CATEGORIES: Pneumonia; Infection, bone; Infection, central nervous system; Infection, intra-abdominal; Infection, joint; Infection, skin and skin structure; Peritonitis; Septicemia; Infection, lower respiratory tract; Infection, gynecologic; Endometritis; Empyema; Endocarditis; Meningitis; Prophylaxis, surgical; Abscess, intra-abdominal; Abscess, tubo-ovarian; Infection, vaginal cuff; Endomyometritis; Acne rosacea; Abscess, brain; Abscess, liver; Abscess, lung; Amebiasis; Infection, anaerobic bacterial; Trichomoniasis; Pregnancy Category B; WHO Formulary; FDA Approved February 1980
Drug Classes: Anti-infectives, topical; Antibiotics, miscellaneous; Antiprotozoals; Dermatologics
BRAND NAMES: Flagyl; Flagyl 375; Flagyl ER; Flagyl I.V. RTU; MetroCream; MetroGel; MetroGel-Vaginal; Metro I.V.; MetroLotion; Metronidazole Benzoate; Noritate; Protostat; Rozex
FOREIGN BRAND AVAILABILITY:
Acea Gel (England, Ireland);
Acromona (Ecuador);
Amevan (Ecuador);
Amiyodazol (Mexico);
Anaerobex (Austria);
Anerobia (Philippines);
Apo-Metronidazole (Canada);
Arcazol (Taiwan);
Arilin (Germany, Switzerland);
Ariline (Austria);
Asiazole (Thailand);
Asuzol (Japan);
Biotazol (Mexico);
Camezol (South Africa);
Clont (Germany);
Debetrol (Argentina);
Deflamon (Italy);
Dumozol (Indonesia);
Elyzol (Israel, Denmark, Finland, Norway, Sweden, Switzerland);
Endazole (Philippines);
Epaq (Mexico);
Farnat (Indonesia);
Fladex (Indonesia, Singapore);
Flagenase (Mexico);
Flagizole (Israel);
Flasinyl (Korea);
Flazol (Israel);
Frotin (Taiwan);
Gynoplix (Hong Kong);
Ivemetro (Republic of Yemen);
Metrogyl (Australia, Greece);
Metrolag (South Africa, Puerto Rico, Israel, Switzerland, Taiwan);
Metrolex (Thailand);
Metronidazol McKesson (Costa Rica, Dominican Republic, El Salvador, Guatemala, Honduras, Nicaragua, Panama);
Metronide (Australia);
Metrozin (Colombia);
Metrozine (Indonesia);
Nalox (Argentina);
Nida (Japan);
Nor-Metrogel (Dominican Republic, El Salvador, Guatemala, Panama);
Novazole (South Africa);
Novonidazole (Canada);
Otrozol (Colombia);
Protozol (South Africa);
Robaz (Philippines);
Rosaced Gel (France);
Rozacreme (France);
Rozagel (France);
Rozex (Belgium, England, France, Hong Kong, South Africa, Switzerland);
Rozex Gel (Israel, Netherlands, Peru);
Sharizole (Israel);
Supplin (Israel);
Takimetol (Japan);
Trichex (Austria);
Trichozole (New Zealand);
Tricowas B (Spain);
Trikacide (Indonesia);
Trogiar (Indonesia);
Unigo (Hong Kong);
Zadstat (England);
Zidoval Gel (Israel);
Zol (Philippines)
COST OF THERAPY:
|
|
For Intravenous Infusion Only.
Flagyl IV, sterile and Flagyl IV RTU, sterile, are parenteral dosage forms of the synthetic antibacterial agents 1-(β-hydroxyethyl)-2-methyl-5-nitroimidazole hydrochloride and 1-(β-hydroxyethyl)-methyl-5-nitroimidazole, respectively.
Each single-dose vial of lyophilized Flagyl IV contains sterile, nonpyrogenic metronidazole hydrochloride, equivalent to 500 mg metronidazole, and 415 mg mannitol.
Each Flagyl IV RTU (ready-to-use) 100-ml single-dose plastic container contains a sterile, nonpyrogenic, isotonic, buffered solution of 500 mg metronidazole, 47.6 mg sodium phosphate, 22.9 mg citric acid, and 790 mg sodium chloride in water for injection. Flagyl IV RTU has a tonicity of 310 mOsm/L and a pH of 5-7. Each container contains 14 mEq of sodium.
The plastic container is fabricated from a specially formulated polyvinyl chloride plastic. Water can permeate from inside the container into the overwrap in amounts insufficient to affect the solution significantly. Solutions in contact with the plastic container can leach out certain of its chemical components in very small amounts within the expiration period, e.g., di 2-ethyhexyl phthalate (DEHP), up to 5 parts per million. However, the safety of the plastic has been confirmed in tests in animals according to USP biological tests for plastic containers as well as by tissue culture toxicity studies.
Metronidazole is a synthetic antibacterial compound. Disposition of metronidazole in the body is similar for both oral and IV 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-(β-hydroxyethyl)-2-hydroxymethyl-5-nitroimidazole and 2-methyl-5-nitroimidazole-1-yl-acetic acid] and glucuronide conjugation, with unchanged metronidazole accounting for approximately 20% of the total. Renal clearance of metronidazole is approximately 10 ml/min/1.73 m2.
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 IV infusion of 100-4000 mg of metronidazole in normal subjects showed a linear relationship between dose and peak concentration.
In patients treated with metronidazole IV, using a dosage regimen of 15 mg/kg loading dose followed 6 hours later by 7.5 mg/kg every 6 hours, peak steady-state plasma concentrations of metronidazole averaged 25 µg/ml with trough (minimum) concentrations averaging 18 µg/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:
Anaerobic Gram-Positive Bacilli, Including:
Anaerobic Gram-Positive Cocci, Including:
Susceptibility Testing
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 thetaiotamicron ATCC 29741. The mode metronidazole MICs for those three strains are reported to be 0.25, 0.25, and 0.5 μg/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 μg/ml. An organism is considered resistant if the MIC is greater than 16 μg/ml. A report of "resistant" from the laboratory indicates that the infecting organism is not likely to respond to therapy.
Treatment of Anaerobic Infections
Metronidazole IV is indicated in the treatment of serious infections caused by susceptible anaerobic bacteria. Indicated surgical procedures should be performed in conjunction with metronidazole IV therapy. In a mixed aerobic and anaerobic infection, antibiotics appropriate for the treatment of the aerobic infection should be used in addition to metronidazole IV.
Metronidazole IV is effective in Bacteroides fragilis infections resistant to clindamycin, chloramphenicol, and penicillin.
