METRONIDAZOLE- metronidazole_injection, solution

CLINICAL PHARMACOLOGY
In patients treated with intravenous metronidazole, using a dosage regimen of 15 mg/kg loading dose followed 6 hours later by 7. 5 mg/kg every 6 hours, the average peak steady-state plasma concentrations (C max min 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 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. 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 The major route of elimination of metronidazole and its metabolites is via the urine (60-80% 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 m 2 Decreased renal function does not alter the single-dose pharmacokinetics of metronidazole. Subjects with end-stage renal disease (ESRD; CL CR CR PRECAUTIONS 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 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 Following a single intravenous infusion of 500 mg metronidazole, the mean AUC 24 24 DOSAGE AND ADMINISTRATION PRECAUTIONS DOSAGE AND ADMINISTRATION Following a single 500 mg oral or IV 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 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. 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 DOSAGE AND ADMINISTRATION 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. 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 Metronidazole has been shown to be active against most isolates of the following bacteria both in vitro INDICATIONS AND USAGE Gram-positive anaerobes Clostridium Eubacterium Peptococcus Peptostreptococcus Gram-negative anaerobes Bacteroides fragilis B. distasonis B. thetaiotaomicron B. vulgatus Fusobacterium The following in vitro but their clinical significance is unknown. Metronidazole exhibits in vitro Gram-negative anaerobes Bacteroides fragilis B. uniformis Prevotella P. disiens 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.
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 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
Excretion
The major route of elimination of metronidazole and its metabolites is via the urine (60-80% 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 m 2
Microbiology
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. 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 Metronidazole has been shown to be active against most isolates of the following bacteria both in vitro INDICATIONS AND USAGE Gram-positive anaerobes Clostridium Eubacterium Peptococcus Peptostreptococcus Gram-negative anaerobes Bacteroides fragilis B. distasonis B. thetaiotaomicron B. vulgatus Fusobacterium The following in vitro but their clinical significance is unknown. Metronidazole exhibits in vitro Gram-negative anaerobes Bacteroides fragilis B. uniformis Prevotella P.

