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WARNINGMetronidazole has been shown to be carcinogenic in mice and rats (see Precautions ). Its use, therefore, should be reserved for the conditions described in the and Usage section below. |
Flagyl I.V., sterile (metronidazole hydrochloride), is a parenteral dosage form of the synthetic antibacterial agent 1-((beta)-hydroxyethyl)-2-methyl-5-nitroimidazole hydrochloride.
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Each single-dose vial of lyophilized Flagyl I.V. contains sterile, nonpyrogenic metronidazole hydrochloride, equivalent to 500 mg metronidazole, and 415 mg mannitol.
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 8 hours.
The major route of elimination of metronidazole and its metabolites is via the urine (60-80% of the dose), with fecal excretion accounting for 6-15% of the dose. The metabolites that appear in the urine result primarily from side-chain oxidation [1-((beta)-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 breast 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 8-hour intravenous infusion of 100-4,000 mg of metronidazole in normal subjects showed a linear relationship between dose and peak plasma concentration.
In patients treated with Flagyl I.V., using a dosage regimen of 15 mg/kg loading dose followed 6 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.
In one study newborn infants appeared to demonstrate diminished capacity to eliminate metronidazole. The elimination half-life, measured during the first 3 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.
Microbiology: Metronidazole is active in vitro against most obligate anaerobes, but does not appear to possess any clinically relevant activity against facultative anaerobes or obligate aerobes. Against susceptible organisms, metronidazole is generally bactericidal at concentrations equal to or slightly higher than the minimal inhibitory concentrations. Metronidazole has been shown to have in vitro and clinical activity against the following organisms:
Anaerobic gram-negative bacilli, including:
Bacteroides species, including the Bacteroides fragilis group ( B. fragilis, B. distasonis, B. ovatus, B. thetaiotaomicron, B. vulgatus )
Fusobacterium species
Anaerobic gram-positive bacilli, including:
Anaerobic gram-positive cocci, including:
Peptococcus species
Peptostreptococcus species
Susceptibility Tests: Bacteriologic studies should be performed to determine the causative organisms and their susceptibility to metronidazole; however, the rapid, routine susceptibility testing of individual isolates of anaerobic bacteria is not always practical, and therapy may be started while awaiting these results.
Quantitative methods give the most accurate estimates of susceptibility to antibacterial drugs. A standardized agar dilution method and a broth microdilution method are recommended. 1
Control strains are recommended for standardized susceptibility testing. Each time the test is performed, one or more of the following strains should be included: Clostridium perfringens ATCC 13124, Bacteroides fragilis ATCC 25285, and Bacteroides thetaiotaomicron ATCC 29741. The mode metronidazole MICs for those three strains are reported to be 0.25, 0.25, and 0.5 mcg/mL, respectively.
A clinical laboratory test is considered under acceptable control if the results of the control strains are within one doubling dilution of the mode MICs reported for metronidazole.
A bacterial isolate may be considered susceptible if the MIC value for metronidazole is not more than 16 mcg/mL. An organism is considered resistant if the MIC is greater than 16 mcg/mL. A report of "resistant" from the laboratory indicates that the infecting organism is not likely to respond to therapy.
Flagyl I.V. (metronidazole hydrochloride) is indicated in the treatment of serious infections caused by susceptible anaerobic bacteria. Indicated surgical procedures should be performed in conjunction with Flagyl I.V. therapy. In a mixed aerobic and anaerobic infection, antibiotics appropriate for the treatment of the aerobic infection should be used in addition to Flagyl I.V.
Flagyl I.V. 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
SKIN AND SKIN STRUCTURE INFECTIONS caused by Bacteroides species including the B. fragilis group Clostridium species Peptococcus species Peptostreptococcus species, and Fusobacterium species
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, and Peptostreptococcus species
BACTERIAL SEPTICEMIA caused by Bacteroides species including the B. fragilis group, and Clostridium species
BONE AND JOINT INFECTIONS, as adjunctive therapy, caused by Bacteroides species including the B. fragilis group
CENTRAL NERVOUS SYSTEM (CNS) INFECTIONS, including meningitis and brain abscess, caused by Bacteroides species including the B. fragilis group
LOWER RESPIRATORY TRACT INFECTIONS, including pneumonia, empyema, and lung abscess, caused by Bacteroides species including the B. fragilis group
ENDOCARDITIS caused by Bacteroides species including the B. fragilis group
The prophylactic administration of Flagyl I.V. preoperatively, intraoperatively, and postoperatively may reduce the incidence of postoperative infection in patients undergoing elective colorectal surgery which is classified as contaminated or potentially contaminated.
