Antibacterial – Antiprotozoal
Action And Clinical Pharmacology: Metronidazole is bactericidal against anaerobic bacteria, it exerts trichomonacidal activity and is also active against Giardia lamblia and Entamoeba histolytica. Its exact mechanism of action has not been entirely determined as yet. It has been proposed that an intermediate in the reduction of metronidazole, produced only in anaerobic bacteria and protozoa is bound to deoxyribonucleic acid and electron-transport proteins, inhibits subsequent nucleic acid synthesis.
Following oral administration, metronidazole is completely absorbed with plasma concentration usually reaching a peak within 1 to 2 hours. After single oral 500 mg doses, peak plasma levels of approximately 13 mg/L were obtained. On a regimen of 500 mg t.i.d. administered by the i.v. route, a steady state was achieved after approximately 3 days. The mean peak and trough concentrations measured at that time were 26 and 12 mg/L respectively, and the elimination half-life was approximately 7 to 8 hours. Comparison of the pharmacokinetics of oral and i.v. metronidazole revealed that the area under the plasma metronidazole concentration against time curves were essentially identical.
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 (i.e. 1-(b-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.
Metronidazole is the major component appearing in the plasma with lesser quantities of the 2-hydroxymethyl metabolite also being present. The ratio of these components varies with time but the maximum concentration of the metabolite (Cmax) is approximately 20% of the Cmax of metronidazole for the oral route of administration.
Less than 20% of the circulating metronidazole is bound to plasma proteins.
Decreased renal function does not appear to alter the single dose pharmacokinetics of metronidazole although the elimination half-life of the metabolites is prolonged.
During hemodialysis, the hydroxy metabolite is removed from the plasma about 3 times more rapidly than in normal subjects. Therefore, no accumulation should occur in anuric patients undergoing regular dialysis.
In patients with impaired liver function, the plasma clearance of metronidazole is decreased and accumulation can therefore result.
Indications And Clinical Uses: Bacterial Infections: I.V. metronidazole is indicated in the treatment of serious anaerobic intra-abdominal infections due to susceptible anaerobic bacteria, such as B. fragilis (and other species of Bacteroides), Clostridium, Fusobacterium, Peptococcus, and Peptostreptococcus species.
Culture and susceptibility studies should be performed to determine the causative organisms and their susceptibility to metronidazole. Based on clinical judgment and anticipated bacteriological findings, therapy may be started while awaiting the results of these tests. However, modification of the treatment may be necessary once these results become available.
In mixed aerobic and anaerobic infections, consideration should be given to the concomitant administration of an antibiotic appropriate for the treatment of the aerobic component of the infection (see Warnings).
Metronidazole has also been used in the treatment of a small number of cases of brain or lung infections (some with abscesses) caused by anaerobic bacteria.
Bacterial Vaginosis: The 1988 Canadian Guidelines for the Treatment of Sexually Transmitted Diseases in Neonates, Children, Adolescents and Adults recommends metronidazole for the treatment of this condition.
Protozoal Infections: Trichomonal infections in men as well as in women. Hepatic and intestinal amebiasis. Giardiasis.
Contra-Indications: Hypersensitivity to metronidazole or other nitroimidazole derivatives.
Metronidazole should not be administered to patients with active neurological disorders or a history of blood dyscrasia, hypothyroidism and hypoadrenalism.
Manufacturers’ Warnings In Clinical States: Metronidazole has no direct activity against aerobic or facultative anaerobic bacteria. In patients with mixed aerobic-anaerobic infections, appropriate concomitant antibiotics active against the aerobic component should be considered.
Known or previously unrecognized moniliasis may present more prominent symptoms after treatment with metronidazole.
Studies in rats and mice have provided some evidence that metronidazole may cause tumors in these species when administered orally for a long period at high doses. The relevance of these findings in humans is not known. However, it is therefore recommended that in the treatment of trichomoniasis, the use of metronidazole should be confined to those patients in whom significant T. vaginalis infection has been confirmed by appropriate diagnostic techniques.
Severe neurological disturbances (i.e. convulsive seizures and peripheral neuropathy) have been reported in patients treated with metronidazole. These have been observed very infrequently.
Precautions: Where there is clinical evidence of a trichomonal infection in the sexual partner, he should be treated concomitantly to avoid reinfection.
A rare case of reversible but profound neurological deterioration has been reported following a single oral dose of metronidazole; it is therefore advisable that a patient taking this drug for the first time not be left unattended for a period of 2 hours. The appearance of abnormal neurologic signs demands prompt discontinuation of metronidazole therapy and, when severe, immediate medical attention. Gastric lavage may be considered if no more than 2 or 3 hours have elapsed since administration of the drug.
