DESCRIPTION INDICATIONS AND USAGE, DOSAGE AND ADMINISTRATION.
Oral
Metronidazole is an oral synthetic antiprotozoal and antibacterial agent, 1-(beta-hydroxyethyl)-2-methyl-5-nitroimidazole, which has the following structural formula:
Metronidazole tablets contain 250 mg or 500 mg of metronidazole. Inactive ingredients include cellulose, FD&C Blue No. 2 Lake, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyethylene glycol, stearic acid, and titanium dioxide.
I.V. Injection
Metronidazole HCl Sterile IV and Metronidazole Sterile IV, are parenteral dosage forms of the synthetic antibacterial agents 1-(beta-hydroxyethyl)-2-methyl-5 -nitroimidazole hydrochloride and 1-(beta-hydroxyethyl)-methyl- 5-nitroimidazole, respectively.
Each single-dose vial of lyophilized Metronidazole IV contains sterile, nonpyrogenic Metronidazole HCl, equivalent to 500 mg metronidazole, and 415 mg mannitol.
Each Metronidazole 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 USP. Metronidazole IV RTU has a tonicity of 310 mOsm/L and a pH of 5 to 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 animal according to USP biological tests for plastic containers as well as by tissue culture toxicity studies
CLINICAL PHARMACOLOGY
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 eight hours.
The major route of elimination of metronidazole and its metabolites is via the urine (60 to 80% of the dose), with fecal excretion accounting for 6 to 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/1.73m2.
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 breast 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 one and two hours after administration. Plasma concentrations of metronidazole are proportional to the administered dose. Oral administration of 250 mg, 500 mg, or 2,000 mg produced peak plasma concentrations of 6 mcg/ml, 12 mcg/ml, and 40 mcg/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.
Decreased renal function dose not alter the single-dose pharmacokinetics of metronidazole. However, plasma clearance of metronidazole is decreased in patients with decreased liver function.
Microbiology
Trichomonas vaginalis, Entamoeba histolytica. Metronidazole possesses direct trichomonacidal and amebicidal activity against T. vaginalis and E. histolytica. The in vitro minimal inhibitory concentration (MIC) for most strains of these organisms is 1 mcg/ml or less.
Anaerobic Bacteria. 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 havein 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:
Clostridium species and susceptible strains of Eubacterium
Anaerobic gram-positive cocci, including:
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Peptostreptococcus species
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 precise 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 A.C. 13124,Bacteroides fragilis ATCC 25285, and Bacteroides thetaiotamicron A.C. 29741. The mode metronidazole M.C. for those three strains are reported to be 0.25, 0.25, and 0.5 mcg/ml, respectively.
A clinical laboratory is considered under acceptable control if the results of the control strains are within one doubling dilution of the mode M.C. 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.
INDICATIONS
Oral Tablets
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 the 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, antibiotics appropriate for the treatment of the aerobic infection should be used in addition to Metronidazole.
In the treatment of most serious anaerobic infections, Metronidazole IV RTU (metronidazole) is usually administered initially. This may be followed by oral therapy with Metronidazole at the discretion of the physician.
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 niger, and Peptostreptococcus species.
Skin and Skin Structure Infections caused by Bacteroides species including the B. fragilis group, Clostridium species,Peptococcus niger, Peptostreptococcus species, and Fusobacterium species.
Gynecological Infections, including endometritis, endomyometritis, tubo-ovarian abscess, and postsurgical vaginal cuff infection, caused byBacteroides species including the B. fragilis group,Clostridium species, Peptococcus niger, and Peptostreptococcus species.
Bacterial Septicemia caused by Bacteroides species including theB. fragilis group, and Clostridium species.
Bone and Joint Infections, as adjunctive therapy, caused byBacteroides 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. To reduce the development of drug-resistant bacteria and maintain the effectiveness of Flagyl and other antibacterial drugs, Flagyl 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.
IV Injection
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.
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.
Gynecological Infections, including endometritis, endomyometritis, tubo- ovarian abscess, and postsurgical vaginal cuff infection, caused byBacteroides species including the B. fragilis group,Clostridium species, Peptococcus species, and Peptostreptococcus species.
