with ciprofloxacin or levofloxacin for human bites, is an effective and recommended alternative for treatment of bite wounds.

Clostridium difficile infection (adults)

Metronidazole is recommended in national practice guidelines for the management of mild to moderate or severe, complicated C. difficile infections. Metronidazole should not be used beyond the first recurrence or for long-term therapy (beyond 14 days) because of the potential for cumulative neurotoxicity.

Crohn disease, mild to moderate

Data from a randomized, controlled trial suggest that metronidazole, in combination with ciprofloxacin, may be beneficial for the treatment of patients with colonic Crohn disease. Additional data may be necessary to further define the role of metronidazole in this condition [Steinhart 2002].

Based on the American College of Gastroenterology practice guidelines for the management of Crohn disease in adults, metronidazole is a suggested alternative agent in the management of mild to moderate Crohn disease not responding to sulfasalazine and in patients with colonic involvement (ileocolitis and colitis).

Dientamoeba fragilis (adults)

Based on the Centers for Disease Control and Prevention (CDC) Resources for Health Professionals, metronidazole is an effective and recommended agent for the treatment of this condition.

Giardiasis

In a meta-analysis of trials evaluating the treatment of giardiasis, the use of metronidazole was found to be of similar effectiveness to albendazole for the treatment of this condition although metronidazole may have slightly more adverse effects [Granados 2012].

Based on the American Academy of Pediatrics Report of the Committee on Infectious Disease, metronidazole is an effective and recommended drug of choice for the treatment of children and adolescents with giardiasis [AAP [Red Book 2012]].

Helicobacter pylori eradication

Based on the American College of Gastroenterology Guideline on the Management of Helicobacter pylori Infection and the ESPGHAN/NASPGHAN Guidelines for Helicobacter pylori Infection in Children, metronidazole is an effective and recommended component of a multiple-drug regimen for the treatment of this condition.

Periodontitis

Data from a randomized, 12 month double-blind placebo controlled trial, though small, evaluating the use of either amoxicillin and metronidazole or placebo in conjunction with aggressive dental care demonstrated that amoxicillin (in combination with metronidazole) significantly improved dental parameters and increased beneficial bacteria [Silva-Senem 2013]. Additional trials may be necessary to further define the role of metronidazole for the treatment of periodontitis.

Pouchitis (acute)

In a systematic review of available clinical trials evaluating the treatment and prevention of pouchitis after ileal pouch-anal anastomosis for chronic ulcerative colitis, metronidazole was found to be less effective than ciprofloxacin but as effective as budesonide enemas for inducing remission in acute pouchitis. Metronidazole is considered an effective treatment and as a first line agent for the treatment of this condition [Holubar 2010].

Prophylaxis against sexually-transmitted diseases following sexual assault

Based on the Centers for Disease Control and Prevention (CDC) sexually transmitted diseases treatment guidelines, metronidazole, in combination with ceftriaxone and azithromycin, is an effective and recommended regimen for prophylaxis against sexually transmitted diseases following sexual assault.

Skin and soft tissue necrotizing infections

Based on the Infectious Diseases Society of America (IDSA) guidelines for the diagnosis and management of skin and soft tissue infections (SSTI), metronidazole, in combination with cefotaxime or ceftriaxone, is an effective and recommended alternative for empiric treatment of mixed (polymicrobial) necrotizing infections of the skin, fascia, and muscle.

Surgical infection prophylaxis (preoperative)

Based on the American Society of Health-System Pharmacists (ASHP), the Infectious Diseases Society of America (IDSA), the Surgical Infection Society (SIS), and the Society of Healthcare Epidemiology of America (SHEA) guidelines for antimicrobial prophylaxis in surgery, metronidazole is an effective and recommended agent (in combination with other antimicrobials) for appendectomy secondary to uncomplicated appendicitis, open biliary tract procedures, elective high risk laparoscopic biliary tract procedures, obstructed small intestine procedures, colorectal procedures (oral; IV is FDA-approved for this indication), clean-contaminated head and neck cancer surgery, other clean-contaminated procedures (except tonsillectomy and some endoscopic sinus procedures), hysterectomy (vaginal or abdominal), and clean-contaminated urologic procedures.

