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 metronidazole 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.
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
tablets should only be used to treat bacterial infections. They do not treat
viral infections (e.g., the common cold). When metronidazole tablets are
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 tablets or other antibacterial drugs in the
future.
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 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 lymphomas 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 be negative.
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
Teratogenic Effects-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).
Nursing Mothers
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. Metronidazole is secreted in human milk in
concentrations similar to those found in plasma.
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 in pediatric patients have not been
established, except for the treatment of amebiasis.
