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:

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.

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.

SEVERE CUTANEOUS ADVERSE REACTIONS:

Severe cutaneous adverse reactions (SCARs) including toxic epidermal necrolysis (TEN), Stevens-Johnson syndrome (SJS), drug reaction with eosinophilia and systemic symptoms (DRESS), and acute generalized exanthematous pustulosis (AGEP) have been reported with the use of metronidazole. Symptoms can be serious and potentially life threatening. If symptoms or signs of SCARs develop, discontinue Metronidazole injection immediately and institute appropriate therapy.

CENTRAL AND PERIPHERAL NERVOUS SYSTEM EFFECTS:

Convulsive seizures, encephalopathy, aseptic meningitis, optic and peripheral neuropathy, the latter characterized mainly by numbness or paresthesia of an extremity, have been reported in patients treated with metronidazole products. Since persistent peripheral neuropathy has been reported in some patients receiving prolonged oral administration of metronidazole, patients should be observed carefully. The appearance of abnormal neurologic signs demands the prompt evaluation of the benefit/risk ratio of the continuation of therapy.

GENERAL:

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.

Administration of solutions containing sodium ions may result in sodium retention. Care should be taken when administering Metronidazole Injection to patients receiving corticosteroids or to patients predisposed to edema.

Known or previously unrecognized candidiasis may present more prominent symptoms during therapy with Metronidazole Injection and requires treatment with a candicidal agent.

Prescribing Metronidazole Injection in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria.

INFORMATION FOR PATIENTS:

Patients should be counseled that antibacterial drugs including Metronidazole Injection USP should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When Metronidazole Injection USP is prescribed to treat a bacterial infection, patients should be told that although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed. Skipping doses or not completing the full course of therapy may (1) decrease the effectiveness of the immediate treatment and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by Metronidazole Injection USP or other antibacterial drugs in the future.

Advise patients that Metronidazole Injection may increase the risk of serious and sometimes fatal dermatologic reactions, including toxic epidermal necrolysis (TEN), Stevens-Johnson syndrome (SJS), and drug reaction with eosinophilia and systemic symptoms (DRESS). Instruct the patient to be alert for skin rash, blisters, fever or other signs and symptoms of these hypersensitivity reactions. Advise patients to stop Metronidazole injection immediately if they develop any type of rash and seek medical attention.

LABORATORY TESTS:

Metronidazole is a nitroimidazole, and Metronidazole Injection USP should be used with caution in patients with evidence of or history of blood dyscrasia. A mild leukopenia has been observed during its administration; however, no persistent hematologic abnormalities attributable to metronidazole have been observed in clinical studies. Total and differential leukocyte counts are recommended before and after therapy.

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.

DRUG/LABORATORY TEST INTERACTIONS:

Metronidazole may interfere with certain types of determinations of serum chemistry values, such as aspartate aminotransferase (AST, SGOT), alanine aminotransferase (ALT, SGPT), lactate dehydrogenase (LDH), triglycerides, and hexokinase glucose. Values of zero may be observed. All of the assays in which interference has been reported involve enzymatic coupling of the assay to oxidation-reduction of nicotinamide adenine dinucleotide (NAD+ NADH). Interference is due to the similarity in absorbance peaks of NADH (340 nm) and metronidazole (322 nm) at pH 7.

CARCINOGENESIS, MUTAGENESIS, IMPAIRMENT OF FERTILITY

PREGNANCY:

NURSING MOTHERS:

Metronidazole is secreted in human milk in concentrations similar to those found in plasma. Because of the potential for tumorigenicity shown for metronidazole in mouse and rat studies, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

PEDIATRIC USE:

Pediatric Patients Less than 4 Months of Age

The safety and effectiveness of Metronidazole Injection have been established for the treatment of intra-abdominal infections in pediatric patients from birth to less than 4 months. Use of Metronidazole Injection in this age group is supported by evidence from data in adults with additional pharmacokinetic and safety data in pediatric patients from birth to less than 4 months of age.

A partially randomized, open-label, phase 2/3 study of intravenous Metronidazole Injection in combination with other intravenous antibacterial drugs was conducted in 62 preterm infants (≤ 33 weeks gestational age at birth, and postnatal age <121 days) and 55 late preterm and term infants (≥ 34 weeks gestational age at birth, and postnatal age <121 days), with complicated intra-abdominal infections. The primary objective of this study was to evaluate the safety of metronidazole-containing regimens, which were administered for up to 10 days. The adverse reactions reported in patients receiving metronidazole-containing regimens were comparable to patients receiving other antibacterial regimens in the study and generally similar to adverse reactions described in adults.

The safety and effectiveness of Metronidazole Injection in pediatric patients less than 4 months of age have not been established for (1) the treatment of anaerobic infections other than intra-abdominal infections or for (2) prophylaxis of postoperative infections (see INDICATIONS AND USAGE, CLINICAL PHARMACOLOGY, Pediatric Patients and DOSAGE AND ADMINISTRATION).

Pediatric Patients 4 Months of Age and Older

The safety and effectiveness of Metronidazole Injection in pediatric patients 4 months of age and older have not been established.

TREATMENT:

There is no specific antidote for overdose; therefore, management of the patient should consist of symptomatic and supportive therapy.

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

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

*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:

1. 15 mg/kg infused over 30 to 60 minutes and completed approximately one hour before surgery, followed by:
2. 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.

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.