Surgical site infections

Based on the Infectious Diseases Society of America (IDSA) guidelines for the diagnosis and management of skin and soft tissue infections (SSTI), metronidazole, in combination with ceftriaxone, ciprofloxacin or levofloxacin, is an effective and recommended option for treatment of surgical site infections occurring after surgery of the intestinal or genitourinary tract, perineum, or axilla. Systemic antibacterials are not routinely indicated for surgical site infections, but may be beneficial (in conjunction with suture removal plus incision and drainage) in patients with significant systemic response (eg, temperature >38.5°C, heart rate >110 beats per minute, erythema/induration extending >5 cm from incision, WBC >12,000/mm3)..

Tetanus (adults)

Data from an open-label clinical trial in patients with moderate tetanus treated with either metronidazole or intramuscular procaine penicillin suggests that metronidazole may be beneficial and possibly superior to the use of penicillin for the treatment of this condition [Ahmadsyah 1985].

Tetanus (children)

Based on the American Academy of Pediatrics Report of the Committee on Infectious Disease, metronidazole is effective in decreasing the number of vegetative forms of C. tetani and is the recommended drug of choice for the treatment of children and adolescents with tetanus [AAP [Red Book 2012]].

Urethritis, nongonococcal (persistent and recurrent)

Based on the Centers for Disease Control and Prevention (CDC) sexually transmitted diseases treatment guidelines, metronidazole is effective and recommended as treatment for recurrent and persistent urethritis for men who have sex with women and who live in areas where T. vaginalis is prevalent. Compliance with initial regimen and lack of re-exposure to an untreated sex partner should be excluded prior to use. Sex partners should be referred for evaluation and appropriate treatment.

A 50 mg/mL oral suspension may be made with tablets and a 1:1 mixture of Ora-Sweet and Ora-Plus. Crush twenty-four 250 mg tablets in a mortar and reduce to a fine powder. Add small portions of the vehicle and mix to a uniform paste; mix while adding the vehicle in incremental portions to almost 120 mL; transfer to a calibrated bottle, rinse mortar with vehicle, and add quantity of vehicle sufficient to make 120 mL. Label "shake well". Stable for 60 days at room temperature or refrigerated (Allen, 1996).

IV: Infuse intravenously over 30 to 60 minutes. Avoid contact of drug solution with equipment containing aluminum.

Oral: Immediate-release tablets and capsules may be administered with food to minimize stomach upset. Extended-release tablets should be administered on an empty stomach (1 hour before or 2 hours after meals); do not split, crush, or chew.

Alcohol (Ethyl): MetroNIDAZOLE (Systemic) may enhance the adverse/toxic effect of Alcohol (Ethyl). A disulfiram-like reaction may occur. Avoid combination

BCG (Intravesical): Antibiotics may diminish the therapeutic effect of BCG (Intravesical). Avoid combination

BCG Vaccine (Immunization): Antibiotics may diminish the therapeutic effect of BCG Vaccine (Immunization). Monitor therapy

Busulfan: MetroNIDAZOLE (Systemic) may increase the serum concentration of Busulfan. Management: The toxic effects of busulfan may be greatly increased with concomitant use of metronidazole. This combination should probably be avoided when possible. If these agents must be used together, increased monitoring for busulfan toxicity is recommended. Consider therapy modification

Capecitabine: MetroNIDAZOLE (Systemic) may increase serum concentrations of the active metabolite(s) of Capecitabine. Monitor therapy

Carbocisteine: MetroNIDAZOLE (Systemic) may enhance the adverse/toxic effect of Carbocisteine. Specifically, metronidazole may enhance adverse effects of alcohol that is present in liquid formulations of carbocisteine-containing products. Avoid combination

Cholera Vaccine: Antibiotics may diminish the therapeutic effect of Cholera Vaccine. Avoid combination

Disulfiram: May enhance the adverse/toxic effect of MetroNIDAZOLE (Systemic). In particular, the risk for CNS toxicities such as psychosis may be increased. Avoid combination

Dronabinol: MetroNIDAZOLE (Systemic) may enhance the adverse/toxic effect of Dronabinol. Specifically, metronidazole may produce severe intolerance to the alcohol contained in the dronabinol oral solution. Consider therapy modification

Fluorouracil (Systemic): MetroNIDAZOLE (Systemic) may increase the serum concentration of Fluorouracil (Systemic). Monitor therapy

