Distribution

Metronidazole is the major component appearing in the plasma, with lesser quantities of metabolites also being present. Less than 20% of the circulating metronidazole is bound to plasma proteins. Metronidazole appears in cerebrospinal fluid, saliva and breast milk in concentrations similar to those found in plasma. Bactericidal concentrations of metronidazole have also been detected in pus from hepatic abscesses.

Following a single intravenous dose of metronidazole 500 mg, 4 healthy subjects who underwent gastrointestinal endoscopy had peak gastric juice metronidazole concentrations of 5 mcg/mL to 6 mcg/mL at one hour post-dose. In patients receiving intravenous metronidazole 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.

Metabolism

The metabolites of metronidazole result primarily from side-chain oxidation [1-(ß-hydroxyethyl)-2-hydroxymethyl-5-nitroimidazole and 2-methyl-5-nitroimidazole-1-yl-acetic acid] and glucuronide conjugation. Both the parent compound and the hydroxyl metabolite possess in vitro antimicrobial activity.

Excretion

The major route of elimination of metronidazole and its metabolites is via the urine (60% to 80% of the dose), with approximately 20% of the amount excreted appearing as unchanged metronidazole. Renal clearance of metronidazole is approximately 10 mL/min/1.73 m2. Fecal excretion accounts for 6% to 15% of the dose.

Renal Impairment

Decreased renal function does not alter the single-dose pharmacokinetics of metronidazole.

Subjects with end-stage renal disease (ESRD; CLCR = 8.1 mL/min ± 9.1 mL/min) and who received a single intravenous infusion of metronidazole 500 mg had no significant change in metronidazole pharmacokinetics but had 2-fold higher Cmax of hydroxy-metronidazole and 5-fold higher Cmax of metronidazole acetate, compared to healthy subjects with normal renal function (CLCR = 126 mL/min ± 16 mL/min). Thus, on account of the potential accumulation of metronidazole metabolites in ESRD patients, monitoring for metronidazole associated adverse events is recommended (see PRECAUTIONS).

Effect of Dialysis

Following a single intravenous infusion or oral dose of metronidazole 500 mg, the clearance of metronidazole was investigated in ESRD subjects undergoing hemodialysis or continuous ambulatory peritoneal dialysis (CAPD). A hemodialysis session lasting for 4 hours to 8 hours removed 40% to 65% of the administered metronidazole dose, depending on the type of the dialyzer membrane used and the duration of the dialysis session. If the administration of metronidazole cannot be separated from the dialysis session, supplementation of metronidazole dose following hemodialysis should be considered (see DOSAGE AND ADMINISTRATION). A peritoneal dialysis session lasting for 7.5 hours removed approximately 10% of the administered metronidazole dose. No adjustment in metronidazole dose is needed in ESRD patients undergoing CAPD.

Hepatic Impairment

Following a single intravenous infusion of 500 mg metronidazole, the mean AUC24 of metronidazole was higher by 114% in patients with severe (Child-Pugh C) hepatic impairment, and by 54% and 53% in patients with a mild (Child-Pugh A) and moderate (Child-Pugh B) hepatic impairment, respectively, compared to healthy control subjects. There were no significant changes in the AUC24 of hydroxy-metronidazole in these hepatically impaired patients. A reduction in metronidazole dosage by 50% is recommended in patients with severe (Child-Pugh C) hepatic impairment (see DOSAGE AND ADMINISTRATION). No dosage adjustment is needed for patients with mild to moderate hepatic impairment. Patients with mild to moderate hepatic impairment should be monitored for metronidazole associated adverse events (see PRECAUTIONS and DOSAGE AND ADMINISTRATION).

Geriatric Patients

Following a single 500 mg oral or intravenous dose of metronidazole, subjects > 70 years old with no apparent renal or hepatic dysfunction had a 40% to 80% higher mean AUC of hydroxy-metronidazole (active metabolite), with no apparent increase in the mean AUC of metronidazole (parent compound), compared to young healthy controls < 40 years old. In geriatric patients, monitoring for metronidazole associated adverse events is recommended (see PRECAUTIONS).

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 weeks and 40 weeks, the corresponding elimination half-lives ranged from 109 hours to 22.5 hours.