Prophylaxis
The prophylactic administration of metronidazole IV preoperatively, intraoperatively, 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 metronidazole IV 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).
Non-FDA Approved Indications
Metronidazole has been investigated for the treatment of generalized idiopathic lichen planus, Crohn's disease, and granulomatous cheilitis. It is also used in the treatment of giardiasis, although this is not an FDA-approved use.
Metronidazole 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 ration 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 IV RTU to patients receiving corticosteroids or to patients presdisposed to edema.
Known or previously unrecognized candidiasis may present more prominent symptoms during therapy with metronidazole and requires treatment with a candicidal agent.
Laboratory Tests
Metronidazole is a nitroimidazole and 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/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+↔ NADH). Interference is due to the similarity in absorbance peaks of NADH (340 nm) and metronidazole (322 nm) at pH 7.
Carcinogenesis, Mutagenesis, and 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) have 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 5 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, this drug 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 children have not been established.
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 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 2 weeks.
Two serious adverse reactions reported in patients treated with metronidazole 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 metronidazole, patients should be oberved 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 metronidazole:
The following reactions have been reported during treatment with oral metronidazole:
Crohn's 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'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.
Use of dosages of metronidazole HCl IV higher than those recommended has been reported. These include the use of 27 mg/kg 3 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 5-7 days of doses of 6-10.4 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.
Treatment of Anaerobic Infections
The recommended dosage schedule for Adults is:
Parenteral therapy may be changed to oral metronidazole when conditions warrant, based upon the severity of the disease and the response of the patient to metronidazole IV 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 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 dose of metronidazole should not be specifically reduced in anuric patients since accumulated metabolites may be rapidly removed by dialysis.
The usual duration of therapy is 7-10 days; however, infections of the bone and joint, lower respiratory tract, and endocardium may require longer treatment.
Prophylaxis
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 1 hour before surgery so that adequate drug levels are present in the serum and tissues at the time of initial incision, and (2) metronidazole IV be administered, if necessary, at 6-hour intervals to maintain effective drug levels. Prophylactic use of metronidazole IV should be limited to the day of surgery only, following the above guidelines.
CAUTION: Metronidazole IV is to be administered by slow IV 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 the metronidazole IV RTU solution. If used with a primary IV 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.
Flagyl IV
Flagyl IV cannot be given by direct IV injection (IV bolus) because of the low pH (0.5-2.0) of the reconstituted product. FLAGYL IVE MUST BE FURTHER DILUTED AND NEUTRALIZED FOR IV INFUSION.
DO NOT REFRIGERATE NEUTRALIZED SOLUTIONS; otherwise, precipitation may occur.
Storage and Stability: Reconstituted vials of Flagyl IV are chemically stable for 96 hours when sotred below 30°C (86°F) in room light.
Use diluted and neutralized IV solutions containing Flagyl IV within 24 hours of mixing.
Flagyl IV RTU
Flagyl IV RTU is a ready-to-use isotonic solution. NO DILUTION OR BUFFERING IS REQUIRED. Do not refrigerated. Each container of Flagyl IV RTU contains 14 mEq of sodium.
REFERENCES
1.Flagyl IV
Flagyl IV, sterile, is supplied in single-dose lyophilized vials each containing 500 mg metronidazole equivalent.
Storage: Flagyl IV, prior to reconstitution, should be stored below 30°C (86°F) and protected from light.
Flagyl IV RTU
Flagyl IV RTU, sterile, is supplied in 100-ml single-dose plastic containers, each containing an isotonic, buffered solution of 500 mg metronidazole.
Storage: Flagyl IV RTU should be stored at controlled room temperature, 15-30°C (59-86°F), and protected from light during storage.
|
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 bacteria.
Metronidazole is an oral synthetic antiprotozoal and antibacterial agent, 1-(β-hydroxyethyl)-2-methyl-5-nitroimidazole.
Flagyl tablets contain 250 or 500 mg of metronidazole. Inactive ingredients include cellulose, FD&C blue no. 2 lake, hydroxypropyl cellulose, hypromellose, polyethylene glycol, stearic acid, and titanium dioxide.
Flagyl 375 capsules contain 375 mg of metronidazole. Inactive ingredients include corn starch, magnesium stearate, gelatin, black iron oxide, titanium dioxide, FD&C green no. 3, and D&C yellow no. 10.
Flagyl ER 750 mg tablets contain 750 mg of metronidazole. Inactive ingredients include hypromellose, lactose, magnesium stearate, polyethylene glycol, poly (meth) acrylic acid ester copolymers, polysorbate 80, silicon dioxide, simethicone emulsion, talc, titanium dioxide, FD&C blue no. 2 aluminum lake.
Pharmacokinetics
Disposition of metronidazole in the body is similar for both oral and IV 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-(β-hydroxyethyl)-2-hydroxymethyl-5-nitroimidazole and 2-methyl-5-nitroimidazole-1-yl-acetic acid] and glucuronide conjugation, with unchanged metronidazole accounting for approximately 20% of the total. Renal clearance of metronidazole is approximately 10 ml/min/1.73 m2. 1
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 and in vitro trichomonacidal activity.
Metronidazole appears in cerebrospinal fluid, saliva, and human milk in concentrations similar to those found in plasma. Bactericidal concentrations of metronidazole have also been detected in pus from hepatic abscesses.
Following oral administration, metronidazole is well absorbed, with peak plasma concentrations occurring between 1 and 2 hours after administration. Plasma concentrations of metronidazole are proportional to the administered dose. Oral administration of 250 mg, 500 mg, or 2000 mg produced peak plasma concentrations of 6 µg/ml, 12 µg/ml, and 40 µg/ml, respectively. Studies reveal no significant bioavailability differences between males and females; however, because of weight differences, the resulting plasma levels in males are generally lower.
Metronidazole capsules have been shown to have a rate and extent of absorption similar to metronidazole tablets and were bioequivalent at an equal single dose of 750 mg. In a study conducted with 23 adult, healthy, female volunteers, oral administration of two 375-mg metronidazole capsules under fasted conditions produced a mean (±1 SD) peak plasma concentration (Cmax) of 21.4 (±2.8) µg/ml with a mean Tmax of 1.6 (±0.7) hours and a mean area under the plasma concentration-time curve (AUC) of 223 (±44) µg·h/ml. In the same study, three 250-mg metronidazole tablets produced a mean Cmax of 20.4 (±3.8) µg/ml with a mean Tmax of 1.4 (±0.4) hours and a mean AUC of 218 (±50) µg·h/ml.