Fosphenytoin: May decrease the serum concentration of MetroNIDAZOLE (Systemic). MetroNIDAZOLE (Systemic) may increase the serum concentration of Fosphenytoin. Monitor therapy

Highest Risk QTc-Prolonging Agents: QTc-Prolonging Agents (Indeterminate Risk and Risk Modifying) may enhance the QTc-prolonging effect of Highest Risk QTc-Prolonging Agents. Management: Avoid such combinations when possible. Use should be accompanied by close monitoring for evidence of QT prolongation or other alterations of cardiac rhythm. Consider therapy modification

Lactobacillus and Estriol: Antibiotics may diminish the therapeutic effect of Lactobacillus and Estriol. Monitor therapy

Lopinavir: MetroNIDAZOLE (Systemic) may enhance the adverse/toxic effect of Lopinavir. Specifically, the combination of metronidazole and lopinavir/ritonavir solution, which contains 42% alcohol, may result in a disulfiram-like reaction. MetroNIDAZOLE (Systemic) may enhance the arrhythmogenic effect of Lopinavir. Management: Avoid the concomitant use of lopinavir/ritonavir and metronidazole if possible. If these agents are used concomitantly, monitor for QTc prolongation/arrhythmia and if the lopinavir/ritonavir solution is used, development of a disulfiram-like reaction. Consider therapy modification

Mebendazole: May enhance the adverse/toxic effect of MetroNIDAZOLE (Systemic). Particularly the risk for Stevens-Johnson syndrome or toxic epidermal necrolysis may be increased. Avoid combination

MiFEPRIStone: May enhance the QTc-prolonging effect of QTc-Prolonging Agents (Indeterminate Risk and Risk Modifying). Management: Though the drugs listed here have uncertain QT-prolonging effects, they all have some possible association with QT prolongation and should generally be avoided when possible. Consider therapy modification

Moderate Risk QTc-Prolonging Agents: QTc-Prolonging Agents (Indeterminate Risk and Risk Modifying) may enhance the QTc-prolonging effect of Moderate Risk QTc-Prolonging Agents. Monitor therapy

Mycophenolate: MetroNIDAZOLE (Systemic) may decrease the serum concentration of Mycophenolate. Specifically, metronidazole may decrease concentrations of the active metabolite of mycophenolate. Monitor therapy

PHENobarbital: May decrease the serum concentration of MetroNIDAZOLE (Systemic). Monitor therapy

Phenytoin: May decrease the serum concentration of MetroNIDAZOLE (Systemic). MetroNIDAZOLE (Systemic) may increase the serum concentration of Phenytoin. Monitor therapy

Primidone: May decrease the serum concentration of MetroNIDAZOLE (Systemic). Monitor therapy

Ritonavir: May enhance the adverse/toxic effect of MetroNIDAZOLE (Systemic). Specifically, the combination of ritonavir oral solution or ritonavir soft gelatin capsule, both of which contain alcohol, and metronidazole may result in a disulfiram-like reaction. Avoid combination

Sodium Picosulfate: Antibiotics may diminish the therapeutic effect of Sodium Picosulfate. Management: Consider using an alternative product for bowel cleansing prior to a colonoscopy in patients who have recently used or are concurrently using an antibiotic. Consider therapy modification

Tegafur: MetroNIDAZOLE (Systemic) may increase serum concentrations of the active metabolite(s) of Tegafur. Monitor therapy

Tipranavir: MetroNIDAZOLE (Systemic) may enhance the adverse/toxic effect of Tipranavir. A disulfiram-like reaction may occur due to the alcohol contained in tipranavir capsules. Monitor therapy

Typhoid Vaccine: Antibiotics may diminish the therapeutic effect of Typhoid Vaccine. Only the live attenuated Ty21a strain is affected. Management: Vaccination with live attenuated typhoid vaccine (Ty21a) should be avoided in patients being treated with systemic antibacterial agents. Use of this vaccine should be postponed until at least 3 days after cessation of antibacterial agents. Consider therapy modification

Vitamin K Antagonists (eg, warfarin): MetroNIDAZOLE (Systemic) may increase the serum concentration of Vitamin K Antagonists. Management: Consider alternatives to concomitant therapy with these agents. If concomitant therapy cannot be avoided, consider reducing the dose of the vitamin K antagonist and monitor for increased INR/bleeding. Consider therapy modification