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Product Name
:
STATIZOL (Vial)
Chemical Name
:
Metronidazole
Therapeutic Category
:
Antiprotozoal & Anthelmintic drugs
Pharmacologic Category
:
Amebicide - Antibiotic, Miscellaneous - Antiprotozoal, Nitroimidazole
Pharmaceutical Form
:
Vial
Composition
:
Metronidazole 500mg/100ml
Monitoring Parameters
Dosing
 
Dosing: Adult
Anaerobic infections (diverticulitis, intra-abdominal, peritonitis, cholangitis, or abscess): Oral, I.V.: 500 mg every 6-8 hours, not to exceed 4 g/day; Note: Initial: 1 g I.V. loading dose may be administered
Antibiotic-associated pseudomembranous colitis: IDSA Guidelines (Cohen, 2010):
Severe complicated infection: I.V.: 500 mg 3 times/day with oral vancomycin (recommended agent) for 10-14 days
Note: Due to the emergence of a new strain of C. difficile, some clinicians recommend converting to oral vancomycin therapy if the patient does not show a clear clinical response after 2 days of metronidazole therapy.
Intra-abdominal infection, complicated, community-acquired, mild-to-moderate (in combination with cephalosporin or fluoroquinolone): I.V.: 500 mg every 8-12 hours or 1.5 g every 24 hours for for 4-7 days (provided source controlled)
Surgical prophylaxis (colorectal): I.V. 15 mg/kg 1 hour prior to surgery; followed by 7.5 mg/kg 6 and 12 hours after initial dose

Dosing: Pediatric

Infants and Children:
Anaerobic infections:
I.V.: 30 mg/kg/day in divided doses every 6 hours

Dosing: Geriatric

Refer to adult dosing. Use the lower end of the dosing recommendations for adults; do not administer as single dose as efficacy has not been established.

Dosing: Renal Impairment

Clcr <10 mL/minute (not on dialysis): Recommendations vary: To reduce possible accumulation in patients receiving multiple doses, consider reduction to 50% of dose or administer normal dose every 12 hours; Note: Dosage reduction is unnecessary in short courses of therapy. Some references do not recommend reduction at any level of renal impairment (Lamp, 1999).
Intermittent hemodialysis (IHD) (administer after hemodialysis on dialysis days): Dialyzable (50% to 100%): 500 mg every 8-12 hours. Note: Dosing regimen highly dependent on clinical indication (trichomoniasis vs C. difficile colitis) (Heintz, 2009). Note: Dosing dependent on the assumption of thrice weekly, complete IHD sessions.
Peritoneal dialysis (PD): Dose as for Clcr <10 mL/minute
Continuous renal replacement therapy (CRRT) (Heintz, 2009; Trotman, 2005): Drug clearance is highly dependent on the method of renal replacement, filter type, and flow rate. Appropriate dosing requires close monitoring of pharmacologic response, signs of adverse reactions due to drug accumulation, as well as drug concentrations in relation to target trough (if appropriate). The following are general recommendations only (based on dialysate flow/ultrafiltration rates of 1-2 L/hour and minimal residual renal function) and should not supersede clinical judgment:
CVVH/CVVHD/CVVHDF: 500 mg every 6-12 hours (or per clinical indication; dosage reduction generally not necessary)

Dosing: Hepatic Impairment

Unchanged in mild liver disease; reduce dosage in severe liver disease.
Use
 
Treatment of susceptible anaerobic bacterial and protozoal infections in the following conditions: Amebiasis, symptomatic and asymptomatic trichomoniasis; skin and skin structure infections, bone and joint infections, CNS infections, endocarditis, gynecologic infections, intra-abdominal infections (as part of combination regimen), respiratory tract infections (lower), systemic anaerobic infections; treatment of antibiotic-associated pseudomembranous colitis (AAPC); as part of a multidrug regimen for H. pylori eradication to reduce the risk of duodenal ulcer recurrence; surgical prophylaxis (colorectal)
Use - Unlabeled/Investigational
Crohn's disease
Adverse Reactions
 
Frequency not always defined.
Cardiovascular: Flattening of the T-wave, flushing, syncope
Central nervous system: Aseptic meningitis, ataxia, confusion, coordination impaired, depression, dizziness, encephalopathy, fever, headache, insomnia, irritability, seizure, vertigo
Dermatologic: Erythematous rash, pruritus, Stevens-Johnson syndrome, toxic epidermal necrolysis, urticaria
Endocrine & metabolic: Disulfiram-like reaction, dysmenorrhea
Gastrointestinal: Nausea (~12%), anorexia, abdominal cramping, constipation, diarrhea, epigastric distress, furry tongue, glossitis, pancreatitis (rare), proctitis, stomatitis, unusual/metallic taste, vomiting, xerostomia
Genitourinary: Cystitis, darkened urine (rare), dyspareunia, dysuria, incontinence, libido decreased, pelvic pressure, polyuria, vaginal dryness, vaginitis
Hematologic: Neutropenia (reversible), thrombocytopenia (reversible, rare)
Local: Thrombophlebitis
Neuromuscular & skeletal: Dysarthria, peripheral neuropathy, weakness
Ocular: Optic neuropathy
Respiratory: Nasal congestion, pharyngitis, rhinitis, sinusitis, pharyngitis
Miscellaneous: Flu-like syndrome, joint pains resembling serum sickness, moniliasis
Contraindications
 