Administration of metronidazole capsules with food does not affect the extent of absorption of metronidazole; however, the presence of food results in a lower Cmax and a delayed Tmax compared to fasted conditions. In a study of 14 healthy, adult, female volunteers, administration of metronidazole capsules under fasting conditions produced a mean Cmax of 10.9 (±1.5) µg/ml, a mean Tmax of 1.5 (±1.4) hours, and a mean AUC of 110 (±34) µg·h/ml compared to a mean Cmax of 8.6 (±1.6) µg/ml, a mean Tmax of 4.2 (±1.7) hours, and a mean AUC of 99 (±14) µg·h/ml under fed conditions.
Metronidazole extended-release tablets contain 750 mg of metronidazole in an extended-release formulation which allows for once-daily dosing. The steady-state pharmacokinetics were determined in 24 healthy adult female subjects with a mean ±SD age of 28.8 ± 8.8 years (range: 19-46). 2 The pharmacokinetic parameters of metronidazole after administration of metronidazole extended-release 750 mg under fed and fasting conditions are summarized in TABLE 1.
|
||||||||||||||||||||||||||||||
Relative to the fasting state, the rate of metronidazole absorption from the extended-release tablet is increased in the fed state resulting in alteration of the extended-release characteristics.
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.
Microbiology
Metronidazole exerts an antimicrobial effect in an anaerobic environment by the following possible mechanism: once metronidazole enters the organism, the drug is reduced by intracellular electron transport proteins. Because of this alteration to the metronidazole molecule, a concentration gradient is maintained which promotes the drug’s intracellular transport. Presumably, free radicals are formed which, in turn, react with cellular components resulting in death of the microorganism.
The following in vitro data are available, but their clinical significance is unknown:
Metronidazole exhibits in vitro minimal inhibitory concentrations (MICs) of 8 µg/ml or less against most (≥90%) strains of the following microorganisms; however, the safety and effectiveness of metronidazole in treating clinical infections due to these microorganisms have not been established in adequate and well-controlled clinical trials.
Metronidazole has shown minimal to no activity against clinically relevant facultative anaerobes or obligate aerobes. Metronidazole has minimal activity against Lactobacillus spp and other aerobic microorganisms commonly isolated from the vaginal tract.
Susceptibility Tests
Dilution Techniques
Quantitative methods that are used to determine minimum inhibitory concentrations provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. For anaerobic bacteria, the susceptibility to metronidazole can be determined by the reference agar dilution method or by alternate standardized test methods. 3 The MIC values obtained should be interpreted according to the criteria in TABLE 2.
|
||||||||||
For protozoal parasites: Standardized tests do not exist for use in clinical microbiology laboratories.
A report of “Susceptible” indicates that the pathogen is likely to be inhibited by usually achievable concentrations of the antimicrobial compound in the blood. A report of “Intermediate” indicates that the result should be considered equivocal, and if the microorganism is not fully susceptible to alternative, clinically feasible drugs, the test should be repeated. This category implies possible clinical applicability in body sites where the drug is physiologically concentrated or in situations where high dosage of drug can be used. This category also provides a buffer zone which prevents small uncontrolled technical factors from causing major discrepancies in interpretation. A report of “Resistant” indicates that usually achievable concentrations of the antimicrobial compound in the blood are unlikely to be inhibitory and other therapy should be selected.
Standardized susceptibility test procedures require the use of laboratory control microorganisms that are used to control the technical aspects of the laboratory procedures. Standard metronidazole powder should provide the MIC values shown in TABLE 3.
|
||||||||
BV is a clinical syndrome that results from a replacement of the normal, Lactobacillus-dominant flora with several other organisms including Gardnerella vaginalis, Mobiluncus spp, Mycoplasma hominis and anaerobes (Peptostreptococcus spp and Bacteroides spp).
Metronidazole extended-release was studied in patients with BV in two randomized, multicenter, well-controlled, investigator blind clinical trials. 4,5 A total of 557 otherwise healthy nonpregnant patients with BV were randomized to treatment with metronidazole extended-release once a day for 7 days (n=270) or 2% clindamycin vaginal cream 1 applicator full (5 g) once a day for 7 days (n=287).
The primary efficacy endpoint for each treatment regimen was defined as clinical cure assessed at 28-32 days post-therapy. Clinical cure was defined as a return to normal of the vaginal pH (≤4.5), absence of a “fishy” amine odor, and absence of clue cells.
The study results are presented in TABLE 4.
|
||||||||||||
| * p <0.05 versus clindamycin cream. | ||||||||||||
At 1 month post-therapy the pH of the vagina returned to normal earlier and in a greater percentage of patients in the metronidazole extended-release treatment group when compared to the 2% clindamycin vaginal cream group; 72% vs 65%, respectively. Likewise, metronidazole extended-release restored the normal Lactobacillus-predominant vaginal flora in a larger percentage of patients at 1 month post-therapy when compared to the 2% clindamycin treated group; 74% vs 63%, respectively.
Symptomatic Trichomoniasis
Metronidazole is indicated for the treatment of symptomatic trichomoniasis in females and males when the presence of the trichomonad has been confirmed by appropriate laboratory procedures (wet smears and/or cultures).
Asymptomatic Trichomoniasis
Metronidazole is indicated in the treatment of asymptomatic females when the organism is associated with endocervicitis, cervicitis, or cervical erosion. Since there is evidence that presence of the trichomonad can interfere with accurate assessment of abnormal cytological smears, additional smears should be performed after eradication of the parasite.
Treatment of Asymptomatic Consorts
T. vaginalis infection is a venereal disease. Therefore, asymptomatic sexual partners of treated patients should be treated simultaneously if the organism has been found to be present, in order to prevent reinfection of the partner. The decision as to whether to treat an asymptomatic male partner who has a negative culture or one for whom no culture has been attempted is an individual one. In making this decision, it should be noted that there is evidence that a woman may become reinfected if her consort is not treated. Also, since there can be considerable difficulty in isolating the organism from the asymptomatic male carrier, negative smears and cultures cannot be relied upon in this regard. In any event, the consort should be treated with metronidazole in cases of reinfection.
Amebiasis
Metronidazole is indicated in the treatment of acute intestinal amebiasis (amebic dysentery) and amebic liver abscess.
In amebic liver abscess, metronidazole therapy does not obviate the need for aspiration or drainage of pus.
