Metronidazole

INDICATIONS AND USAGE Bacterial Vaginosis (BV). Metronidazole extended-release 750 mg tablets are indicated in the treatment of BV in non-pregnant women. To reduce the development of drug-resistant bacteria and maintain the effectiveness of metronidazole extended-release tablets and other antibacterial drugs, metronidazole extended-release tablets 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.

DOSAGE AND ADMINISTRATION Bacterial Vaginosis: 750 mg once daily by mouth for seven consecutive days. Metronidazole extended-release 750 mg tablets should be taken under fasting conditions, at least one hour before or two hours after meals. The optimum extended-release characteristics of metronidazole extended-release tablets 750 mg are obtained when the drug is taken under fasting conditions (See CLINICAL PHARMACOLOGY, Absorption). Metronidazole extended-release tablets should not be split, chewed, or crushed. Dosage Adjustments Patients Undergoing Hemodialysis Hemodialysis removes significant amounts of metronidazole and its metabolites from systemic circulation. The clearance of metronidazole will depend on the type of dialysis membrane used, the duration of the dialysis session, and other factors. If the administration of metronidazole cannot be separated from a hemodialysis session, supplementation of metronidazole dosage following the hemodialysis session should be considered, depending on the patient’s clinical situation (see CLINICAL PHARMACOLOGY ).

WARNINGS Central and Peripheral Nervous System Effects Encephalopathy and peripheral neuropathy: Cases of encephalopathy and peripheral neuropathy (including optic neuropathy) have been reported with metronidazole. Encephalopathy has been reported in association with cerebellar toxicity characterized by ataxia, dizziness, and dysarthria. CNS lesions seen on MRI have been described in reports of encephalopathy. CNS symptoms are generally reversible within days to weeks upon discontinuation of metronidazole. CNS lesions seen on MRI have also been described as reversible. Peripheral neuropathy, mainly of sensory type has been reported and is characterized by numbness or paresthesia of an extremity. Convulsive seizures have been reported in patients treated with metronidazole. Aseptic meningitis: Cases of aseptic meningitis have been reported with metronidazole. Symptoms can occur within hours of dose administration and generally resolve after metronidazole therapy is discontinued. The appearance of abnormal neurologic signs and symptoms demands the prompt evaluation of the benefit/risk ratio of the continuation of therapy (see ADVERSE REACTIONS ).

CONTRAINDICATIONS Hypersensitivity Metronidazole extended-release 750 mg tablets are contraindicated in patients with a prior history of hypersensitivity to metronidazole or other nitroimidazole derivatives. Psychotic Reaction with Disulfiram Use of oral metronidazole is associated with psychotic reactions in alcoholic patients who were using disulfiram concurrently. Do not administer metronidazole to patients who have taken disulfiram within the last two weeks (see PRECAUTIONS , Drug Interactions ). Interaction with Alcohol Use of oral metronidazole is associated with a disulfiram-like reaction to alcohol, including abdominal cramps, nausea, vomiting, headaches, and flushing. Discontinue consumption of alcohol or products containing propylene glycol during and for at least three days after therapy with metronidazole (see PRECAUTIONS , Drug Interactions ). Cockayne Syndrome Metronidazole Extended-Release 750 mg tablets are contraindicated in patients with Cockayne syndrome. Severe irreversible hepatotoxicity/acute liver failure with fatal outcomes have been reported after initiation of metronidazole in patients with Cockayne syndrome (see ADVERSE REACTIONS ).

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 2 weeks (see CONTRAINDICATIONS ). 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 (see CONTRAINDICATIONS ). 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 375 capsules 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. If no therapeutic alternatives to metronidazole are available, and concomitant administration with busulfan is medically needed, frequent monitoring of busulfan plasma concentration should be performed and the busulfan dose should be adjusted accordingly. 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 been reported. Drugs that Prolong the QT interval QT prolongation has been reported, particularly when metronidazole was administered with drugs with the potential for prolonging the QT interval.

