Metronidazole - Metronidazole solution prescribing information
WARNING
Metronidazole has been shown to be carcinogenic in mice and rats (see PRECAUTIONS ). Its use, therefore, should be reserved for the conditions described in the INDICATIONS AND USAGE section below.
INDICATIONS AND USAGE
To reduce the development of drug-resistant bacteria and maintain the effectiveness of Metronidazole Injection USP and other antibacterial drugs, Metronidazole Injection USP should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy.
TREATMENT OF ANAEROBIC INFECTIONS
Metronidazole Injection is indicated in the treatment of serious infections caused by susceptible anaerobic bacteria. Indicated surgical procedures should be performed in conjunction with Metronidazole Injection therapy. In a mixed aerobic and anaerobic infection, antibacterial drugs appropriate for the treatment of the aerobic infection should be used in addition to Metronidazole Injection.
Metronidazole Injection USP is effective in Bacteroides fragilis infections resistant to clindamycin, chloramphenicol, and penicillin.
- Intra-Abdominal Infections , including peritonitis, intra-abdominal abscess, and liver abscess, caused by Bacteroides species including the B. fragilis group ( B. fragilis, B. distasonis, B. ovatus, B. thetaiotaomicron, B. vulgatus), Clostridium species, Eubacterium species, Peptococcus species, and Peptostreptococcus species in adults and pediatric patients less than 4 months of age.
- Skin and Skin Structure Infections caused by Bacteroides species including the B. fragilis group, Clostridium species, Peptococcus species, Peptostreptococcus species, and Fusobacterium species in adults.
- Gynecologic Infections , including endometritis, endomyometritis, tubo-ovarian abscess, and post-surgical vaginal cuff infection, caused by Bacteroides species including the B. fragilis group, Clostridium species, Peptococcus species, and Peptostreptococcus species in adults.
- Bacterial Septicemia caused by Bacteroides species including the B. fragilis group and Clostridium species in adults.
- Bone and Joint Infections , as adjunctive therapy, caused by Bacteroides species including the B. fragilis group in adults.
- Central Nervous System (CNS) Infections , including meningitis and brain abscess, caused by Bacteroides species including the B. fragilis group in adults.
- Lower Respiratory Tract Infections , including pneumonia, empyema, and lung abscess, caused by Bacteroides species including the B. fragilis group in adults.
- Endocarditis caused by Bacteroides species including the B. fragilis group in adults.
PROPHYLAXIS INDICATION
The prophylactic administration of Metronidazole Injection preoperatively, intraoperatively, and postoperatively may reduce the incidence of postoperative infection in adult patients undergoing elective colorectal surgery which is classified as contaminated or potentially contaminated.
Prophylactic use of Metronidazole Injection should be discontinued within 12 hours after surgery. If there are signs of infection, specimens for cultures should be obtained for the identification of the causative organism(s) so that appropriate therapy may be given (see DOSAGE AND ADMINISTRATION ).
Usage
To reduce the development of drug-resistant bacteria and maintain the effectiveness of metronidazole and other antibacterial drugs, metronidazole should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antimicrobial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy.
DOSAGE AND ADMINISTRATION
RECOMMENDED DOSAGE FOR THE TREATMENT OF ANAEROBIC BACTERIAL INFECTIONS
The recommended dosage schedule for adults for the treatment of anaerobic infections is presented in Table 1:
Table 1: Recommended Dosage Schedule for the Treatment of Anaerobic Bacterial Infections in Adults
| Loading Dose | 15 mg/kg infused over one hour (approximately 1 g for a 70-kg adult). |
| Maintenance Dose | 7.5 mg/kg infused over one hour every six hours (approximately 500 mg for a 70-kg adult). The first maintenance dose should be instituted six hours following the initiation of the loading dose. |
Parenteral therapy may be changed to oral metronidazole therapy when conditions warrant, based upon the severity of the disease and the response of the patient to treatment with Metronidazole Injection. The usual adult oral dosage is 7.5 mg/kg every six hours.
A maximum of 4 grams should not be exceeded during a 24-hour period.