Prophylactic use of Flagyl I.V. 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 ).
Flagyl I.V. is contraindicated in patients with a prior history of hypersensitivity to metronidazole or other nitroimidazole derivatives.
Convulsive Seizures and Peripheral Neuropathy: Convulsive seizures and peripheral neuropathy, the latter characterized mainly by numbness or paresthesia of an extremity, have been reported in patients treated with metronidazole. 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.
Known or previously unrecognized candidiasis may present more prominent symptoms during therapy with Flagyl I.V. and requires treatment with a candidacidal agent.
Laboratory Tests: Metronidazole is a nitroimidazole, and Flagyl I.V. should be used with care 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 Flagyl I.V. 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.
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 nicotine adenine dinucleotide (NAD + [rlarr2] 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: Tumorigenicity in Rodents--Metronidazole has shown evidence of carcinogenic activity in studies involving chronic, oral administration in mice and rats, but similar studies in the hamster gave negative results. Also, metronidazole has shown mutagenic activity in a number of in vitro assay systems, but studies in mammals ( in vivo ) failed to demonstrate a potential for genetic damage.
Pregnancy: Teratogenic Effects--Pregnancy Category B. Metronidazole crosses the placental barrier and enters the fetal circulation rapidly. Reproduction studies have been performed in rats at doses up to five times the human dose and have revealed no evidence of impaired fertility or harm to the fetus due to metronidazole. Metronidazole administered intraperitoneally to pregnant mice at approximately the human dose caused fetotoxicity; administered orally to pregnant mice, no fetotoxicity was observed. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, and because metronidazole is a carcinogen in rodents, these drugs should be used during pregnancy only if clearly needed.
Nursing Mothers: 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. Metronidazole is secreted in breast milk in concentrations similar to those found in plasma.
Pediatric Use: Safety and effectiveness in pediatric patients have not been established.
Two serious adverse reactions reported in patients treated with Flagyl I.V. have been convulsive seizures and peripheral neuropathy, the latter characterized mainly by numbness or paresthesia of an extremity. Since persistent peripheral neuropathy has been reported in some patients receiving prolonged oral administration of Flagyl® (metronidazole), patients should be observed carefully if neurologic symptoms occur and a prompt evaluation made of the benefit/risk ratio of the continuation of therapy.
The following reactions have also been reported during treatment with Flagyl I.V. (metronidazole hydrochloride):
Gastrointestinal: Nausea, vomiting, abdominal discomfort, diarrhea, and an unpleasant metallic taste.
Hematopoietic: Reversible neutropenia (leukopenia).
Dermatologic: Erythematous rash and pruritus.
Central Nervous System: Headache, dizziness, syncope, ataxia, and confusion.
Local Reactions: Thrombophlebitis after intravenous infusion. This reaction can be minimized or avoided by avoiding prolonged use of indwelling intravenous catheters.
Other: Fever. Instances of a 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.
The following adverse reactions have been reported during treatment with oral Flagyl (metronidazole):
Gastrointestinal: Nausea, sometimes accompanied by headache, anorexia, and occasionally vomiting; diarrhea, epigastric distress, abdominal cramping, and constipation.
Mouth: A sharp, unpleasant metallic taste is not unusual. Furry tongue, glossitis, and stomatitis have occurred; these may be associated with a sudden overgrowth of Candida which may occur during effective therapy.
Hematopoietic: Reversible neutropenia (leukopenia); rarely, reversible thrombocytopenia.
Cardiovascular: Flattening of the T-wave may be seen in electrocardiographic tracings.
Central Nervous System: Convulsive seizures, peripheral neuropathy, dizziness, vertigo, incoordination, ataxia, confusion, irritability, depression, weakness, and insomnia.
Hypersensitivity: Urticaria, erythematous rash, flushing, nasal congestion, dryness of the mouth (or vagina or vulva), and fever.
Renal: Dysuria, cystitis, polyuria, incontinence, a sense of pelvic pressure, and darkened urine.
Other: 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. Rare cases of pancreatitis, which abated on withdrawal of the drug, have been reported.
Crohn' disease patients 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' 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' disease is not an approved indication for Flagyl I.V.
Use of dosages of Flagyl I.V. (metronidazole hydrochloride) higher than those recommended has been reported. These include the use of 27 mg/kg three times a day for 20 days, and the use of 75 mg/kg as a single loading dose followed by 7.5 mg/kg maintenance doses. No adverse reactions were reported in either of the two cases.
Single oral doses of metronidazole, up to 15 g, have been reported in suicide attempts and accidental overdoses. Symptoms reported include nausea, vomiting, and ataxia.