Anaerobic Bacterial Infections
Metronidazole is indicated in the treatment of serious infections caused by susceptible anaerobic bacteria. Indicated surgical procedures should be performed in conjunction with metronidazole therapy. In a mixed aerobic and anaerobic infection, antimicrobials appropriate for the treatment of the aerobic infection should be used in addition to metronidazole.
In the treatment of most serious anaerobic infections, Flagyl IV (metronidazole hydrochloride) or Flagyl IV RTU (metronidazole) is usually administered initially. This may be followed by oral therapy with Flagyl (metronidazole) at the discretion of the physician.
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 antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy.
Non-FDA Approved Indications
Metronidazole has been investigated for the treatment of generalized idiopathic lichen planus, Crohn's disease, and granulomatous cheilitis. It is also used in the treatment of giardiasis, although this is not an FDA-approved use.
Metronidazole is contraindicated in patients with a prior history of hypersensitivity to metronidazole or other nitroimidazole derivatives.
In patients with trichomoniasis, metronidazole is contraindicated during the first trimester of pregnancy. (See WARNINGS.)
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 discontinuation of metronidazole therapy. Metronidazole should be administered with caution to patients with central nervous system diseases.
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.
Known or previously unrecognized candidiasis may present more prominent symptoms during therapy with metronidazole and requires treatment with a candidacidal agent.
Prescribing metronidazole 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 the Patient
Alcoholic beverages should be avoided while taking metronidazole and for at least 3 days afterward. See DRUG INTERACTIONS.
Patients should be counseled that antibacterial drugs including metronidazole should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When metronidazole 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 or other antibacterial drugs in the future.
Laboratory Tests
Metronidazole is a nitroimidazole and 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 for trichomoniasis and amebiasis, especially if a second course of therapy is necessary, and before and after therapy for anaerobic infections.
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, and Impairment of Fertility
Metronidazole has shown evidence of carcinogenic activity in a number of studies involving chronic, oral administration in mice and rats but similar studies in the hamster gave negative results.
Prominent among the effects in the mouse was the promotion of pulmonary tumorigenesis. This has been observed in all six reported studies in that species, including one study in which the animals were dosed on an intermittent schedule (administration during every fourth week only). At very high dose levels (approx. 500 mg/kg/day which is approximately 33 times the most frequently recommended human dose for a 50 kg adult based on mg/kg body weight) there was a statistically significant increase in the incidence of malignant liver tumors in males. Also, the published results of one of the mouse studies indicate an increase in the incidence of malignant lymphomas as well as pulmonary neoplasms associated with lifetime feeding of the drug. All these effects are statistically significant.
Several long-term, oral-dosing studies in the rat have been completed. There were statistically significant increases in the incidence of various neoplasms, particularly in mammary and hepatic tumors, among female rats administered metronidazole over those noted in the concurrent female control groups.
Two lifetime tumorigenicity studies in hamsters have been performed and reported to be negative. Although metronidazole has shown mutagenic activity in a number of in vitro assay systems, studies in mammals (in vivo) have failed to demonstrate a potential for genetic damage.
Fertility studies have been performed in mice at doses up to 6 times the maximum recommended human dose based on mg/m2 and have revealed no evidence of impaired fertility.
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 5 times the human dose and have revealed no evidence of impaired fertility or harm to the fetus due to metronidazole. No fetotoxicity was observed when metronidazole was administered orally to pregnant mice at 20 mg/kg/day, approximately 1½ times the most frequently recommended human dose (750 mg/day) based on mg/kg body weight; however in a single small study where the drug was administered intraperitoneally, some intrauterine deaths were observed. The relationship of these findings to the drug is unknown. 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, this drug should be used during pregnancy only if clearly needed. (See CONTRAINDICATIONS.)
Metronidazole use in the second and third trimesters of pregnancy should be restricted to those patients in whom alternative treatment has been inadequate. Use of metronidazole in the first trimester should be carefully evaluated because metronidazole crosses the placental barrier and its effects on human fetal organogenesis are not known. (See above.)
Metronidazole extended-release has not been studied in pregnant women.
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 human milk in concentrations similar to those found in plasma.
Geriatric Use
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. Therefore, in elderly patients, monitoring of serum levels may be necessary to adjust the metronidazole dosage accordingly.
Pediatric Use
Safety and effectiveness in pediatric patients have not been established, except for the treatment of amebiasis.
Safety and effectiveness of the extended-release tablets of metronidazole in pediatric patients have not been established.
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 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. 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. Serum lithium and serum creatinine levels should be obtained several days after beginning metronidazole to detect any increase that may precede clinical symptoms of lithium intoxication.
Alcoholic beverages should not be consumed during metronidazole therapy and for at least 3 days afterward 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 2 weeks.
The following reactions have also been reported during treatment with metronidazole:
Crohn’s 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’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.
In two multicenter clinical trials, a total of 270 patients received 750 mg metronidazole extended-release tablets orally once daily for 7 days, and 287 were treated with a comparator agent administered intravaginally once daily for 7 days. (See CLINICAL STUDIES.) 4,5
Most adverse events were described as being of mild or moderate severity. Among patients taking metronidazole extended-release who reported headaches, 10% considered them severe, and less than 2% of reported episodes of nausea were considered severe. Metallic taste was reported by 9% of patients taking metronidazole extended-release.
Adverse events reported at ≥2% incidence for either treatment group, irrespective of treatment causality, are summarized in TABLE 5.
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Vulvovaginal candidiasis is a recognized consequence of treatment with many anti-infective agents. In these multicenter clinical trials, there were no statistically significant differences in the incidence rates of yeast vaginitis for groups of patients treated with metronidazole extended-release or the vaginal comparator.
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 5-7 days of doses of 6-10.4 g every other day.
Treatment: There is no specific antidote for metronidazole 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.
Trichomoniasis
In the Female
The dosage regimen should be individualized. Single-dose treatment can assure compliance, especially if administered under supervision, in those patients who cannot be relied on to continue the 7-day regimen. A 7-day course of treatment may minimize reinfection by protecting the patient long enough for the sexual contacts to obtain appropriate treatment. Further, some patients may tolerate one treatment regimen better than the other.
Pregnant patients should not be treated during the first trimester. (See CONTRAINDICATIONS.) In pregnant patients in whom alternative treatment has been inadequate, the 1-day course of therapy should not be used, as it results in higher serum levels which can reach the fetal circulation (see PRECAUTIONS, Pregnancy, Teratogenic Effects, Pregnancy Category B).
When repeat courses of the drug are required, it is recommended that an interval of 4-6 weeks elapse between courses and that the presence of the trichomonad be reconfirmed by appropriate laboratory measures. Total and differential leukocyte counts should be made before and after re-treatment.