The usual duration of therapy is 7 to 10 days; however, infections of the bone and joint, lower respiratory tract, and endocardium may require longer treatment.
Recommended Dosage for the Treatment of Intra-Abdominal Infections in Pediatric Patients Less than 4 Months of Age:
The recommended dosage schedule for pediatric patients less than 4 months of age for the treatment of intra-abdominal infections is described in Table 2 below.
These dosage schedules achieve drug exposures in pediatric patients similar to adults treated with Metronidazole Injection for this indication.
Table 2: Recommended Dosage Schedule for the Treatment of Intra-Abdominal Infections in Pediatric Patients Less than 4 months of Age
| Post-menstrual age (Completed weeks) | Loading Dose (mg/kg) | Maintenance Dose• (mg/kg) | Dosing interval (hours) |
| 23 - < 34 | 15 | 7.5 | 12 |
| 34 – 40 | 15 | 7.5 | 8 |
| >40 – 48 | 15 | 7.5 | 6 |
•The first maintenance dose is given 24 hours after the start of the loading dose.
Patients with severe hepatic disease metabolize metronidazole slowly, with resultant accumulation of metronidazole and its metabolites in the plasma. Accordingly, for such patients, doses below those usually recommended should be administered cautiously. Close monitoring of plasma metronidazole levels and toxicity is recommended. 1
In patients receiving Metronidazole Injection in whom gastric secretions are continuously removed by nasogastric aspiration, sufficient metronidazole may be removed in the aspirate to cause a reduction in serum levels.
The dose of Metronidazole Injection should not be specifically reduced in anuric patients since accumulated metabolites may be rapidly removed by dialysis.
Dosage Considerations in Geriatric Patients
In elderly patients the pharmacokinetics of metronidazole may be altered and, therefore, monitoring of serum levels may be necessary to adjust the Metronidazole Injection dosage accordingly.
RECOMMENDED PROPHYLAXIS DOSAGE
For surgical prophylactic use, to prevent postoperative infection in contaminated or potentially contaminated colorectal surgery, the recommended dosage schedule for adults is:
- 15 mg/kg infused over 30 to 60 minutes and completed approximately one hour before surgery, followed by:
- 7.5 mg/kg infused over 30 to 60 minutes at 6 and 12 hours after the initial dose.
It is important that (1) administration of the initial preoperative dose be completed approximately one hour before surgery so that adequate drug levels are present in the serum and tissues at the time of initial incision, and (2) Metronidazole Injection be administered, if necessary, at 6-hour intervals to maintain effective drug levels. Prophylactic use of Metronidazole Injection should be limited to the day of surgery only, following the above guidelines.
IMPORTANT PREPARATION AND ADMINISTRATION INSTRUCTIONS
Caution: Metronidazole Injection - is to be administered by slow intravenous drip infusion only, either as a continuous or intermittent infusion. IV admixtures containing metronidazole and other drugs should be avoided. Additives should not be introduced into this solution. If used with a primary intravenous fluid system, the primary solution should be discontinued during metronidazole infusion. DO NOT USE EQUIPMENT CONTAINING ALUMINUM (E.G., NEEDLES, CANNULAE) THAT WOULD COME IN CONTACT WITH THE DRUG SOLUTION.
Metronidazole Injection USP is a ready-to-use isotonic solution. NO DILUTION OR BUFFERING IS REQUIRED. Do not refrigerate. Each container of Metronidazole Injection contains 13.5 mEq of sodium.
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Do not use if cloudy or precipitated or if the seals are not intact.
Use sterile equipment. It is recommended that the intravenous administration apparatus be replaced at least once every 24 hours.
CONTRAINDICATIONS
- Hypersensitivity
Metronidazole Injection is contraindicated in patients with a prior history of hypersensitivity to metronidazole or other nitroimidazole derivatives.
- Psychotic Reaction with Disulfiram
Use of oral metronidazole is associated with psychotic reactions in alcoholic patients who were using disulfiram concurrently. Do not administer metronidazole to patients who have taken disulfiram within the last two weeks (see PRECAUTIONS -Drug Interactions ).