Two other trials included infants 23 weeks to 48 weeks post-menstrual age, (0 days to 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 ADMINISTRATION).

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 is activated in the cytoplasm of susceptible anaerobic bacteria, it is reduced; this process includes intra-cellular electron transport proteins such as ferredoxin, transfer of an electron to the nitro group of the metronidazole, and 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 can interact with DNA leading to inhibition of DNA synthesis and DNA degradation leading to 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.

Activity In Vitro and in Clinical Infections

Metronidazole has been shown to be active against most isolates of the following bacteria both in vitro and in clinical infections as described in the INDICATIONS AND USAGE section.

Gram-positive anaerobes

Clostridium species

Eubacterium species

Peptococcus species

Peptostreptococcus species

Gram-negative anaerobes

Bacteroides fragilis group (B. fragilis, B. distasonis, B. ovatus, B. thetaiotaomicron, B. vulgatus)

Fusobacterium 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 Tests

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 Bacterial 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 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 postsurgical vaginal cuff infection, caused by Bacteroides species including the B. fragilis group, Clostridium species, Peptococcus species, Peptostreptococcus species and Fusobacterium 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 injection and other antibacterial drugs, metronidazole injection 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.

General

Hepatic Impairment

Patients with hepatic impairment metabolize metronidazole slowly, with resultant accumulation of metronidazole and increase the plasma concentrations. Reduce the dose of metronidazole injection by 50% in patients with severe hepatic impairment (Child-Pugh C). For patients with mild to moderate hepatic impairment, no dosage adjustment is needed but these patients should be monitored for metronidazole associated adverse events (see CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION).

Patients with severe hepatic encephalopathy metabolize metronidazole slowly, with resultant accumulation of metronidazole. This may cause exacerbation of CNS adverse effects. Reduce the dose of metronidazole injection as necessary.

Renal Impairment

For patients with mild to moderate renal impairment dose adjustment is not considered necessary as elimination half-life is not significantly altered. In patients with severe renal impairment or end stage of renal disease, metronidazole and metronidazole metabolites may accumulate significantly because of reduced urinary excretion in those patients. Monitoring for metronidazole associated adverse events is recommended when metronidazole is administered in patients with severe renal impairment or end stage of renal disease who are not undergoing hemodialysis (see CLINICAL PHARMACOLOGY).

Hemodialysis removes significant amounts of metronidazole and its metabolites from systemic circulation. Therefore, supplementation of metronidazole following a hemodialysis session may be necessary.

Patients receiving peritoneal dialysis should be monitored for signs of toxicity due to the potential accumulation of metronidazole metabolites.

Fungal Superinfections

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

Use in Patients with Blood Dyscrasias

Metronidazole is a nitroimidazole and should be used with care in patients with evidence of or history of blood dyscrasia. Agranulocytosis, leukopenia and neutropenia have been associated with metronidazole administration. Monitor complete blood count in these patients.

Monitoring for Leukopenia

Monitoring of complete blood count (CBC) is recommended before, during and after prolonged or repeated courses of metronidazole therapy.

Sodium Retention

Metronidazole injection contains 790 mg of sodium per 100 mL. Care should be taken when administering metronidazole injection to patients receiving a controlled sodium diet or corticosteroids or to patients predisposed to edema.

Drug-Resistant Bacteria

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

• Interaction with Alcohol

Discontinue consumption of alcoholic beverages or products containing propylene glycol while taking metronidazole injection and for at least three days afterward because abdominal cramps, nausea, vomiting, headaches, and flushing may occur (see CONTRAINDICATIONS, PRECAUTIONS-Drug Interactions).

• Treatment of Bacterial Infections

Patients should be counseled that antibacterial drugs including metronidazole injection should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When metronidazole injection 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 or other antibacterial drugs in the future.

• Severe Cutaneous Adverse Reactions

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.

Drug Interactions

• Disulfiram

Psychotic reactions and confusion have been reported in alcoholic patients who are using metronidazole and disulfiram concurrently. Do not administer metronidazole injection to patients who have taken disulfiram within the last two weeks (see CONTRAINDICATIONS).