Treatment with metronidazole should be discontinued if ataxia or any other symptom of CNS involvement occurs.
Patients with severe hepatic disease metabolize metronidazole slowly with resultant accumulation of metronidazole and its metabolites in the plasma. Accordingly, for such patients, doses of metronidazole below those usually recommended should be administered and with caution.
Treatment with metronidazole should be discontinued should pancreatitis occur once other causes of this disease are excluded.
Administration of solutions containing sodium ions may result in sodium retention. Care should be taken when administering metronidazole injection to patients receiving corticosteroids or to those predisposed to edema.
Hematologic: Transient eosinophilia and leukopenia have been observed during treatment with metronidazole. Regular total and differential leukocyte counts are advised if administration for more than 10 days or a second course of therapy is considered to be necessary.
Pregnancy: Metronidazole crosses the placental barrier and enters the fetal circulation rapidly. Although it has been given to pregnant women without apparent complication, it is advisable that oral administration be avoided in pregnant patients and metronidazole be withheld during the first trimester of pregnancy. In serious anaerobic infections, if the administration of metronidazole to pregnant patients is considered to be necessary, its use requires that the potential benefits be weighed against the possible risks to the fetus.
Lactation: Metronidazole is secreted in breast milk in concentrations similar to those found in plasma. Administration of metronidazole should be avoided in the nursing mother.
Children: Clinical experience in children is very limited. The monitoring of this group of patients is particularly important. The safety and effectiveness of i.v. metronidazole in children has not been established.
Laboratory Test Interferences: Metronidazole interferes with serum AST, ALT, LDH, triglycerides and hexokinase glucose determinations which are based on the decrease in ultraviolet absorbance which occurs when NADH is oxidized to NAD. Metronidazole causes an increase in absorbance at the peak of NADH (340 nm) resulting in falsely decreased values.
Drug Interactions: Patients taking metronidazole should be warned against consuming alcohol during therapy and for at least 1 day afterwards, because of a possible disulfiram-like reaction. This reaction appears to be due to the inhibition of the oxidation of acetaldehyde, the primary metabolite of alcohol.
Administration of disulfiram and metronidazole has been associated with acute psychoses and confusion in some patients; therefore, these drugs should not be used concomitantly.
Metronidazole has been reported to potentiate the anticoagulant effect of warfarin 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.
In single dose studies, metronidazole injection did not interfere with the biotransformation of diazepam, antipyrine or phenytoin in man.
However, patients maintained on phenytoin were found to have toxic blood levels after oral metronidazole administration. Phenytoin concentration returned to therapeutic blood level after discontinuance of metronidazole.
The metabolism of metronidazole has been reported to be increased by concurrent administration of phenobarbital. It is recommended that increased doses of metronidazole injection be considered in such cases.
A slight potentiation of the neuromuscular blocking activity of vecuronium has been reported in patients administered metronidazole at a dose of 15 mg/kg.
Concomitant use of lithium and metronidazole may result in lithium intoxication due to decreased renal clearance of lithium. Persistent renal damage may develop. When metronidazole must be administered to patients on lithium therapy, it may be prudent to consider tapering or discontinuing lithium temporarily when feasible. Otherwise frequent monitoring of lithium, creatinine and electrolyte levels and urine osmolality should be done.
Adverse Reactions: Gastrointestinal: diarrhea, nausea, vomiting, anorexia, epigastric distress, dyspepsia, constipation and rare cases of pseudomembranous colitis. Reversible cases of pancreatitis have been reported infrequently.
Mouth: furred tongue, dry mouth, unpleasant metallic taste.
Hematopoietic: transient eosinophilia or leukopenia.
Dermatologic: rash and pruritus.
Cardiovascular: palpitation and chest pain.
CNS: convulsive seizures, peripheral neuropathy, transient ataxia, dizziness, drowsiness, insomnia, headache and psychiatric disorders, such as confusion and hallucinations.
Peripheral neuropathies have been reported in a few patients on moderately high to high dose prolonged oral treatment with metronidazole. It would appear that the occurrence is not directly related to the daily dosage and that an important predisposing factor is the continuation of oral and/or i.v. medication for several weeks or months.
Profound neurological deterioration, within 2 hours after metronidazole administration has been reported. The occurrence is not directly related to the dosage level.
Metabolic: An antithyroid effect has been reported by some investigators but three different clinical studies failed to confirm this.
Local Reactions: Thrombophlebitis has occurred with i.v. administration.