- Interaction with Alcohol
Use of oral metronidazole is associated with a disulfiram-like reaction to alcohol, including abdominal cramps, nausea, vomiting, headaches, and flushing. Discontinue consumption of alcohol or products containing propylene glycol during and for at least three days after therapy with metronidazole (see PRECAUTIONS -Drug Interactions ).
- Cockayne Syndrome
Metronidazole Injection is contraindicated in patients with Cockayne syndrome. Severe irreversible hepatotoxicity/acute liver failure with fatal outcomes have been reported after initiation of metronidazole in patients with Cockayne syndrome (see ADVERSE REACTIONS ).
ADVERSE REACTIONS
The following are the most serious adverse reactions reported in patients treated with metronidazole and are also described elsewhere in the labeling: convulsive seizures, encephalopathy, aseptic meningitis, optic and peripheral neuropathy (characterized mainly by numbness or paresthesia of an extremity) (see WARNINGS ).
The following adverse reactions associated with the use of metronidazole products were identified in clinical studies or postmarketing reports or published literature. Because some of these reactions were reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
GASTROINTESTINAL: Nausea, anorexia, vomiting, abdominal discomfort, diarrhea, an unpleasant metallic taste, epigastric distress, abdominal cramping, constipation and pancreatitis.
MOUTH: A sharp metallic taste. Furry tongue, glossitis, and stomatitis have occurred; these may be associated with a sudden overgrowth of Candida which may occur during therapy with metronidazole.
HEMATOPOIETIC: Reversible neutropenia (leukopenia); thrombocytopenia, eosinophilia.
HEPATOBILIARY DISORDERS: Hepatotoxicity and liver failure especially in patients with Cockayne syndrome (see CONTRAINDICATIONS ), jaundice.
CARDIOVASCULAR: QT prolongation has been reported, particularly when metronidazole was administered with drugs with the potential for prolonging the QT interval. Flattening of the T-wave may be seen in electrocardiographic tracings.
SKIN AND SUBCUTANEOUS DISORDERS: Toxic epidermal necrolysis, Stevens-Johnson syndrome, Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), erythematous rash, bullae, pruritus, swelling face, urticaria, and hyperhidrosis.
CENTRAL NERVOUS SYSTEM: Encephalopathy, aseptic meningitis, convulsive seizures, optic neuropathy, peripheral neuropathy (mainly numbness or paresthesia of an extremity), dizziness, vertigo, incoordination, ataxia, confusion, psychosis, dysarthria, irritability, depression, weakness, headache, tinnitus, hearing impairment, hearing loss, and insomnia.
LABORATORY INVESTIGATIONS: Hepatic enzymes increased.
HYPERSENSITIVITY: Toxic epidermal necrolysis (TEN), Stevens-Johnson Syndrome (SJS), drug reaction with eosinophilia and systemic symptoms (DRESS), acute generalized exanthematous pustulosis (AGEP) (see WARNINGS ), anaphylaxis, angioedema, hypotension, flushing, nasal congestion, and dryness of mouth (or vagina or vulva).
RENAL: Dysuria, cystitis, polyuria, incontinence, a sense of pelvic pressure, and darkened urine.
HEPATIC : Cases of severe irreversible hepatotoxicity/acute liver failure, including cases with fatal outcomes with very rapid onset after initiation of systemic use of metronidazole, have been reported in patients with Cockayne Syndrome (latency from drug start to signs of liver failure as short as 2 days) (see CONTRAINDICATIONS ).
LOCAL REACTIONS: Thrombophlebitis after intravenous infusion. This reaction can be minimized or avoided by avoiding prolonged use of indwelling intravenous catheters.
OTHER ADVERSE REACTIONS: Fever, hiccup, proliferation of Candida in the vagina, dyspareunia, decrease of libido, proctitis, and fleeting joint pains sometimes resembling “serum sickness”. If patients receiving metronidazole drink alcoholic beverages, they may experience abdominal distress, nausea, vomiting, flushing, or headache. A modification of the taste of alcoholic beverages has also been reported.
Patients with Crohn’s disease 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. Crohn’s disease is not an approved indication for Metronidazole Injection USP.