• Alcoholic Beverages

Abdominal cramps, nausea, vomiting, headaches, tachycardia and flushing may occur if alcoholic beverages or products containing propylene glycol are consumed during or following metronidazole therapy. Discontinue consumption of alcohol or products containing propylene glycol before, during and up to 72 hours after therapy with metronidazole injection (see CONTRAINDICATIONS).

• Warfarin and other Oral Anticoagulants

Metronidazole has been reported to potentiate the anticoagulant effect of warfarin and other oral coumarin anticoagulants, resulting in a prolongation of prothrombin time and increased risk of hemorrhages. When metronidazole injection is prescribed for patients on this type of anticoagulant therapy, prothrombin time and international normalized ratio (INR) should be carefully monitored and their anticoagulant dose adjusted accordingly. Monitor patients for signs and symptoms of bleeding.

• Lithium

In patients stabilized on relatively high doses of lithium, short-term metronidazole therapy has been associated with elevation of serum lithium and, in a few cases, signs of lithium toxicity. Lithium toxicity may lead to renal damage. Frequent monitoring of serum lithium and serum creatinine levels is necessary.

• Busulfan

Metronidazole has been reported to increase plasma concentrations of busulfan, which can result in an increased risk for serious busulfan toxicity such as sinusoidal obstruction syndrome, gastrointestinal mucositis and hepatic veno-occlusive disease. Metronidazole injection should not be administered concomitantly with busulfan unless the benefit outweighs the risk. If no therapeutic alternatives to metronidazole are available, and concomitant administration with busulfan is medically needed, frequent monitoring of busulfan plasma concentration should be performed and the busulfan dose should be adjusted accordingly.

• Drugs that Inhibit CYP450 Enzymes

The simultaneous administration of drugs that decrease microsomal liver enzyme activity, such as cimetidine, may decrease metabolism and reduce plasma clearance of metronidazole which may result in metronidazole toxicity.

• Drugs that Induce CYP450 Enzymes

The simultaneous administration of drugs that induce microsomal liver enzyme activity, such as phenytoin or phenobarbital, may accelerate the elimination of metronidazole and therefore decrease its efficacy.

• Cytochrome P450 3A4 (CYP3A4) substrates

Concomitant use of metronidazole injection and CYP3A4 substrates (e.g., amiodarone, tacrolimus, cyclosporine, carbamazepine, phenytoin and quinidine) may increase respective CYP3A4-substrate plasma levels. Monitoring of plasma concentrations of CYP3A4 substrates may be necessary.

• 5-Fluorouracil

Metronidazole injection decreases the clearance of 5-fluorouracil and may therefore cause 5-fluorouracil toxicity.

• Vecuronium

Metronidazole injection may potentiate the effects of vecuronium.

• Drugs that Prolong the QT interval

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 glucose hexokinase. Metronidazole causes an increase in ultraviolet absorbance at 340 nm resulting in falsely decreased values.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Tumors affecting the liver, lung, mammary and lymphatic tissues have been detected in several studies of metronidazole in rats and mice, but not hamsters.

Pulmonary tumors have been observed in all six reported studies in the mouse, including one study in which the animals were dosed on an intermittent schedule (administration during every fourth week only). Malignant tumors were increased in male mice treated at approximately 1,500 mg/m2 (similar to the maximum recommended daily dose, based on body surface area comparisons). Malignant lymphomas and pulmonary neoplasms were also increased with lifetime feeding of the drug to mice. Mammary and hepatic tumors were increased among female rats administered oral metronidazole compared to concurrent controls. Two lifetime tumorigenicity studies in hamsters have been performed and reported to be negative.

Metronidazole has shown mutagenic activity in in vitro assay systems including the Ames test. Studies in mammals in vivo have failed to demonstrate a potential for genetic damage.

Metronidazole failed to produce any adverse effects on fertility or testicular function in male rats at doses up to 400 mg/kg/day (approximately 2 times the maximum recommended daily dose based on body surface area comparison) for 28 days. However, rats treated at the same dose for 6 weeks, or longer were infertile and showed severe degeneration of the seminiferous epithelium in the testes as well as marked decreases in testicular spermatid counts and epididymal sperm counts. Fertility was restored in most rats after an eight week, drug-free recovery period.

