Included as part of the PRECAUTIONS section.
Peripheral neuropathy, characterized by numbness or paresthesia of an extremity
has been reported in patients treated with systemic metronidazole. Although
not evident in clinical trials for topical metronidazole, peripheral neuropathy
has been reported with the post approval use. The appearance of abnormal neurologic
signs should prompt immediate reevaluation of METROGEL therapy. Metronidazole
should be administered with caution to patients with central nervous system
Metronidazole is a nitroimidazole; use with care in patients with evidence
of, or history of, blood dyscrasia.
Irritant and allergic contact dermatitis have been reported. If dermatitis
occurs, patients may need to discontinue use.
Topical metronidazole has been reported to cause tearing of the eyes. Avoid
contact with the eyes.
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, but not in studies
In several long-term studies in mice, oral doses of approximately 225 mg/m²/day
or greater (approximately 37 times the human topical dose on a mg/m² basis)
were associated with an increase in pulmonary tumors and lymphomas. Several
long-term oral studies in the rat have shown statistically significant increases
in mammary and hepatic tumors at doses > 885 mg/m²/day (144 times the
Metronidazole has shown evidence of mutagenic activity in several in vitro
bacterial assay systems. In addition, a dose-related increase in the frequency
of micronuclei was observed in mice after intraperitoneal injections. An increase
in chromosomal aberrations in peripheral blood lymphocytes was reported in patients
with Crohn's disease who were treated with 200 to 1200 mg/day of metronidazole
for 1 to 24 months. However, in another study, no increase in chromosomal aberrations
in circulating lymphocytes was observed in patients with Crohn's disease treated
with the drug for 8 months.
In one published study, using albino hairless mice, intraperitoneal administration
of metronidazole at a dose of 45 mg/m²/day (approximately 7 times the human
topical dose on a mg/m² basis) was associated with an increase in ultraviolet
radiation-induced skin carcinogenesis. Neither dermal carcinogenicity nor photocarcinogenicity
studies have been performed with METROGEL or any marketed metronidazole formulations.
Use In Specific Populations
Teratogenic Effects - Pregnancy Category B
There are no adequate and well-controlled studies with the use of METROGEL
in pregnant women. Metronidazole crosses the placental barrier and enters the
fetal circulation rapidly. No fetotoxicity was observed after oral administration
of metronidazole in rats or mice at 200 and 20 times, respectively, the expected
clinical dose. However, oral metronidazole has shown carcinogenic activity in
rodents. Because animal reproduction studies are not always predictive of human
response, METROGEL (metronidazole) should be used during pregnancy only if clearly needed.
After oral administration, metronidazole is secreted in breast milk in concentrations
similar to those found in the plasma. Even though blood levels taken after topical
metronidazole application are significantly lower than those achieved after
oral 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 and the risk to the infant.
Safety and effectiveness in pediatric patients have not been established.
Sixty-six subjects aged 65 years and older were treated with metronidazole
gel, 1% in the clinical study. No overall differences in safety or effectiveness
were observed between these subjects and younger subjects, and other reported
clinical experience has not identified differences in responses between the
elderly and younger patients, but greater sensitivity of some older individuals
cannot be ruled out.