In the Male
Treatment should be individualized as for the female.
Amebiasis
Adults:
Pediatric Patients:
Anaerobic Bacterial Infections
In the treatment of most serious anaerobic infections, IV metronidazole is usually administered initially.
The usual adult oral dosage is 7.5 mg/kg every 6 hours (approx. 500 mg for a 70-kg adult). A maximum of 4 g should not be exceeded during a 24-hour period.
The usual duration of therapy is 7-10 days; however, infections of the bone and joint, lower respiratory tract, and endocardium may require longer treatment.
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 6 and toxicity is recommended.
The dose of metronidazole should not be specifically reduced in anuric patients since accumulated metabolites may be rapidly removed by dialysis.
Bacterial Vaginosis
Metronidazole extended-release 750 mg tablets should be taken under fasting conditions, at least 1 hour before or 2 hours after meals. The optimum extended-release characteristics of metronidazole extended-release 750 mg are obtained when the drug is taken under fasting conditions. (See CLINICAL PHARMACOLOGY, Pharmacokinetics.)
REFERENCES
1.
Flagyl Tablets:
Flagyl 375 Capsules:
Flagyl ER Tablets:
Storage and Stability: Store at controlled room temperature 15-25°C (59-77°F). Dispense in a well-closed container with a child-resistant closure.
FOR TOPICAL USE ONLY (NOT FOR OPHTHALMIC USE).
Chemically, metronidazole is 2-methyl-5-nitro-1H-imidazole-1-ethanol. The molecular formula for metronidazole is C6H9N3O3.
Metronidazole has a molecular weight of 171.16. It is a white to pale yellow crystalline powder. It is slightly soluble in alcohol and has a solubility in water of 10 mg/ml at 20°C. Metronidazole is a member of the imidazole class of antibacterial agents and is classified as an antiprotozoal and antibacterial agent.
Pharmacokinetics
When 1-g dose of metronidazole cream, 1%, was applied in a single application to the face of 16 healthy volunteers, low concentrations of metronidazole were detected in the plasma of 7 of the volunteers. The mean ± SD Cmax of metronidazole was 27.6 ± 7.3 ng/ml, which is about 1% of the value reported for a single 250-mg oral dose of metronidazole. The time to maximum plasma concentration (Tmax) in the volunteers with detectable metronidazole was 8-12 hours after topical application.
Bioavailability studies on the topical administration of 1 g of metronidazole topical gel (7.5 mg of metronidazole) to the face of 10 rosacea patients showed a maximum serum concentration of 66 ng/ml in 1 patient. This concentration is approximately 100 times less than concentrations afforded by a single 250-mg oral tablet. The serum metronidazole concentrations were below the detectable limits of the assay at the majority of time points in all patients. Three of the patients had no detectable serum concentrations of metronidazole at any time point. The mean dose of gel applied during clinical studies was 600 mg which represents 4.5 mg of metronidazole per application. Therefore, under normal usage levels, the formulation affords minimal serum concentrations of metronidazole. The mechanisms by which metronidazole topical gel acts in the treatment of rosacea are unknown, but appear to include an anti-inflammatory effect.
Absorption of metronidazole after topical application of metronidazole topical lotion is less complete and more prolonged than after oral administration. Detectable plasma levels were found in all subjects following the administration of a 1-g dose of metronidazole topical lotion (containing 7.5 mg of metronidazole) applied every morning and evening for 4 days to the faces of 8 patients. The highest concentration (96 ng/ml) seen following the morning dose on Day 5 was approximately 80 times lower than the peak concentrations produced by a single 250-mg tablet of metronidazole. The mean (±SD) AUC(0-24) after twice daily administration was 962 ± 373 ng·h/ml.
Pharmacodynamics
The mechanisms by which metronidazole acts in reducing inflammatory lesions of rosacea are unknown.
Safety and efficacy of metronidazole cream, 1% were evaluated in two randomized vehicle-controlled clinical studies for the treatment of rosacea, which excluded patients who had nodules, moderate or severe rhinophyma, dense telangiectases, plaque-like facial edema or ocular involvement and those who had a history of not responding to metronidazole therapy for rosacea. Of the patients included in the efficacy database (n=416), there were 142 men and 274 women.
Endpoint efficacy data comparisons for patients treated with daily metronidazole cream, 1% or vehicle applications are listed in TABLE 6.
Safety Studies: Studies of contact sensitization (n=258), phototoxicity (n=21), and photocontact sensitization (n=29) of metronidazole cream, 1% were conducted. No evidence of sensitization or phototoxicity was seen in these studies.
A controlled clinical study was conducted in 144 patients with moderate to severe rosacea, in which metronidazole topical lotion was compared with its vehicle. Applications were made twice daily for 12 weeks during which patients were instructed to avoid spicy foods, thermally hot foods and drinks, alcoholic beverages, and caffeine. Patients were also provided samples of a soapless cleansing lotion and, if requested, a moisturizer. Metronidazole topical lotion was significantly more effective than its vehicle in mean percent reduction of inflammatory lesions associated with rosacea and in the investigators' global assessment of improvement. The results of the mean percent reduction in inflammatory lesion counts from baseline after 12 weeks of treatment and the investigators' global assessment of improvement at Week 12 are presented in TABLE 7.
|
||||||||||||||||||||||||||||||||||||||||||||
The scale is based on the following definitions: |
||||||||||||||||||||||||||||||||||||||||||||
Topical metronidazole is indicated for the topical treatment of inflammatory lesions and erythema of rosacea.
Non-FDA Approved Indications
Metronidazole has been investigated for the treatment of generalized idiopathic lichen planus, Crohn's disease, and granulomatous cheilitis. It is also used in the treatment of giardiasis, although this is not an FDA-approved use.
Metronidazole is contraindicated in those patients with a history of hypersensitivity to metronidazole or to any other ingredient in the formulation.
General
If a reaction suggesting local skin irritation occurs, patients should be directed to discontinue use of the medication. Conjunctivitis associated with topical use of metronidazole on the face has been reported. Contact with the eyes should be avoided. Metronidazole is a nitroimidazole and should be used with care in patients with evidence of, or history of, blood dyscrasia.
Information for the Patient
Patients using topical metronidazole should receive the following information and instructions:
Carcinogenesis, Mutagenesis and Impairment of Fertility
Metronidazole has shown evidence of carcinogenic activity in a number of studies involving chronic, oral administration in mice and rats but not in studies involving hamsters. Neither carcinogenicity nor photocarcinogenicity studies have been performed by the topical route of metronidazole.