Darkened Urine:
Instances of darkened urine have also been reported, and this manifestation has been the subject of a special investigation. Although the pigment which is probably responsible for this phenomenon has not been positively identified, it is almost certainly a metabolite of metronidazole and seems to have no clinical significance.
DRUG INTERACTIONS:
Metronidazole has been reported to potentiate the anticoagulant effect of warfarin and other oral coumarin anticoagulants, resulting in a prolongation of prothrombin time. This possible drug interaction should be considered when Metronidazole Injection USP is prescribed for patients on this type of anticoagulant therapy.
The simultaneous administration of drugs that induce microsomal liver enzymes, such as phenytoin or phenobarbital, may accelerate the elimination of metronidazole, resulting in reduced plasma levels; impaired clearance of phenytoin has also been reported.
The simultaneous administration of drugs that decrease microsomal liver enzyme activity, such as cimetidine, may prolong the half-life and decrease plasma clearance of metronidazole.
Alcoholic beverages should not be consumed during metronidazole therapy because abdominal cramps, nausea, vomiting, headaches, and flushing may occur.
Psychotic reactions have been reported in alcoholic patients who are using metronidazole and disulfiram concurrently. Metronidazole should not be given to patients who have taken disulfiram within the last two weeks.
QT prolongation has been reported, particularly when metronidazole was administered with drugs with the potential for prolonging the QT interval.
DESCRIPTION
Metronidazole Injection USP is a sterile, parenteral dosage form of metronidazole in water.
Each 100 mL of Metronidazole Injection USP contains a sterile, nonpyrogenic, isotonic, buffered solution of Metronidazole USP 500 mg, Sodium Chloride USP 740 mg, Dibasic Sodium Phosphate•7H 2 O USP 112 mg, and Citric Acid Anhydrous USP 40 mg in Water for Injection USP. Metronidazole Injection USP has a calculated osmolarity of 297 mOsmol/liter and a pH of 5.8 (4.5–7.0). Sodium content: 13.5 mEq/container.
Metronidazole is classified as a nitroimidazole antimicrobial and is administered by the intravenous route.
Metronidazole USP is chemically designated 2-methyl-5-nitroimidazole-1-ethanol (C 6 H 9 N 3 O 3 ):
Not made with natural rubber latex, PVC, or DEHP.
The plastic container is a copolymer of ethylene and propylene formulated and developed for parenteral drugs. The copolymer contains no plasticizers. The safety of the plastic container has been confirmed by biological evaluation procedures.
The material passes Class VI testing as specified in the U.S. Pharmacopeia for Biological Tests – Plastic Containers. The container/solution unit is a closed system and is not dependent upon entry of external air during administration. No vapor barrier is necessary.
CLINICAL PHARMACOLOGY
Metronidazole is a synthetic antibacterial compound. Disposition of metronidazole in the body is similar for both oral and intravenous dosage forms, with an average elimination half-life in healthy humans of eight hours.
The major route of elimination of metronidazole and its metabolites is via the urine (60 to 80% of the dose), with fecal excretion accounting for 6 to 15% of the dose. The metabolites that appear in the urine result primarily from side-chain oxidation (1-[ β -hydroxyethyl]-2-hydroxymethyl-5-nitroimidazole and 2-methyl-5-nitroimidazole-1-yl-acetic acid) and glucuronide conjugation, with unchanged metronidazole accounting for approximately 20% of the total. Renal clearance of metronidazole is approximately 10 mL/min/1.73 m 2 .
Metronidazole is the major component appearing in the plasma, with lesser quantities of the 2-hydroxymethyl metabolite also being present. Less than 20% of the circulating metronidazole is bound to plasma proteins. Both the parent compound and the metabolite possess in vitro bactericidal activity against most strains of anaerobic bacteria.
Metronidazole appears in cerebrospinal fluid, saliva, and human milk in concentrations similar to those found in plasma. Bactericidal concentrations of metronidazole have also been detected in pus from hepatic abscesses.