Pregnancy Teratogenic effects: There are no adequate and well-controlled studies of metronidazole extended-release tablets in pregnant women. There are published data from case-control studies, cohort studies, and 2-meta-analyses that include more than 5000 pregnant women who used metronidazole during pregnancy. Many studies included first trimester exposures. One study showed an increased risk of cleft lip, with or without cleft palate, in infants exposed to metronidazole in-utero ; however, these finding were not confirmed. In addition, more than ten randomized placebo-controlled clinical trials enrolled more than 5000 pregnant women to assess the use of antibiotic treatment (including metronidazole) for bacterial vaginosis on the incidence of preterm delivery. Most studies did not show an increased risk for congenital anomalies or other adverse fetal outcomes following metronidazole exposure during pregnancy. Three studies conducted to assess the risk of infant cancer following metronidazole exposure during pregnancy did not show an increased risk; however, the ability of these studies to detect such a signal was limited. Metronidazole crosses the placental barrier and its effects on the human fetal organogenesis are not known. Reproduction studies have been performed in rats, rabbits, and mice at doses about four times the recommended human dose based on body surface area comparisons. There was no evidence of harm to the fetus due to metronidazole.

Nursing mothers Metronidazole is present in human milk at concentrations similar to maternal serum levels, and infant serum levels can be close to or comparable to infant therapeutic levels. 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. Alternatively, a nursing mother may choose to pump and discard human milk for the duration of metronidazole therapy, and for 24 hours after therapy ends and feed her infant stored human milk or formula.

ADVERSE REACTIONS 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). 3,4 Most adverse events were described as being of mild or moderate severity. Among patients taking metronidazole extended-release tablets 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 tablets. Adverse events reported at ≥2% incidence for either treatment group, irrespective of treatment causality, are summarized in the table below. Adverse Events (≥2% Incidence Rate)—Irrespective of Treatment Causality Metronidazole Extended-Release Tablets 7 days (N=267) Vaginal Preparation (N=285) Headache 48 (18%) 44 (15%) Vaginitis 39 (15%) 32 (12%) Nausea 28 (10%) 8 (3%) Taste Perversion (metallic taste) 23 (9%) 1 (0%) Infection Bacterial 19 (7%) 17 (6%) Influenza-like Symptoms 17 (6%) 20 (7%) Pruritus Genital 14 (5%) 25 (9%) Abdominal Pain 10 (4%) 13 (5%) Dizziness 11 (4%) 3 (1%) Diarrhea 11 (4%) 3 (1%) Upper Respiratory Tract Infection 11 (4%) 10 (4%) Rhinitis 12 (4%) 10 (4%) Sinusitis 7 (3%) 6 (2%) Urine Abnormal 7 (3%) 4 (1%) Pharyngitis 8 (3%) 4 (1%) Dysmenorrhea 9 (3%) 7 (2%) Moniliasis 9 (3%) 8 (3%) Mouth Dry 5 (2%) 2 (1%) Urinary Tract Infection 6 (2%) 16 (6%) 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 tablets or the vaginal comparator. The following reactions have been reported during treatment with metronidazole: Central Nervous System: The most serious adverse reactions reported in patients treated with metronidazole have been convulsive seizures, encephalopathy, aseptic meningitis, optic 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 metronidazole, 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. In addition, patients have reported headache, syncope, dizziness, vertigo, incoordination, ataxia, confusion, dysarthria, irritability, depression, weakness, and insomnia (See WARNINGS ). Gastrointestinal: The most common adverse reactions reported have been referable to the gastrointestinal tract, particularly nausea, sometimes accompanied by headache, anorexia, and occasionally vomiting, diarrhea, epigastric distress; abdominal cramping; and constipation. Mouth: A sharp, unpleasant metallic taste is not unusual. Furry tongue, glossitis, and stomatitis have occurred; these may be associated with a sudden overgrowth of Candida which may occur during 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. Although the pigment which is probably responsible for this phenomenon has not been positively i…