Fertility studies have been performed in male mice at doses up to six times the maximum recommended human dose based on mg/m2 and have revealed no evidence of impaired fertility. However, metronidazole was associated with reversible adverse effects on the male reproductive system (significantly decreased testes and epididymides weight, decreased sperm viability, and increased the incidence of abnormal sperm).

Pregnancy

Teratogenic Effects

There are no adequate and well-controlled studies of metronidazole injection in pregnant women. There are published data from case-control studies, cohort studies and 2 meta-analyses that include more than 5,000 pregnant women who used metronidazole during pregnancy. Many studies included first trimester exposures. One study showed an increased risk of cleft lip, with or without cleft palate, in infants exposed to metronidazole in utero; however, these findings were not confirmed. In addition, more than ten randomized, placebo-controlled clinical trials enrolled more than 5,000 pregnant women to assess the use of antibiotic treatment (including metronidazole) for bacterial vaginosis on the incidence of preterm delivery. Most studies did not show an increased risk for congenital anomalies or other adverse fetal outcomes following metronidazole exposure during pregnancy. Three studies conducted to assess the risk of infant cancer following metronidazole exposure during pregnancy did not show an increased risk; however, the ability of these studies to detect such a signal was limited.

Metronidazole crosses the placental barrier and its effects on the human fetal organogenesis are not known. Reproduction studies have been performed in rats, rabbits and mice at doses similar to the maximum recommended daily dose based on body surface area comparisons. There was no evidence of harm to the fetus due to metronidazole.

Healthcare provider should carefully consider the potential risks and benefits for each specific patient before prescribing metronidazole injection.

Nursing Mothers

Metronidazole is present in human milk at concentrations similar to maternal serum levels, and infant serum levels can be close to or comparable to infant therapeutic levels. 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. Alternatively, a nursing mother may choose to pump and discard human milk for the duration of metronidazole therapy, and for 24 hours after therapy ends and feed her infant stored human milk or formula.

Geriatric Use

In general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

In geriatric patients, monitoring for metronidazole associated adverse events is recommended (see CLINICAL PHARMACOLOGY, PRECAUTIONS). Decreased liver function in geriatric patients can result in increased concentrations of metronidazole that may necessitate adjustment of metronidazole dosage (see DOSAGE AND ADMINISTRATION).

Pediatric Use

Pediatric Patients Less than 4 Months of Age

The safety and effectiveness of Metronidazole Injection have been established for the treatment of intraabdominal 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 pre-term 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 for 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.

DIRECTIONS FOR USE OF PLASTIC CONTAINER

Metronidazole injection is a ready-to-use iso-osmotic solution. No dilution or buffering is required. Do not refrigerate. Each container of metronidazole injection contains 14 mEq of sodium.

Do not connect flexible plastic containers in series in order to avoid air embolism due to possible residual air contained in the primary container.

Pressurizing intravenous solutions contained in flexible plastic containers to increase flow rates can result in air embolism if the residual air in the container is not fully evacuated prior to administration.

Use of a vented intravenous administration set with the vent in the open position could result in air embolism. Vented intravenous administration sets with the vent in the open position should not be used with flexible plastic containers.

Discard any unused portion.

For single-dose only.

To open

Tear overwrap at notch and remove solution container. Visually inspect the container. If the twist-off port is damaged, detached, or not present, discard container as solution path sterility may be impaired. Some opacity of the plastic due to moisture absorption during the sterilization process may be observed. This is normal and does not affect the solution quality or safety. The opacity will diminish gradually. Check for leaks. Do not add supplementary medication.

Preparation for Administration

1.     Suspend container from eyelet support.

2.     Remove twist-off port from bag.

3.     Attach administration set. Refer to complete directions accompanying set.

To report SUSPECTED ADVERSE REACTIONS, contact Amneal Pharmaceuticals LLC at 1-877-835-5472 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

Manufactured by:

Amneal Pharmaceuticals Pvt. Ltd.

Ahmedabad 382110, INDIA

Distributed by:

Amneal Pharmaceuticals LLC

Bridgewater, NJ 08807

Rev. 05-2025-03