INDICATIONS AND USAGE
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 Intra-Abdominal Infections, Bacteroides B. distasonis B. thetaiotaomicron B. vulgatus Clostridium Eubacterium Peptococcus Peptostreptococcus Skin and Skin Structure Infections Bacteroides B. fragilis Clostridium Peptococcus Peptostreptococcus Fusobacterium Gynecologic Infections Bacteroides B. fragilis Clostridium Peptococcus Peptostreptococcus Fusobacterium Bacterial Septicemia Bacteroides B. fragilis Clostridium Bone and Joint Infections Bacteroides B. fragilis Central Nervous System (CNS) Infections Bacteroides B. fragilis Lower Respiratory Tract Infections Bacteroides B. fragilis Endocarditis Bacteroides B. fragilis 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 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.
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 Intra-Abdominal Infections, Bacteroides B. fragilis B. fragilis B. distasonis B. ovatus B. thetaiotaomicron B. vulgatus Clostridium Eubacterium Peptococcus Peptostreptococcus Skin and Skin Structure Infections Bacteroides B. fragilis Clostridium Peptococcus Peptostreptococcus Fusobacterium Gynecologic Infections Bacteroides B. fragilis Clostridium Peptococcus Peptostreptococcus Fusobacterium Bacterial Septicemia Bacteroides B. fragilis Clostridium Bone and Joint Infections Bacteroides B. fragilis Central Nervous System (CNS) Infections Bacteroides B. fragilis Lower Respiratory Tract Infections Bacteroides B. fragilis Endocarditis Bacteroides B. fragilis
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.
DOSAGE AND ADMINISTRATION
Dosage, rate of administration, and duration of treatment are to be individualized and depend upon the indication for use, the patient’s age, weight, clinical condition and concomitant treatment, and on the patient’s clinical and laboratory response to the treatment. The recommended dosage schedule for adults for the treatment of anaerobic infections is presented in the Table 1 Table 1. Recommended Dosage Schedule for the Treatment of Anaerobic Bacterial Infections in Adults Loading Dose 15 mg/kg infused intravenously over one hour (approximately 1 gram for a 70-kg adult). Maintenance Dosage 7. 5 mg/kg infused intravenously 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 (approximately 500 mg for a 70-kg adult). 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. The recommended dosage schedule for pediatric patients less than 4 months of age Table 2 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 Maintenance Dose The first maintenance dose is given 24 hours after the start of the loading dose. Dosing interval 23 to <34 15 7. 5 12 34 to 40 15 7. 5 8 >40 to 48 15 7. 5 6 Recommended Dosage in Patients with Severe Hepatic Impairment CLINICAL PHARMACOLOGY PRECAUTIONS ). Recommended Dosage in Patients Undergoing Hemodialysis Hemodialysis removes significant amounts of metronidazole and its metabolites from systemic circulation. The clearance of metronidazole will depend on the type of dialysis membrane used, the duration of the dialysis session, and other factors. If the administration of metronidazole cannot be separated from a hemodialysis session, supplementation of metronidazole dosage following a hemodialysis session should be considered, depending on the patient’s clinical situation (see CLINICAL PHARMACOLOGY 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 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: a. 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 Administration and Preparation Instructions Caution: Metronidazole Injection is to be administered by slow intravenous drip infusion only, either as a continuous or intermittent infusion. Additives should not be introduced into Metronidazole Injection, unless compatibility is known. If used with a primary intravenous fluid system, the primary solution should be discontinued during metronidazole infusion. DO NOT USE EQUIPMENT CONTAINING ALUMINUM ( e. , Metronidazole Injection is incompatible with (includes but is not limited to): Aztreonam, Cefamandole nafate, Cefoxitin, Penicillin G. In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products (see DIRECTIONS FOR USE OF VIAFLEX PLUS PLASTIC CONTAINER Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Do not administer unless the solution is clear and the seal is intact.
Recommended Dosage for the Treatment of Anaerobic Bacterial Infections
The recommended dosage schedule for adults for the treatment of anaerobic infections is presented in the Table 1 Table 1. Recommended Dosage Schedule for the Treatment of Anaerobic Bacterial Infections in Adults Loading Dose 15 mg/kg infused intravenously over one hour (approximately 1 gram for a 70-kg adult). Maintenance Dosage 7.5 mg/kg infused intravenously 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 (approximately 500 mg for a 70-kg adult). 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 Table 2 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 Maintenance Dose The first maintenance dose is given 24 hours after the start of the loading dose. Dosing interval 23 to <34 15 7.5 12 34 to 40 15 7.5 8 >40 to 48 15 7.5 6 Recommended Dosage in Patients with Severe Hepatic Impairment CLINICAL PHARMACOLOGY PRECAUTIONS ). Recommended Dosage in Patients Undergoing Hemodialysis Hemodialysis removes significant amounts of metronidazole and its metabolites from systemic circulation. The clearance of metronidazole will depend on the type of dialysis membrane used, the duration of the dialysis session, and other factors. If the administration of metronidazole cannot be separated from a hemodialysis session, supplementation of metronidazole dosage following a hemodialysis session should be considered, depending on the patient’s clinical situation (see CLINICAL PHARMACOLOGY 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 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: a. b. 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 Administration and Preparation Instructions Caution: Metronidazole Injection is to be administered by slow intravenous drip infusion only, either as a continuous or intermittent infusion. Additives should not be introduced into Metronidazole Injection, unless compatibility is known. 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., Metronidazole Injection is incompatible with (includes but is not limited to): Aztreonam, Cefamandole nafate, Cefoxitin, Penicillin G. In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products (see DIRECTIONS FOR USE OF VIAFLEX PLUS PLASTIC CONTAINER Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Do not administer unless the solution is clear and the seal is intact.
DIRECTIONS FOR USE OF VIAFLEX PLUS PLASTIC CONTAINER
Metronidazole Injection is a ready-to-use iso-osmotic solution. No dilution or buffering is required 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. Tear overwrap down side at slit and remove solution container. Visually inspect the container. If the outlet port protector 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. 2. 3.