Bacterial Septicemia, caused by Bacteroides species including theB. fragilis group, and Clostridium species.
Bone and Joint Infection, as adjunctive therapy, caused byBacteroides 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 the Bacteroides species, including theB. Fragilis group.
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
).
DOSAGE AND ADMINISTRATION
Oral Tablets
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: One-day treatment: two grams of Metronidazole, given either as a single dose or in two divided doses of one gram each given in the same day. Seven-day course of treatment: 250 mg three times daily for seven consecutive days. There is some indication from controlled comparative studies that cure rates as determined by vaginal smears, signs and symptoms, may be higher after a seven-day course of treatment than after a one-day treatment regimen.
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 seven-day regimen. A seven-day course of treatment may minimize reinfection of the female long enough to treat sexual contacts. Further, some patients may tolerate one course of therapy better than the other.
Pregnant patients should not be treated during the first trimester with either regimen. If treated during the second or third trimester, the one-day course of therapy should not be used, as it results in higher serum levels which reach the fetal circulation. (See CONTRAINDICATIONS and PRECAUTIONS.)
When repeat courses of the drug are required, it is recommended that an interval of four to six 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: For acute intestinal amebiasis (acute amebic dysentery): 750 mg orally three times daily for 5 to 10 days.
For amebic liver abscess: 500 mg or 750 mg orally three times daily for 5 to 10 days.
Children: 36 to 50 mg/kg/24 hours, divided into three doses, orally for 10 days.
Anaerobic Bacterial Infections
In the treatment of most serious anaerobic infections, Metronidazole HCl IV or Metronidazole IV RTU is usually administered initially.
The usual adult oral dosage is 7.5 mg/kg every six hours (approx. 500 mg for a 70-kg adult). A maximum of 4 g should not be exceeded during a 24-hours period.
The usual duration of therapy is 7 to 10 days; however, infections of the bone and joint, lower respiratory tract, and endocardium may require longer treatment.
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 levels2 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.
Store below 86°F (30°C) and protect from light.
Intravenous Injection
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 adultsis:
Loading Dose: 15 mg/kg infused over one hour (approximately 1 g for a 70-kg adult).
Maintenance Dose: 7.5 mg/kg infused over one hour every six hours (approximately 500 mg for a 70-kg adult). The first maintenance dose should be instituted six hours following the initiation of the loading dose.
Parenteral therapy may be changed to oral Metronidazole 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 six 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 te plasma. Accordingly, for such patients, doses below those usually recommended should be administered cautiously. Close monitoring of plasma metronidazole levels1 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 rescued 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.
Prophylaxis
For surgical; prophylactic use, to prevent postoperative infection in contaminated or potentially contaminated colorectal surgery, the recommended dosage schedule for adults is:
15 mg/kg infused over 30 to 60 minutes and completed approximately one hour before surgery; followed by
7.5 mg/kg infused over 30 to 60 minutes at 6 and 12 hours after the initial dose.
It is important that (1) administration of the initial preoperative dose be completed approximately one hour before surgery so that adequate drug levels are present in the serum and tissues at the time of initial incision, and (2) Metronidazole IV be administered, if necessary, at 6- hours 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 intravenous drip infusion only, either as a continuous or intermittent infusion. IV admixtures containing metronidazole and other drugs should be avoided. Additives should not be introduced into the Metronidazole IV RTU solution. If used with a primary intravenous fluid system, the primary solution should be discontinued during metronidazole infusion. DO NOT USE EQUIPMENT CONTAINING ALUMINUM (EG, NEEDLES, CANNULAE) T.A. WOULD C.M. IN CONTACT WITH THE DRUG SOLUTION.
Metronidazole IV
Metronidazole IV cannot be given by direct intravenous injection (IV bolus) because of the low pH (0.5 to 2.0) of the reconstituted product. Metronidazole IV MUST BE FURTHER DILUTED AND NEUTRALIZED FOR IV INFUSION.
Metronidazole IV is prepared for use in two steps:
NOTE: ORDER OF MIXING IS IMPORTANT
Reconstitution
Dilution in intravenous solution followed by pH neutralization with sodium bicarbonate injection into the dilution.
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 will be in the range of 0.5 to 2.0. Reconstituted Metronidazole IV is clear, and pale yellow to yellow-green in color.
