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.
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 Patients
Alcoholic beverages should be avoided while taking metronidazole and for at least one day 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.
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 Interactions: 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.
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, 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, 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 Iymphomas 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 benegative.
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 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. No fetotoxicity was observed when metronidazole was administered orally to pregnant mice at 20 mg/kg/day approximately one and a half 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.
Use of metronidazole for trichomoniasis during pregnancy should be restricted to those in whom alternative treatment has been inadequate. Use of 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).
Because of the potential for tumorigenicity shown for metronidazole inmouse 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.
No overall differences have been reported in safety and effectiveness between younger and older individuals, but greater sensitivity of some older individuals cannot be ruled out. Systemic exposure to the active metabolite, 2-hydroxymethyl metronidazole, is higher in the elderly.
Metronidazole is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Although decreased renal function does not alter the single dose pharmacokinetics of metronidazole, because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.
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.
Safety and effectiveness in pediatric patients have not been established, except for the treatment of amebiasis.