Plasma concentrations of metronidazole are proportional to the administered dose. An eight-hour intravenous infusion of 100 to 4,000 mg of metronidazole in normal subjects showed a linear relationship between dose and peak plasma concentration.
In patients treated with metronidazole injection using a dosage regimen of 15 mg/kg loading dose followed six hours later by 7.5 mg/kg every six hours, peak steady-state plasma concentrations of metronidazole averaged 25 mcg/mL with trough (minimum) concentrations averaging 18 mcg/mL.
Decreased renal function does not alter the single-dose pharmacokinetics of metronidazole. However, plasma clearance of metronidazole is decreased in patients with decreased liver function.
Pediatric Patients
In one study newborn infants appeared to demonstrate diminished capacity to eliminate metronidazole. The elimination half-life, measured during the first three days of life, was inversely related to gestational age. In infants whose gestational ages were between 28 and 40 weeks, the corresponding elimination half-lives ranged from 109 to 22.5 hours.
Two other trials included infants 23-48 weeks post-menstrual age, (0-80 days postnatal age) with complicated intra-abdominal infections. Clearance increased with increasing post-menstrual age, while volume of distribution and half-life decreased ( see PRECAUTIONS, Pediatric Use and DOSAGE AND AMINISTRATION ).
MICROBIOLOGY:
Mechanism of Action
Metronidazole, a nitroimidazole, exerts antibacterial effects in an anaerobic environment against most obligate anaerobes. Once metronidazole enters the organism by passive diffusion and activated in the cytoplasm of susceptible anaerobic bacteria, it is reduced; this process includes intra-cellular electron transport donors such as ferredoxin and transfer of an electron to the nitro group of the metronidazole leading to formation of a short-lived nitroso free radical. Because of this alteration of the metronidazole molecule, a concentration gradient is created and maintained which promotes the drug’s intracellular transport. The reduced form of metronidazole and free radicals may interact with DNA leading to inhibition of DNA synthesis, DNA degradation, and death of bacteria. The precise mechanism of action of metronidazole is unclear.
Drug Resistance
A potential for development of resistance exists against metronidazole.
Resistance may be due to multiple mechanisms that include decreased uptake of the drug, altered reduction efficiency, overexpression of the efflux pumps, inactivation of the drug, and/or increased DNA damage repair.
Metronidazole does not possess any clinically relevant activity against facultative anaerobes or obligate aerobes.
Antimicrobial Activity
Metronidazole has been shown to be active against most isolates of the following bacteria both in vitro and clinical infections as described in the INDICATIONS AND USAGE section.
Gram negative anaerobes:
Bacteroides fragilis group (B. fragilis, B. distasonis, B. ovatus, B. thetaiotaomicron, B. vulgatus)
Fusobacterium species
Gram positive anaerobes:
Clostridium species
Eubacterium species
Peptococcus species
Peptostreptococcus species
The following in vitro data are available, but their clinical significance is unknown: Metronidazole exhibits in vitro minimal inhibitory concentrations (MIC’s) of 8 mcg/mL or less against most (≥90%) isolates of the following bacteria; however, the safety and effectiveness of metronidazole in treating clinical infections due to these bacteria have not been established in adequate and well-controlled clinical trials.
Gram negative anaerobes
Bacteroides fragilis group (B. caccae, B. uniformis)
Prevotella species (P. bivia, P. buccae, P. disiens)
Susceptibility Testing:
For specific information regarding susceptibility test interpretive criteria, and associated test methods and quality control standards recognized by FDA for this drug, please see: http://www.fda.gov/STIC .
HOW SUPPLIED
Metronidazole Injection USP, sterile, is supplied in 100 mL fill PAB® containers, each containing an isotonic, buffered solution of 500 mg metronidazole; packaged 24 per case. Metronidazole injection is sterile premixed solution intended for single use only.
| NDC | REF | Fill Volume |
|---|---|---|
| Metronidazole Injection USP 0264-5535-32 | D5353-5224 | 100 mL |
Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat. Protect from freezing. It is recommended that the product be stored at room temperature (25°C); however, brief exposure up to 40°C does not adversely affect the product.
Protect from light until use.