Dilution in Intravenous Solution: Properly reconstituted Metronidazole HCl IV may be added to a glass or plastic IV 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's 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 Metronidazole HCl IV with approximately 5 mEq of sodium bicarbonate injection for each 500 mg of Metronidazole HCl IV 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 Metronidazole HCl IV in the neutralized intravenous solution, since neutralization will decrease the aqueous solubility and precipitation may occur. DO NOT REFRIGERATE NEUTRALIZED SOLUTION; otherwise, precipitation may occur.
Metronidazole IV RTU (Ready To Use)
Metronidazole IV RTU is a ready-to-use isotonic solution. NO DILUTION OR BUFFERING IS REQUIRED. Do not refrigerate. Each container of Metronidazole IV RTU contains 14 mEq of sodium.
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Do not use if cloudy or precipitated or if the seal is not intact.
Use sterile equipment. It is recommended that the intravenous administration apparatus be replaced at least once every 24 hours.
Store Metronidazole HCl IV, prior to reconstitution, should be stored below 86°F (30°C) and protected from light.
Metronidazole IV RTU should be stored at controlled room temperature , 59° to 86°F (15° to 30°C), and protected from light during storage.
HOW SUPPLIED
Flagyl 250-mg tablets are round, blue, film coated, with SEARLE and 1831 debossed on one side and FLAGYL and 250 on the other side; bottles of 50 and 100. Flagyl 500-mg tablets are oblong, blue, film coated, with FLAGYL debossed on one side and
500 on the other side; bottles of 50 and 100.
Storage and Stability: Store below 77°F (25°C) and
protect from light.
SIDE EFFECTS
Two serious adverse reactions reported in patients treated with Flagyl (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 administration of Flagyl, patients should be specifically warned about these reactions and should be told to stop the drug and report immediately to their physicians if any neurologic symptoms occur.
The most common adverse reactions reported have been referable to the gastrointestinal tract, particularly nausea reported by about 12% of patients, sometimes accompanied by headache, anorexia, and occasionally vomiting; diarrhea; epigastric distress; and abdominal cramping. Constipation has also been reported.
The following reactions have also been reported during treatment with Metronidazole:
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, and a sense of pelvic pressure. Instances of darkened urine have been reported by approximately one patient in 100,000. Although the pigment which is 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.
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'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.
DRUG INTERACTIONS
Tablets
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 one day 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 two weeks.
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.
PRECAUTIONS
General
Tablets/IV Injection: 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 candicidal 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.
Laboratory Tests
Tablets/IV Injection: 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 for trichomoniasis and amebiasis, especially if a second course of therapy is necessary, and before and after therapy for anaerobic infection.
Drug/Laboratory Test Interactions
Tablets/IV Injection: 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 studies in rodents: 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 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) there was 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 increase 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.
Mutagenicity Studies
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 six 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 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, this drug should be used during pregnancy only if clearly needed (see CONTRAINDICATIONS.)
Use of Metronidazole for trichomoniasis in the second and third trimesters should be restricted to those in whom local palliative treatment has been inadequate to control symptoms.
Use of Flagyl (metronidazole) for trichomoniasis in pregnancy should be carefully evaluated because metronidazole crosses the placental barrier and its effects on the human fetal organogenesis are not known (see above).
Nursing Mothers
Tablets: 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, except for the treatment of amebiasis.
Geriatric use: Decreased renal function does not alter the single-dose harmacokinetics 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.
DESCRIPTION
METROGEL-VAGINAL is the intravaginal dosage form of the synthetic
antibacterial agent, metronidazole, USP 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 C 6 H 9 N 3 0 3 ,
a molecular weight of 171.16, and has the following structure:
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 grams of vaginal gel contains approximately 37.5 mg
of metronidazole.
CLINICAL PHARMACOLOGY
Normal Subjects:
Following a single, intravaginal 5 gram 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 to 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 C max = 12,785 ng/mL, range: 10,013 to
17,400 ng/mL). These peak concentrations were obtained in 6 to 12 hours after
dosing with metronidazole vaginal gel and 1 to 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 gram 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 (4977 ng-hr/mL and approximately
125,000 ng-hr/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 gram 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 to 349 ng/mL) on
day five were reported. Steady-state metronidazole serum concentrations
following oral dosages of 400 to 500 mg BID have been reported to range from
6,000 to 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:
Bacteroides spp.