Hypersensitivity to metronidazole, nitroimidazole derivatives, or any component of the formulation; pregnancy (first trimester)
Warnings / Precautions Drug
 
Boxed warnings:
• Carcinogenic: See “Concerns related to adverse effects” below.
Concerns related to adverse effects:
• Carcinogenic: [U.S. Boxed Warning]: Possibly carcinogenic based on animal data.
• CNS effects: Aseptic meningitis, encephalopathy, seizures, and neuropathies (peripheral and optic) have been reported especially with increased doses and chronic treatment; monitor and consider discontinuation of therapy if signs/symptoms occur. Use with caution in patients with a history of seizure disorder; reduce doses with patients with CNS disease.
• Superinfection: Prolonged use may result in fungal or bacterial superinfection, including C. difficile-associated diarrhea (CDAD) and pseudomembranous colitis; CDAD has been observed >2 months postantibiotic treatment. Candidiasis infection (known or unknown) may be more prominent during metronidazole treatment, antifungal treatment required.
Disease-related concerns:
• Blood dyscrasias: Use with caution in patients with or history of blood dyscrasias; leukopenia has occurred.
• Heart failure: Use injection with caution in patients with heart failure, edema or other sodium retaining states.
• Hepatic impairment: Use with caution in patients with severe liver impairment due to potential accumulation; dosage adjustment recommended.
• H. pylori infection: If H. pylori is not eradicated in patients being treated with metronidazole in a regimen, it should be assumed that metronidazole-resistance has occurred and it should not again be used.
• Renal impairment: Consider dosage reduction in longer-term therapy with severe renal failure (Clcr <10 mL/minute).
Other warnings/precautions:
• Appropriate use: The Infectious Disease Society of America (IDSA) recommends the use of oral metronidazole for initial treatment of mild-to-moderate C. difficile infection and the use of oral vancomycin for initial treatment of severe C. difficile infection with or without I.V. metronidazole depending on the presence of complications. May treat recurrent mild-to-moderate infection once with oral metronidazole; avoid use beyond first reoccurrence due to potential cumulative neurotoxicity (Cohen, 2010).
• Alcohol consumption: Disulfiram-like reactions to ethanol have been reported with oral metronidazole; avoid alcoholic beverages during therapy.
Metabolism/Transport Effects
Inhibits CYP2C9 (weak), 3A4 (moderate)
Interactions
 
