| Pharmacokinetics |
Absorption:
Disposition of metronidazole in the body is similar for both oral and intravenous dosage forms. 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, produced peak plasma concentrations of 6 mcg/mL, 12 mcg/mL, respectively.
Distribution:
Metronidazole is the major component appearing in the plasma, with lesser quantities of metabolites also being present. Less than 20% of the circulating metronidazole is bound to plasma proteins. Metronidazole appears in cerebrospinal fluid, saliva, and breast milk in concentrations similar to those found in plasma. Bactericidal concentrations of metronidazole have also been detected in pus from hepatic abscesses.
Metabolism & Excretion:
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. Renal clearance of metronidazole is approximately 10 mL/min/1.73 m². The average elimination half-life of metronidazole in healthy subjects is 8 hours.
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| Indications and Usage for Metromed |
Symptomatic Trichomoniasis:
Metronidazole is indicated for the treatment of T. vaginalis infection in females and males when the presence of the trichomonas has been confirmed by appropriate laboratory procedures.
Asymptomatic Trichomoniasis:
Metronidazole is indicated in the treatment of asymptomatic T. vaginalis infection in females when the organism is associated with endocervicitis, cervicitis, or cervical erosion.
Treatment of Asymptomatic Sexual Partners:
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.
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.
Intra-abdominal Infections: including peritonitis, intra-abdominal abscess, and liver abscess, caused by Bacteroides species including the B. fragilis group (B. fragilis, B. distasonis, B. ovatus, B. thetaiotaomicron, B. vulgatus), Clostridium species, Eubacterium species, Peptococcus species, and Peptostreptococcus species.
Skin and Skin Structure Infections: caused by Bacteroides species including the B. fragilis group, Clostridium species, Peptococcus species, Peptostreptococcus species, and Fusobacterium species.
Gynecologic Infections: including endometritis, endomyometritis, tubo-ovarian abscess, and postsurgical vaginal cuff infection, caused by Bacteroides species including the B. fragilis group, Clostridium species, Peptococcus species, Peptostreptococcus species, and Fusobacterium species.
Bacterial Septicemia: caused by Bacteroides species including the B. fragilis group and Clostridium species.
Bone and Joint Infections: (such as osteomyelitis) caused by Bacteroides species including the B. fragilis group.
Central Nervous System (CNS) Infections: including meningitis and brain abscess, caused by Bacteroides species including the B. fragilis group.
Lower Respiratory Tract Infections: including pneumonia, empyema, and lung abscess, caused by Bacteroides species including the B. fragilis group.
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| Dosage and Administration for Metromed |
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.
Or seven-day course of treatment — 250 mg three times daily for seven consecutive days.
In the Male
Treatment should be individualized as it is 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.
Pediatric patients: 35 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, intravenous metronidazole 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-hour period. The usual duration of therapy is 7 to 10 days; however, infections of the bone and joint, lower respiratory tract, and endocardium may require longer treatment.
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| Adverse Reactions |
The following reactions have been reported during treatment with metronidazole:
Central Nervous System: The most serious adverse reactions reported have been convulsive seizures, encephalopathy, aseptic meningitis, optic and peripheral neuropathy, the latter characterized mainly by numbness or paresthesia of an extremity. In addition, patients have reported headache, syncope, dizziness, vertigo, incoordination, ataxia, confusion, dysarthria, irritability, depression, weakness, and insomnia.
Gastrointestinal: The most common adverse reactions reported have been nausea, sometimes accompanied by headache, anorexia, and occasionally vomiting; diarrhea; epigastric distress; and abdominal cramping and constipation.
Mouth: A sharp, unpleasant metallic taste is not unusual. Furry tongue, glossitis, and stomatitis have occurred; these may be associated with a sudden overgrowth of Candida which may occur during therapy.
Dermatologic: Erythematous rash and pruritus.
Hematopoietic: Reversible neutropenia (leukopenia); rarely, reversible thrombocytopenia.
Cardiovascular: QT prolongation has been reported, particularly when metronidazole was administered with drugs with the potential for prolonging the QT interval. Flattening of the T-wave may be seen in electrocardiographic tracings.
Hypersensitivity: Urticaria, erythematous rash, Stevens–Johnson Syndrome, toxic epidermal necrolysis, 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.
Other: Proliferation of Candida in the vagina, dyspareunia, decrease of libido, proctitis, and fleeting joint pains sometimes resembling serum sickness. Rare cases of pancreatitis, which generally abated on withdrawal of the drug, have been reported.
This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects.
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| Drug Interactions |
Disulfiram: 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.
Alcoholic Beverages: Abdominal cramps, nausea, vomiting, headaches, and flushing may occur if alcoholic beverages or products containing propylene glycol are consumed during or following metronidazole therapy.
Warfarin and other Oral Anticoagulants: Metronidazole has been reported to potentiate the anticoagulant effect of warfarin and other oral coumarin anticoagulants, resulting in a prolongation of prothrombin time. When metronidazole is prescribed for patients on this type of anticoagulant therapy, prothrombin time and INR should be carefully monitored.
Lithium: 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.
Busulfan: Metronidazole has been reported to increase plasma concentrations of busulfan, which can result in an increased risk for serious busulfan toxicity. Metronidazole should not be administered concomitantly with busulfan unless the benefit outweighs the risk.
Drugs that Inhibit CYP450 Enzymes: 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.
Drugs that Induce CYP450 Enzymes: 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.
Drugs that Prolong the QT interval: QT prolongation has been reported, particularly when metronidazole was administered with drugs with potential for prolonging the QT interval.
Mebendazole: Avoid the concomitant use of metronidazole and mebendazole. Serious skin reactions, such as Stevens–Johnson syndrome and toxic epidermal necrolysis, have been reported with co-administration.
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| Use in Specific Population |
Pregnancy:
There are no adequate and well-controlled studies due to metronidazole. However, metronidazole may be prescribed during pregnancy if benefits outweigh risks. Do not use during the first trimester.
Nursing Mothers:
Metronidazole is excreted in breast milk. A decision should be made 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 pediatric patients have not been established, except for the treatment of amebiasis. In one study, the elimination half-life of metronidazole in neonates decreased with increasing postnatal age. The elimination half-life, measured during the first 3 days of life, was approximately 23 hours compared with 9 hours in adults.
Geriatric Patients:
Decreased clearance of metronidazole has been reported in the elderly. In elderly female subjects >70 years old with no apparent renal or hepatic impairment, decreased elimination of metronidazole was observed, resulting in increased plasma concentrations, with no apparent increase of (parent compound). Dose reduction is not considered necessary unless indicated by the patient’s condition. Clinical monitoring is recommended.
Renal Impairment:
Decreased renal clearance and increased plasma concentrations of metronidazole metabolites in ESRD patients, monitoring for metronidazole associated adverse events is recommended.
Hepatic Impairment:
Plasma clearance of metronidazole is decreased by 50% in severe hepatic impairment as seen in patients with severe (Child-Pugh C) hepatic impairment. No dosage adjustment is needed in patients with mild to moderate hepatic impairment, but they impairment should be monitored for metronidazole associated adverse events.
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