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
Severe neurological disturbances, including encephalopathy, cerebellar symptoms, convulsive seizures, peripheral neuropathy, optic neuropathy, and aseptic meningitis, have been reported in patients treated with metronidazole. Encephalopathy associated with metronidazole may manifest as confusion or decreased level of consciousness, and is associated with widespread lesions on magnetic resonance imaging (MRI) of the brain. Cerebellar toxicity associated with metronidazole may manifest as ataxia, dizziness, dysarthria, nystagmus and saccadic pursuit and is accompanied by T2 flair lesions within the dentate nuclei seen on MRI. Cerebellar toxicity may concurrently occur with encephalopathy, peripheral neuropathy or seizures. CNS symptoms and CNS lesions are generally reversible within days to weeks upon discontinuation of Metronidazole Injection. Peripheral neuropathy, usually symmetric and mainly of sensory type is characterized by numbness or paresthesia of an extremity. Symptoms may be prolonged after drug discontinuation. Aseptic meningitis may occur within hours of dose administration and generally resolve after metronidazole therapy is discontinued (see ADVERSE REACTIONS Advise patients to report neurologic symptoms that occur during metronidazole administration. Discontinue metronidazole treatment if any abnormal neurologic symptoms occur such as ataxia, dizziness, confusion or any other CNS adverse reaction (see ADVERSE REACTIONS
ADVERSE REACTIONS
The following reactions have been reported during treatment with metronidazole formulations: INFECTIONS AND INFESTATIONS: Vaginal candidiasis BLOOD AND LYMPHATIC SYSTEM DISORDERS: Agranulocytosis, Leukopenia, Neutropenia, Thrombocytopenia, Eosinophilia IMMUNE SYSTEM DISORDERS: Anaphylactic reaction, Hypersensitivity METABOLISM AND NUTRITION DISORDERS: Decreased appetite PSYCHIATRIC DISORDERS: Confusional state, Depression, Insomnia, Decreased libido NERVOUS SYSTEM DISORDERS: Encephalopathy, Seizure, Neuropathy peripheral, Ataxia, Dizziness, Hypoesthesia, Paresthesia, Dysgeusia, Headache, Nystagmus, Aseptic meningitis, Somnolence, Dysarthria, Numbness, Syncope EYE DISORDERS: Optic neuropathy, Saccadic eye movement EAR AND LABYRINTH DISORDERS: Vertigo, tinnitus, hearing impairment, hearing loss CARDIAC DISORDERS: 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, Tachycardia, Palpitation RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS: Dyspnea GASTROINTESTINAL DISORDERS: Pancreatitis, Abdominal pain, Diarrhea, Nausea, Vomiting, Asthenia, Proctitis HEPATOBILIARY DISORDERS: Hepatotoxicity/Liver Failure in patients with Cockayne syndrome (see CONTRAINDICATIONS SKIN AND SUBCUTANEOUS DISORDERS: Toxic epidermal necrolysis, Swelling face, Pruritus, Urticaria, Hyperhidrosis, Erythema, Rash; Stevens-Johnson syndrome, Fixed eruption, Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), acute generalized exanthematous pustulosis (AGEP) (see WARNINGS MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS: Muscle spasms, Arthralgia, Myalgia RENAL AND URINARY DISORDERS: Chromaturia, Dysuria Hepatic: CONTRAINDICATIONS REPRODUCTIVE: Dyspareunia GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS: Injection site reaction, Malaise, Face edema, Edema peripheral, Chest pain, Chills, INVESTIGATIONS: Hepatic enzyme increased. 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.