In several long-term studies in mice, oral doses of approximately 198 mg/m2/day or greater (approximately 29-71 times the human topical dose on a mg/m2 basis) were associated with an increase in lung tumors in male mice and lymphomas in female mice.
Several long-term studies by the oral route in rats have shown statistically significant increases in mammary and hepatic tumors in female rats and testicular tumors and pituitary adenomas in male rats at doses (in feed) of 1593 mg/m2/day or greater (approximately 230-573 times the human topical dose on a mg/m2 basis). In another oral study (by gavage), mammary tumors in female rats were observed with a dose of 177 mg/m2/day (approximately 26-64 times the human topical dose on a mg/m2 basis).
In a published study, the ultraviolet radiation-induced carcinogenesis was enhanced in albino hairless mice by intraperitoneal administration of 45 mg/m2 metronidazole, as shown by a decreased latency period to the development of skin neoplasms. The concentration of metronidazole in the skin following the intraperitoneal administration was not determined. This study did not distinguish whether metronidazole must be present during the exposure to ultraviolet radiation in order to enhance tumor formation or whether metronidazole could promote tumor formation from preexisting ultraviolet radiation-initiated cells. The significance of these results in the topical use of metronidazole for the treatment of rosacea is unclear.
Metronidazole has shown evidence of mutagenic activity in several in vitro bacterial assay systems. In addition, a dose-response increase in the frequency of micronuclei was observed in mice after intraperitoneal injections. An increase in chromosome aberrations in peripheral blood lymphocytes was reported in patients with Crohn's disease who were treated with 200-1200 mg/day of metronidazole for 1-24 months. However, in another study, no excess chromosomal aberrations in circulating human lymphocytes were observed in patients treated for 8 months.
In rats, oral metronidazole at doses of 1770 mg/m2/day (approximately 255-637 times the human topical dose on a mg/m2 basis) induced inhibition of spermatogenesis and severe testicular degeneration. In two strains of mice (ICR and CF1), conflicting results have been reported indicating either no effect or a similar effect to that reported in rats.
Pregnancy, Teratogenic Effects, Pregnancy Category B
There are no adequate and well controlled studies with the use of topical metronidazole in pregnant women. Metronidazole crosses the placental barrier and enters the fetal circulation rapidly. No fetotoxicity was observed after oral administration of metronidazole to rats or mice at 200 and 20 times, respectively, the expected clinical dose. However, oral metronidazole has shown carcinogenic activity in rodents. Because animal reproduction studies are not always predictive of human response, metronidazole should be used during pregnancy only if clearly needed.
Nursing Mothers
After oral administration, metronidazole is secreted in breast milk in concentrations similar to those found in the plasma. Even though blood levels taken after topical metronidazole application are significantly lower than those achieved after oral metronidazole, 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 and the risk to the infant.
Pediatric Use
Safety and effectiveness in pediatric patients have not been established.
Oral metronidazole has been reported to potentiate the anticoagulant effect of coumarin and warfarin resulting in a prolongation of prothrombin time. Drug interactions should be kept in mind when topical metronidazole is prescribed for patients who are receiving anticoagulant treatment, although they are less likely to occur with topical metronidazole administration because of low absorption. (See CLINICAL PHARMACOLOGY, Pharmacokinetics.)
Safety data from 302 patients who used metronidazole cream, 1% (n=200) or vehicle control (n=102) once daily in clinical trials and experienced an adverse event considered to be treatment-related include: application site reaction (metronidazole cream, 1% 1, vehicle 1), condition aggravated (metronidazole cream, 1% 1, vehicle 0), paresthesia (metronidazole cream, 1% 0, vehicle 1), acne (metronidazole cream, 1% 1, vehicle 0), dry skin (metronidazole cream, 1% 0, vehicle 2). The majority of adverse reactions were mild to moderate in severity.
Two patients treated with metronidazole cream, 1% once daily discontinued treatment because of adverse events: 1 for a severe flare of comedonal acne and 1 for rosacea aggravated.
In a controlled clinical trial, safety data from 141 patients who used metronidazole topical lotion (n=71), or the lotion vehicle (n=70), twice daily and experienced a local cutaneous adverse event which may or may not have been related to the treatments include: local allergic reaction, metronidazole topical lotion 2 (3%), lotion vehicle 0; contact dermatitis, metronidazole topical lotion 2 (3%), lotion vehicle 1 (1%); pruritus, metronidazole topical lotion 1 (1%), lotion vehicle 0; skin discomfort (burning and stinging), metronidazole topical lotion 1 (1%), lotion vehicle 2 (3%); erythema, metronidazole topical lotion 4 (6%), lotion vehicle 0; dry skin, metronidazole topical lotion 0, lotion vehicle 1 (1%); and worsening of rosacea, metronidazole topical lotion 1 (1%), lotion vehicle 7 (10%).
In controlled clinical trials, the total incidence of adverse reactions associated with the use of metronidazole topical cream, 0.75% was approximately 10%. Skin discomfort (burning and stinging) was the most frequently reported event followed by erythema, skin irritation, pruritus and worsening of rosacea. All individual events occurred in less than 3% of patients.
Additional clinical adverse effects reported spontaneously since the drug was marketed are uncommon and include tingling or numbness of extremities, allergic reactions, skin and eye irritation, rash, headache, nausea, metallic taste and dry mouth.
Metronidazole Cream, 0.1%
Areas to be treated should be cleansed before application of metronidazole cream, 1%. Apply and rub in a thin film of metronidazole cream, 1% once daily to entire affected area(s). Patients may use cosmetics after application of metronidazole cream, 1%.
Metronidazole Cream, 0.75%
Apply and rub in a thin layer of metronidazole topical cream, 0.75% twice daily, morning and evening, to entire affected areas after washing.
Areas to be treated should be washed with a mild cleanser before application. Patients may use cosmetics after application of metronidazole topical cream, 0.75%.
Metronidazole Gel
Apply and rub in a thin film of metronidazole topical gel twice daily, morning and evening, to entire affected areas after washing.
Areas to be treated should be cleansed before application of metronidazole topical gel. Patients may use cosmetics after application of metronidazole topical gel.
Metronidazole Lotion
Apply a thin layer to entire affected areas after washing. Use morning and evening or as directed by physician. Avoid application close to the eyes.
Patients may use cosmetics after waiting for the metronidazole topical lotion to dry (not less than 5 minutes).
Noritate Cream
Noritate cream is supplied in a 30-g aluminum tube.
Keep out of the reach of children.