Alcohol (Ethyl): MetroNIDAZOLE (Systemic) may enhance the adverse/toxic effect of Alcohol (Ethyl). A disulfiram-like reaction may occur. Risk C: Monitor therapy
BCG: Antibiotics may diminish the therapeutic effect of BCG. Risk X: Avoid combination
Budesonide (Systemic, Oral Inhalation): CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Budesonide (Systemic, Oral Inhalation). Management: Consider reducing the oral budesonide dose when used together with a CYP3A4 inhibitor. This interaction is likely less severe with orally inhaled budesonide. Monitor patients closely for signs/symptoms of corticosteroid excess. Risk D: Consider therapy modification
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. Risk D: Consider therapy modification
Calcineurin Inhibitors: MetroNIDAZOLE (Systemic) may decrease the metabolism of Calcineurin Inhibitors. Risk C: Monitor therapy
Colchicine: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Colchicine. Management: Reduce colchicine dose as directed when using with a moderate CYP3A4 inhibitor, and increase monitoring for colchicine-related toxicity. Use extra caution in patients with impaired renal and/or hepatic function. Risk D: Consider therapy modification
CYP3A4 Substrates: CYP3A4 Inhibitors (Moderate) may decrease the metabolism of CYP3A4 Substrates. Risk C: Monitor therapy
Disulfiram: May enhance the adverse/toxic effect of MetroNIDAZOLE (Systemic). Risk D: Consider therapy modification
Eplerenone: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Eplerenone. Management: A lower starting dose of eplerenone (25 mg once daily for adults) is recommended in patients with hypertension who are also taking drugs that are moderate inhibitors of CYP3A4. Risk D: Consider therapy modification
Everolimus: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Everolimus. Management: Everolimus dose reductions are required for patients being treated for subependymal giant cell astrocytoma or renal cell carcinoma. See prescribing information for specific dose adjustment and monitoring recommendations. Risk D: Consider therapy modification
FentaNYL: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of FentaNYL. Management: Monitor patients extra closely for several days following initiation of the combination, and fentanyl dosage reductions should be made as appropriate. Risk D: Consider therapy modification
Fosphenytoin: MetroNIDAZOLE (Systemic) may increase the serum concentration of Fosphenytoin. Fosphenytoin may decrease the serum concentration of MetroNIDAZOLE (Systemic). Risk C: Monitor therapy
Halofantrine: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Halofantrine. Risk D: Consider therapy modification
Lurasidone: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Lurasidone. Risk D: 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. Risk D: Consider therapy modification
Mycophenolate: MetroNIDAZOLE (Systemic) may decrease the serum concentration of Mycophenolate. Specifically, metronidazole may decrease concentrations of the active metabolite of mycophenolate. Risk C: Monitor therapy
PHENobarbital: May decrease the serum concentration of MetroNIDAZOLE (Systemic). Risk C: Monitor therapy
Phenytoin: May decrease the serum concentration of MetroNIDAZOLE (Systemic). MetroNIDAZOLE (Systemic) may increase the serum concentration of Phenytoin. Risk C: Monitor therapy
Pimecrolimus: CYP3A4 Inhibitors (Moderate) may decrease the metabolism of Pimecrolimus. Risk C: Monitor therapy
Ranolazine: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Ranolazine. Management: Limit the ranolazine adult dose to a maximum of 500 mg twice daily in patients concurrently receiving moderate CYP3A4 inhibitors (e.g., diltiazem, verapamil, erythromycin, etc.). Risk D: Consider therapy modification
Salmeterol: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Salmeterol. Risk C: Monitor therapy
Saxagliptin: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Saxagliptin. Risk C: 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. Risk C: Monitor therapy
Tolvaptan: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Tolvaptan. Risk X: Avoid combination
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 24 hours after cessation of antibacterial agents. Risk D: Consider therapy modification
Vilazodone: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Vilazodone. Risk C: Monitor therapy
Vitamin K Antagonists (eg, warfarin): MetroNIDAZOLE (Systemic) may decrease the metabolism of Vitamin K Antagonists. Risk D: Consider therapy modification
Ethanol/Nutrition/Herb Interactions
Ethanol: The manufacturer recommends to avoid all ethanol or any ethanol-containing drugs (may cause disulfiram-like reaction characterized by flushing, headache, nausea, vomiting, sweating, or tachycardia).
Food: Peak antibiotic serum concentration lowered and delayed, but total drug absorbed not affected.
Pregnancy
 
B
Pregnancy Implications
Teratogenic effects have not been observed in animal reproduction studies; therefore, the manufacturer classifies metronidazole as pregnancy category B. Metronidazole crosses the placenta and rapidly distributes into the fetal circulation. Although there have been a few reports of facial anomalies after in utero exposure, most studies have not found an increased risk of congenital abnormalities following maternal use of metronidazole during the first trimester of pregnancy. In studies that included women taking metronidazole during all trimesters of pregnancy, an increased risk of adverse fetal and neonatal outcomes has not been observed. Because metronidazole has been carcinogenic in some animal species, concern has been raised whether metronidazole should be used during pregnancy; however, a strong carcinogenic potential in humans has not been observed, including one study of prenatal exposure.
Lactation
 
Enters breast milk/not recommended (AAP rates "of concern"; AAP 2001 update pending)
Breast-Feeding Considerations
Metronidazole and its active metabolite are measurable in the breast milk and infant plasma. Milk concentrations are similar to those in the maternal plasma and are highly variable. Peak concentrations of metronidazole in breast milk occur ~2-4 hours after the oral dose. In studies, the calculated relative infant doses have ranged from 0.13% to 36% of the weight-adjusted maternal dose. Use of metronidazole in a lactating patient is not recommended by the manufacturer. If metronidazole is given, breast-feeding should be withheld for 12-24 hours after the dose.
Mechanism of Action
 
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
Pharmacodynamics / Kinetics
 
Distribution: To saliva, bile, seminal fluid, bone, liver, and liver abscesses, lung and vaginal secretions; crosses blood-brain barrier
CSF:blood level ratio: Normal meninges: 16% to 43%; Inflamed meninges: 100%
Protein binding: <20%
Metabolism: Hepatic (30% to 60%)
Half-life elimination: Neonates: 25-75 hours; Others: 6-8 hours, prolonged with hepatic impairment; End-stage renal disease: 21 hours
Excretion: Urine (60% to 80% as unchanged drug); feces (6% to 15%)
 
   
 
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