Hypersensitivity Psychotic Reaction with Disulfiram PRECAUTIONS-Drug Interactions Interaction with Alcohol PRECAUTIONS-Drug Interactions Cockayne Syndrome ADVERSE REACTIONS

Renal Impairment
Decreased renal function does not alter the single-dose pharmacokinetics of metronidazole. Subjects with end-stage renal disease (ESRD; CL CR CR PRECAUTIONS
Hepatic Impairment
Following a single intravenous infusion of 500 mg metronidazole, the mean AUC 24 24 DOSAGE AND ADMINISTRATION PRECAUTIONS DOSAGE AND ADMINISTRATION
Geriatric Patients
Following a single 500 mg oral or IV 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 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 DOSAGE AND ADMINISTRATION
Pregnancy
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 5000 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 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 DOSAGE AND ADMINISTRATION
Pediatric Use
Pediatric Patients 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 DOSAGE AND ADMINISTRATION Pediatric Patients 4 Months of Age and Older

Disulfiram CONTRAINDICATIONS Alcoholic Beverages CONTRAINDICATIONS Warfarin and other Oral Anticoagulants Lithium Busulfan Drugs that Inhibit CYP450 Enzymes Drugs that Induce CYP450 Enzymes Cytochrome P450 3A4 (CYP3A4) substrates 5-Fluorouracil Vecuronium Drugs that Prolong the QT interval Drug/Laboratory Test Interactions

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 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
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
WARNINGS
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. Severe neurological disturbances, including encephalopathy, cerebellar symptoms, convulsive seizures, peripheral neuropathy, optic neuropathy, and aseptic meningitis, have been reported in patients treated with metronidazole. Encephalopathy associated with metronidazole may manifest as confusion or decreased level of consciousness, and is associated with widespread lesions on magnetic resonance imaging (MRI) of the brain. Cerebellar toxicity associated with metronidazole may manifest as ataxia, dizziness, dysarthria, nystagmus and saccadic pursuit and is accompanied by T2 flair lesions within the dentate nuclei seen on MRI. Cerebellar toxicity may concurrently occur with encephalopathy, peripheral neuropathy or seizures. CNS symptoms and CNS lesions are generally reversible within days to weeks upon discontinuation of Metronidazole Injection. Peripheral neuropathy, usually symmetric and mainly of sensory type is characterized by numbness or paresthesia of an extremity. Symptoms may be prolonged after drug discontinuation. Aseptic meningitis may occur within hours of dose administration and generally resolve after metronidazole therapy is discontinued (see ADVERSE REACTIONS Advise patients to report neurologic symptoms that occur during metronidazole administration. Discontinue metronidazole treatment if any abnormal neurologic symptoms occur such as ataxia, dizziness, confusion or any other CNS adverse reaction (see ADVERSE REACTIONS.
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 1500 mg/m 2 Metronidazole has shown mutagenic activity in in vitro in vivo 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/m 2
OVERDOSAGE
Signs and symptoms of an overdose may include: nausea, vomiting, and neurotoxic effects, including ataxia, confusion, disorientation, seizures, and peripheral neuropathy. Symptomatic treatment is recommended. There is no specific antidote for an overdose of metronidazole. Discontinue metronidazole administration in the event of an overdose. Hemodialysis removes significant amounts of metronidazole and its metabolites from systemic circulation.
Treatment of Overdosage
Symptomatic treatment is recommended. There is no specific antidote for an overdose of metronidazole. Discontinue metronidazole administration in the event of an overdose. Hemodialysis removes significant amounts of metronidazole and its metabolites from systemic circulation.
To open
Tear overwrap down side at slit and remove solution container. Visually inspect the container. If the outlet port protector 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.

Baxter Healthcare Corporation

METRONIDAZOLE- metronidazole_injection, solution Product manual source documgent