Storage Conditions: Store at controlled room temperature: 20-25°C (68-77°F).
MetroCream
MetroCream topical cream, 0.75% is supplied in a 45-g aluminum tube.
Storage Conditions: STORE AT CONTROLLED ROOM TEMPERATURE: 15-30°C (59-86°F).
MetroGel
Metrogel topical gel is supplied in a 1 oz. (28.4 g) aluminum tube and a 45 g aluminum tube.
Storage Conditions: STORE AT CONTROLLED ROOM TEMPERATURE: 15-30ºC (59-86ºF).
MetroLotion
MetroLotion topical lotion, 0.75% is supplied in the following size: 2 fl oz (59 ml) plastic bottle.
Storage: Store at controlled room temperature 20-25°C (68-77°F). Protect from freezing.
FOR INTRAVAGINAL USE ONLY.
NOT FOR OPHTHALMIC, DERMAL, OR ORAL USE.
MetroGel Vaginal is the intravaginal dosage form of the synthetic antibacterial agent, metronidazole at a concentration of 0.75%. Metronidazole is a member of the imidazole class of antibacterial agents and is classified therapeutically as an antiprotozoal and antibacterial agent. Chemically, metronidazole is a 2-methyl-5-nitroimidazole-1-ethanol. It has a chemical formula of C6H9N3O3 and a molecular weight of 171.16.
MetroGel Vaginal is a gelled, purified water solution, containing metronidazole at a concentration of 7.5 mg/g (0.75%). The gel is formulated at pH 4.0. The gel also contains carbomer 934P, edetate disodium, methyl paraben, propyl paraben, propylene glycol, and sodium hydroxide.
Each applicator full of 5 g of vaginal gel contains approximately 37.5 mg of metronidazole.
Normal Subjects
Following a single, intravaginal 5 g dose of metronidazole vaginal gel (equivalent to 37.5 mg of metronidazole) to 12 normal subjects, a mean maximum serum metronidazole concentration of 237 ng/ml was reported (range: 152-368 ng/ml). This is approximately 2% of the mean maximum serum metronidazole concentration reported in the same subjects administered a single, oral 500 mg dose of metronidazole (mean Cmax = 12,785 ng/ml, range: 10,013-17,400 ng/ml). These peak concentrations were obtained in 6-12 hours after dosing with metronidazole vaginal gel and 1-3 hours after dosing with oral metronidazole.
The extent of exposure [area under the curve (AUC)] of metronidazole, when administered as a single intravaginal 5 g dose of metronidazole vaginal gel (equivalent to 37.5 mg of metronidazole), was approximately 4% of the AUC of a single oral 500 mg dose of metronidazole (4,977 ng·h/ml and approximately 125,000 ng·h/ml, respectively).
Dose-adjusted comparisons of AUCs demonstrated that, on a mg to mg comparison basis, the absorption of metronidazole, when administered vaginally, was approximately half that of an equivalent oral dosage.
Patients With Bacterial Vaginosis
Following single and multiple 5 g doses of metronidazole vaginal gel to 4 patients with bacterial vaginosis, a mean maximum serum metronidazole concentration of 214 ng/ml on Day 1 and 294 ng/ml (range: 228-349 ng/ml) on Day 5 were reported. Steady-state metronidazole serum concentrations following oral dosages of 400-500 mg bid have been reported to range from 6,000-20,000 ng/ml.
Microbiology
The intracellular targets of action of metronidazole on anaerobes are largely unknown. The 5-nitro group of metronidazole is reduced by metabolically active anaerobes, and studies have demonstrated that the reduced form of the drug interacts with bacterial DNA. However, it is not clear whether interaction with DNA alone is an important component in the bactericidal action of metronidazole on anaerobic organisms.
Culture and sensitivity testing of bacteria are not routinely performed to establish the diagnosis of bacterial vaginosis. (See INDICATIONS AND USAGE.)
Standard methodology for the susceptibility testing of the potential bacterial vaginosis pathogens, Gardnerella vaginalis, Mobiluncus spp., and Mycoplasma hominis, has not been defined. Nonetheless, metronidazole is an antimicrobial agent active in vitro against most strains of the following organisms that have been reported to be associated with bacterial vaginosis:
In a randomized, single-blind clinical trial of non-pregnant women with bacterial vaginosis who received metronidazole vaginal gel daily for 5 days, the clinical cure rates for evaluable patients determined at 4 weeks after completion of therapy for the qd and bid regimens were 98/185 (53%) and 109/190 (57%), respectively.
Metronidazole vaginal gel is indicated in the treatment of bacterial vaginosis (formerly referred to as Haemophilus vaginitis, Gardnerella vaginitis, nonspecific vaginitis, Corynebacterium vaginitis, or anaerobic vaginosis).
NOTE: For purposes of this indication, a clinical diagnosis of bacterial vaginosis is usually defined by the presence of a homogeneous vaginal discharge that (a) has a pH of greater than 4.5, (b) emits a “fishy” amine odor when mixed with a 10% KOH solution, and (c) contains clue cells on microscopic examination. Gram’s stain results consistent with a diagnosis of bacterial vaginosis include (a) markedly reduced or absent Lactobacillus morphology, (b) predominance of Gardnerella morphotype, and (c) absent or few white blood cells.
Other pathogens commonly associated with vulvovaginitis, e.g., Trichomonas vaginalis, Chlamydia trachomatis, N. gonorrhoeae, Candida albicans, and Herpes simplex virus should be ruled out.
Non-FDA Approved Indications
Metronidazole has been investigated for the treatment of generalized idiopathic lichen planus, Crohn's disease, and granulomatous cheilitis. It is also used in the treatment of giardiasis, although this is not an FDA-approved use.
Metronidazole vaginal gel is contraindicated in patients with a prior history of hypersensitivity to metronidazole, parabens, other ingredients of the formulation, 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 oral or IV metronidazole. The appearance of abnormal neurologic signs demands the prompt discontinuation of metronidazole vaginal gel therapy. Metronidazole vaginal gel should be administered with caution to patients with central nervous system diseases.
Psychotic Reactions
Psychotic reactions have been reported in alcoholic patients who were using oral metronidazole and disulfiram concurrently. Metronidazole vaginal gel should not be administered to patients who have taken disulfiram within the last 2 weeks.
Metronidazole vaginal gel affords minimal peak serum levels and systemic exposure (AUCs) of metronidazole compared to 500 mg oral metronidazole dosing. Although these lower levels of exposure are less likely to produce the common reactions seen with oral metronidazole, the possibility of these and other reactions cannot be excluded presently. Data from well-controlled trials directly comparing metronidazole administered orally to metronidazole administered vaginally are not available.