Gardnerella vaginalis
Mobiluncus spp.
Peptostreptococcus spp.
INDICATIONS AND USAGE
METROGEL-VAGINAL 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.
CONTRAINDICATIONS
METROGEL-VAGINAL is contraindicated in patients with a prior history of
hypersensitivity to metronidazole, parabens, other ingredients of the
formulation, or other nitroimidazole derivatives.
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 oral or intravenous 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 two
weeks.
PRECAUTIONS
METROGEL-VAGINAL 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 METROGEL-VAGINAL 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.
METROGEL-VAGINAL 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 METROGEL-VAGINAL 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 Interactions: 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.
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 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, 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 (approx. 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 six times the recommended
human oral dose (based on mg/m 2 ) 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 METROGEL-VAGINAL 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 six times the
recommended human dose (based on mg/m 2 ); 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.
ADVERSE EVENTS
Clinical Trials:
There were no deaths or serious adverse events related to drug therapy in
clinical trials involving 800 non-pregnant women who received METROGEL-VAGINAL.
In a randomized, single-blind clinical trial of 505 non-pregnant women who
received METROGEL-VAGINAL once or twice a day, 2 patients (one 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 METROGEL-VAGINAL 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%:
Reproductive: Vaginal discharge (12%), symptomatic Candida cervicitis/vaginitis
(10%), vulva/vaginal irritative symptoms (9%), pelvic discomfort (3%).
Gastrointestinal: Gastrointestinal discomfort (7%), nausea and/or
vomiting (4%), unusual taste (2%), diarrhea/loose stools (1%), decreased
appetite (1%), abdominal bloating/gas; thirsty, dry mouth. Neurologic: Headache
(5%), dizziness (2%), depression. Dermatologic: Generalized itching or
rash. Other: Unspecified cramping (1%), fatigue, darkened urine.
In previous clinical trials submitted for approved labeling of METROGEL-VAGINAL
the following was also reported: Laboratory: Increased/decreased white
blood cell counts (1.7%).
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.
METROGEL-VAGINAL 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:
Cardiovascular: Flattening of the T-wave may be seen in
electrocardiographic tracings.
Central Nervous System: (See WARNINGS. )
Headache, dizziness, syncope, ataxia, confusion, convulsive seizures, peripheral
neuropathy, vertigo, incoordination, irritability, depression, weakness,
insomnia.
Gastrointestinal: Abdominal discomfort, nausea, vomiting, diarrhea, an
unpleasant metallic taste, anorexia, epigastric distress, abdominal cramping,
constipation, "furry" tongue, glossitis, stomatitis, pancreatitis, and
modification of taste of alcoholic beverages.
Genitourinary: Overgrowth of Candida in the vagina, dyspareunia,
decreased libido, proctitis.
Hematopoietic: Reversible neutropenia, reversible thrombocytopenia.
Hypersensitivity Reactions: Urticaria; erythematous rash; flushing;
nasal congestion; dryness of the mouth, vagina, or vulva; fever; pruritus;
fleeting joint pains.
Renal: Dysuria, cystitis, polyuria, incontinence, a sense of pelvic
pressure, darkened urine.
OVERDOSAGE
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 .)
DOSAGE AND ADMINISTRATION
The recommended dose is one applicator full of METROGELVAGINAL (approximately
5 grams containing approximately 37.5 mg of metronidazole) intravaginally once
or twice a day for 5 days. For once a day dosing, METROGEL-VAGINAL should be
administered at bedtime.
HOW SUPPLIED
METROGEL-VAGINAL (metronidazole vaginal gel) 0.75% Vaginal Gel is supplied in
a 70 gram tube and packaged with 5 vaginal applicators. The NDC number for the
70 gram tube is 0089-0200-25. Store at controlled room temperature 15° to 30°C
(59° to 86°F). Protect from freezing.
Clinical Studies
In a randomized, single-blind clinical trial of non-pregnant women with
bacterial vaginosis who received METROGEL-VAGINAL 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.
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