Central and Peripheral Nervous System Effects

Convulsive seizures, encephalopathy, aseptic meningitis, optic 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.

General

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 Flagyl ER (metronidazole extended release tablets) 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

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 should be made before and after re-treatments.

Carcinogenesis, mutagenesis, impairment of fertility

Pulmonary tumors have been observed in all six reported studies in the mouse, including one study in which the animals were dosed on an intermittent schedule (administration during every fourth week only).

Malignant liver tumors were increased in male mice treated at approximately 1500 mg/m². This dose is approximately 3 times the recommended dose.

Malignant lymphomas and pulmonary neoplasms are also increased with lifetime feeding of the drug to mice (published data).

Mammary and hepatic tumors were increased among female rats administered oral metronidazole compared to concurrent controls.

Two lifetime tumorigenicity studies in hamsters have been performed and reported to be negative.

Metronidazole has shown mutagenic activity in in vitro assay systems including the Ames test. 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

Flagyl ER has not been studied in pregnant women. Since metronidazole crosses the placental barrier and enters the fetal circulation rapidly, it should not be administered to pregnant patients during the first trimester. No fetotoxicity was observed when metronidazole was administered orally to pregnant mice at 60 mg/ m²/day, which is approximately 10% of the human dose when expressed as mg/m². 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. (See CONTRAINDICATIONS.)

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

Since metronidazole is secreted in human milk in concentrations similar to those found in plasma, and since tumors were increased in rats and mice treated with metronidazole, 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.

Geriatric use

Decreased renal function does not alter the single-dose pharmacokinetics 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.

Pediatric use

Safety and effectiveness of this dosage form of metronidazole in pediatric patients have not been established.

Last reviewed on RxList: 9/15/2010
This monograph has been modified to include the generic and brand name in many instances.