Other: Proliferation of C. albicans in the vagina, vaginal dryness and burning; dysuria; occasional flushing and headaches, especially with concomitant ingestion of alcohol; altered taste of alcoholic beverages.
Darkening of the urine has been reported. This is probably due to a metabolite of metronidazole and seems to have no clinical significance. Reversible lowering of serum lipids has been reported.
A single case of gynecomastia has been reported which resolved on discontinuing metronidazole administration.
Symptoms And Treatment Of Overdose: Symptoms: Massive ingestion may produce vomiting, ataxia and slight disorientation. Neurotoxic effects, including seizures and peripheral neuropathy have been reported after 5 to 7 days of oral doses of 6 to 10.4 g every other day.
Treatment: There is no specific antidote. Early gastric lavage may remove a large amount of the drug; otherwise, symptomatic treatment.
Dosage And Administration: Anaerobic Infections: Treatment should be initiated by the i.v. route. Oral medication may be substituted when it is feasible and/or practical.
Duration of therapy depends upon clinical and bacteriological assessment. Treatment for 7 days should be satisfactory for most patients. However, in cases where infection sites cannot be drained or which are liable to endogenous recontamination by anaerobic pathogens, a longer treatment may be required.
Adults: Oral: 500 mg every 8 hours.
I.V.: 100 mL (500 mg) by slow i.v. infusion (i.e. at the rate of 5 mL/min) every 8 hours.
Children: The safety and effectiveness of metronidazole in children is not known. Due to lack of pharmacokinetic data, no dosage recommendations can be made (see Precautions).
Bacterial Vaginosis: Adults: 500 mg orally twice a day for 7 days. Concurrent treatment of sexual partners is not usually indicated.
Trichomoniasis: Consideration should be given to use metronidazole therapy (oral or vaginal) in female patients, only when trichomonal infection has been confirmed by appropriate diagnostic techniques. In the male patient, oral metronidazole is recommended in those who are evidently the source of reinfection in female consorts and those with demonstrated urogenital trichomoniasis (see Warnings).
Oral: Single Dose Treatment: For both women and men, 2 g administered as a single dose after a meal.
Standard 10 Day Treatment: Women: 250 mg twice a day, morning and night for 10 consecutive days.
Men: 250 mg twice a day for 10 consecutive days. For both men and women, it may be occasionally necessary to give a second 10 day course after 4 to 6 weeks.
Vaginal Insert: One vaginal insert of 500 mg inserted deep into the vagina every night for 10 or 20 consecutive days, even during menstruation. In order to facilitate disintegration, the vaginal insert may be immersed in water for a few seconds just before introduction into the vagina.
Vaginal Cream: One applicatorful of metronidazole cream once or twice a day into the vagina for 10 or 20 consecutive days even during menstruation.
Amebiasis: Adults: Intestinal Amebiasis: 750 mg 3 times daily for 5 to 7 days. Amebic Abscesses of the Liver: 500 to 750 mg 3 times daily for 5 to 7 days. Children: 35 to 50 mg/kg/day in 3 divided doses for 5 to 7 days.
Giardiasis: Adults: 250 mg 2 times daily for 5 to 7 days. Children: 25 to 35 mg/kg/day in 2 divided doses for 5 to 7 days.
Note: Although efficacy of recommended doses for the treatment of amebiasis and giardiasis has been demonstrated, the optimal dose, duration of treatment and risk of recurrence have not been established.
Availability And Storage: Oral Capsules: Each pale green and light grey capsule, printed
and 500, contains: metronidazole 500 mg. Nonmedicinal ingredients: colloidal silicon dioxide, D&C Red No. 33, D&C Yellow No. 10, FD&C Blue No. 1, FD&C Green No. 3, gelatin, lactose, magnesium stearate, polacrilin potassium, sodium lauryl sulfate and titanium dioxide.
Vaginal Cream: Each tube contains: metronidazole 10% w/w in a cream base. Nonmedicinal ingredients: glycerin, glyceryl monostearate, methylparaben, propylparaben, purified water, stearic acid and triethanolamine. Tartrazine-free. Tubes of 60 g with applicator.
Vaginal Inserts: Each white capsule-shaped insert contains: metronidazole 500 mg. Nonmedicinal ingredients: alginic acid, calcium phosphate, colloidal silicon dioxide, cornstarch, dextrin, magnesium stearate, sodium bicarbonate, sodium oleate and talc. Tartrazine-free. Boxes of 10 with applicator.
FLAGYL® Rh´ne-Poulenc Rorer Metronidazole Antibacterial – Antiprotozoal
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