General
Patients with severe hepatic disease metabolize metronidazole slowly. This results in the accumulation of metronidazole and its metabolites in the plasma. Accordingly, for such patients, metronidazole vaginal gel should be administered cautiously.
Known or previously unrecognized vaginal candidiasis may present more prominent symptoms during therapy with metronidazole vaginal gel. Approximately 6-10% of patients treated with metronidazole vaginal gel developed symptomatic Candida vaginitis during or immediately after therapy.
Disulfiram-like reaction to alcohol has been reported with oral metronidazole, thus the possibility of such a reaction occurring while on metronidazole vaginal gel therapy cannot be excluded.
Metronidazole vaginal gel contains ingredients that may cause burning and irritation of the eye. In the event of accidental contact with the eye, rinse the eye with copious amounts of cool tap water.
Information for the Patient
The patient should be cautioned about drinking alcohol while being treated with metronidazole vaginal gel. While blood levels are significantly lower with metronidazole vaginal gel than with usual doses of oral metronidazole, a possible interaction with alcohol cannot be excluded.
The patient should be instructed not to engage in vaginal intercourse during treatment with this product.
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. Values of zero may be observed. All of the assay assays in which interference has been reported involve enzymatic coupling of the assay to oxidation-reduction of nicotinamide-adenine dinucleotides (NAD + NADH). Interference is due to the similarity in absorbance peaks of NADH (340 nm) and metronidazole (322 nm) at pH 7.
Carcinogenesis, Mutagenesis, and Impairment of Fertility
Metronidazole has shown evidence of carcinogenic activity in a number of studies involving chronic oral administration in mice and rats. Prominent among the effects in the mouse was the promotion of pulmonary tumorigenesis. This has been observed in all six reported studies in that species, including one study in which the animals were dosed on an intermittent schedule (administration during every fourth week only). At very high dose levels (approximately 500 mg/kg/day), there was a statistically significant increase in the incidence of malignant liver tumors in males. Also, the published results of one of the mouse studies indicate an increase in the incidence of malignant lymphomas as well as pulmonary neoplasms associated with lifetime feeding of the drug. All these effects are statistically significant. Several long-term oral dosing studies in the rat have been completed. There were statistically significant increases in the incidence of various neoplasms, particularly in mammary and hepatic tumors, among female rats administered metronidazole over those noted in the concurrent female control groups. Two lifetime tumorigenicity studies in hamsters have been performed and reported to be negative.
These studies have not been conducted with 0.75% metronidazole vaginal gel, which would result in significantly lower systemic blood levels than those obtained with oral formulations.
Although metronidazole has shown mutagenic activity in a number of in vitro assay systems, studies in mammals (in vivo) have failed to demonstrate a potential for genetic damage.
Fertility studies have been performed in mice up to 6 times the recommended human oral dose (based on mg/m2) and have revealed no evidence of impaired fertility.
Pregnancy, Teratogenic Effects, Pregnancy Category B
There has been no experience to date with the use of metronidazole vaginal gel in pregnant patients. Metronidazole crosses the placental barrier and enters the fetal circulation rapidly. No fetotoxicity or teratogenicity was observed when metronidazole was administered orally to pregnant mice at 6 times the recommended human dose (based on mg/m2); however, in a single small study where the drug was administered intraperitoneally, some intrauterine deaths were observed. The relationship of these findings to the drug is unknown.
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, this drug should be used during pregnancy only if clearly needed.
Nursing Mothers
Specific studies of metronidazole levels in human milk following intravaginally administered metronidazole have not been performed. However, metronidazole is secreted in human milk in concentrations similar to those found in plasma following oral administration of metronidazole.
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
Safety and effectiveness in children have not been established.
Oral metronidazole has been reported to potentiate the anticoagulant effect of warfarin and other coumarin anticoagulants, resulting in a prolongation of prothrombin time. This possible drug interaction should be considered when metronidazole vaginal gel is prescribed for patients on this type of anticoagulant therapy.
In patients stabilized on relatively high doses of lithium, short-term oral metronidazole therapy has been associated with elevation of serum lithium levels and, in a few cases, signs of lithium toxicity.
Use of cimetidine with oral metronidazole may prolong the half-life and decrease plasma clearance of metronidazole.
Clinical Trials
There were no deaths or serious adverse events related to drug therapy in clinical trials involving 800 non-pregnant women who received metronidazole vaginal gel.
In a randomized, single-blind clinical trial of 505 non-pregnant women who received metronidazole vaginal gel once or twice a day, 2 patients (1 from each regimen) discontinued therapy early due to drug-related adverse events. One patient discontinued drug because of moderate abdominal cramping and loose stools, while the other patient discontinued drug because of mild vaginal burning. These symptoms resolved after discontinuation of drug.
Medical events judged to be related, probably related, or possibly related to administration of metronidazole vaginal gel once or twice a day were reported for 195/505 (39%) patients. The incidence of individual adverse reactions were not significantly different between the two regimens. Unless percentages are otherwise stipulated, the incidence of individual adverse reactions listed below was less than 1%.
In previous clinical trials submitted for approved labeling of metronidazole vaginal gel the following was also reported:
Other Metronidazole Formulations
Other effects that have been reported in association with the use of topical (dermal) formulations of metronidazole include skin irritation, transient skin erythema, and mild skin dryness and burning. None of these adverse events exceeded an incidence of 2% of patients.
Metronidazole vaginal gel affords minimal peak serum levels and systemic exposure (AUC) of metronidazole compared to 500 mg oral metronidazole dosing. Although these lower levels of exposure are less likely to produce the common reactions seen with oral metronidazole, the possibility of these and other reactions cannot be excluded presently.
The following adverse reactions and altered laboratory tests have been reported with the oral or parenteral use of metronidazole:
There is no human experience with overdosage of metronidazole vaginal gel. Vaginally applied metronidazole gel, 0.75% could be absorbed in sufficient amounts to produce systemic effects. (See WARNINGS.)
The recommended dose is 1 applicator full of metronidazole vaginal gel (approximately 5 g containing approximately 37.5 mg of metronidazole) intravaginally once or twice a day for 5 days. For once a day dosing, metronidazole vaginal gel should be administered at bedtime.
MetroGel Vaginal 0.75% Vaginal Gel is supplied in a 70 g tube and packaged with 5 vaginal applicators.
Storage: Store at controlled room temperature 15-30°C (59-86°F). Protect from freezing.
| ||||||||||||||||||||