Oral metronidazole has been studied as a radiation sensitizer in the treatment of malignant tumors. Neurotoxic effects, including seizures and peripheral neuropathy, have been reported after 5 to 7 days of doses of 6 to 10.4 g every other day.
Treatment: There is no specific antidote for overdose; therefore, management of the patient should consist of symptomatic and supportive therapy.
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.
The recommended dosage schedule for adults is:
15 mg/kg infused over 1 hour (approximately 1 g for a 70-kg adult).
7.5 mg/kg infused over one hour every 6 hours (approximately 500 mg for a 70-kg adult). The first maintenance dose should be instituted 6 hours following the initiation of the loading dose.
Parenteral therapy may be changed to oral Flagyl (metronidazole) when conditions warrant, based upon the severity of the disease and the response of the patient to Flagyl I.V. treatment. The usual adult oral dosage is 7.5 mg/kg every 6 hours.
A maximum of 4 g should not be exceeded during a 24-hour period.
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 2 and toxicity is recommended.
In patients receiving Flagyl I.V. 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 Flagyl I.V. should not be specifically reduced in anuric patients since accumulated metabolites may be rapidly removed by dialysis.
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.
For surgical prophylactic use, to prevent postoperative infection in contaminated or potentially contaminated colorectal surgery, the recommended dosage schedule for adults is:
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) Flagyl I.V. be administered, if necessary, at 6-hour intervals to maintain effective drug levels. Prophylactic use of Flagyl I.V. should be limited to the day of surgery only, following the above guidelines.
FLAGYL I.V.
Flagyl I.V. cannot be given by direct intravenous injection (I.V. bolus) because of the low pH (0.5 to 2.0) of the reconstituted product. FLAGYL I.V. MUST BE FURTHER DILUTED AND NEUTRALIZED FOR I.V. INFUSION.
Flagyl I.V. is prepared for use in two steps:
NOTE: ORDER OF MIXING IS IMPORTANT
Reconstitution: To prepare the solution, add 4.4 mL of one of the following diluents and mix thoroughly: Sterile Water for Injection, USP; Bacteriostatic Water for Injection, USP; 0.9% Sodium Chloride Injection, USP; or Bacteriostatic 0.9% Sodium Chloride Injection, USP. The resultant approximate withdrawal volume is 5.0 mL with an approximate concentration of 100 mg/mL.
The pH of the reconstituted product will be in the range of 0.5 to 2.0. Reconstituted Flagyl I.V. is clear, and pale yellow to yellow-green in color.
Dilution in Intravenous Solutions: Properly reconstituted Flagyl I.V. (metronidazole hydrochloride) may be added to a glass or plastic I.V. container not to exceed a concentration of 8 mg/mL. Any of the following intravenous solutions may be used: 0.9% Sodium Chloride Injection, USP; 5% Dextrose Injection, USP; or Lactated Ringer' Injection, USP.
NEUTRALIZATION IS REQUIRED PRIOR TO ADMINISTRATION. The final product should be mixed thoroughly and used within 24 hours.
Neutralization For Intravenous Infusion: Neutralize the intravenous solution containing Flagyl I.V. with approximately 5 mEq of sodium bicarbonate injection for each 500 mg of Flagyl I.V. used. Mix thoroughly. The pH of the neutralized intravenous solution will be approximately 6.0 to 7.0. Carbon dioxide gas will be generated with neutralization. It may be necessary to relieve gas pressure within the container.
Note: When the contents of one vial (500 mg) are diluted and neutralized to 100 mL, the resultant concentration is 5 mg/mL. Do not exceed an 8 mg/mL concentration of Flagyl I.V. in the neutralized intravenous solution, since neutralization will decrease the aqueous solubility and precipitation may occur. DO NOT REFRIGERATE NEUTRALIZED SOLUTIONS; otherwise, precipitation may occur.
Storage and Stability: Reconstituted vials of Flagyl I.V. are chemically stable for 96 hours when stored below 86°F (30°C) in room light.
Use diluted and neutralized intravenous solutions containing Flagyl I.V. within 24 hours of mixing.
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 seal is not intact.
Use sterile equipment. It is recommended that the intravenous administration apparatus be replaced at least once every 24 hours.
Flagyl I.V., sterile (metronidazole hydrochloride), is supplied in single-dose lyophilized vials each containing 500 mg metronidazole equivalent, individually packaged in cartons of 10 vials.
Flagyl I.V., prior to reconstitution, should be stored below 77°F (25°C) and protected from light.
Rx only 7/23/99·A05040