CONTRAINDICATIONS
Anuria, oliguria, or significant impairment of renal function (creatinine clearance under 60 ml per
minute or clinically significant elevated serum creatinine) are contraindications. Treatment of this
type of patient carries an increased risk of toxicity because of impaired excretion of the drug.
Because of the possibility of hemolytic anemia due to immature erythrocyte enzyme systems
(glutathione instability), the drug is contraindicated in pregnant patients at term (38-42 weeks
gestation), during labor and delivery, or when the onset of labor is imminent. For the same reason,
the drug is contraindicated in neonates under one month of age.
Nitrofurantoin is also contraindicated in those patients with known hypersensitivity to nitrofurantoin.
WARNINGS
ACUTE, SUBACUTE, OR CHRONIC PULMONARY REACTIONS HAVE BEEN
OBSERVED IN PATIENTS TREATED WITH NITROFURANTOIN. IF THESE
REACTIONS OCCUR, MACRODANTIN SHOULD BE DISCONTINUED AND
APPROPRIATE MEASURES TAKEN. REPORTS HAVE CITED PULMONARY
REACTIONS AS A CONTRIBUTING CAUSE OF DEATH.
CHRONIC PULMONARY REACTIONS (DIFFUSE INTERSTITIAL PNEUMONITIS
OR PULMONARY FIBROSIS, OR BOTH) CAN DEVELOP INSIDIOUSLY. THESE
REACTIONS OCCUR RARELY AND GENERALLY IN PATIENTS RECEIVING
THERAPY FOR SIX MONTHS OR LONGER. CLOSE MONITORING OF THE
PULMONARY CONDITION OF PATIENTS RECEIVING LONG-TERM THERAPY IS
WARRANTED AND REQUIRES THAT THE BENEFITS OF THERAPY BE
WEIGHED AGAINST POTENTIAL RISKS. (SEE RESPIRATORY REACTIONS.)
Hepatic reactions, including hepatitis, cholestatic jaundice, chronic active hepatitis, and hepatic
necrosis, occur rarely. Fatalities have been reported. The onset of chronic active hepatitis may be
insidious, and patients should be monitored periodically for changes in liver function. If hepatitis
occurs, the drug should be withdrawn immediately and appropriate measures should be taken.
Peripheral neuropathy (including optic neuritis), which may become severe or irreversible, has
occurred. Fatalities have been reported. Conditions such as renal impairment (creatinine clearance
under 60 ml per minute or clinically significant elevated serum creatinine), anemia, diabetes mellitus,
electrolyte imbalance, vitamin B deficiency, and debilitating disease may enhance the occurrence of
peripheral neuropathy. Patients receiving long-term therapy should be monitored periodically for
changes in renal function.
Cases of hemolytic anemia of the primaquine-sensitivity type have been induced by nitrofurantoin.
Hemolysis appears to be linked to a glucose-6-phosphate dehydrogenase deficiency in the red blood
cells of the affected patients. This deficiency is found in 10 percent of Blacks and a small
percentage of ethnic groups of Mediterranean and Near-Eastern origin. Hemolysis is an indication
for discontinuing Nitrofurantoin; hemolysis ceases when the drug is withdrawn.
PRECAUTIONS
Information for the Patient: Patients should be advised to take nitrofurantoin with food to further
enhance tolerance and improve drug absorption. Patients should be instructed to complete the full
course of therapy; however, they should be advised to contact their physician if any unusual
symptoms occur during therapy.
Many patients who cannot tolerate microcrystalline nitrofurantoin are able to take nitrofurantoin
without nausea.
Patients should be advised not to use antacid preparations containing magnesium trisilicate while
taking nitrofurantoin.
Drug/Laboratory Test Interactions: As a result of the presence of nitrofurantoin, a false-positive
reaction for glucose in the urine may occur. This has been observed with Benedict's and Fehling's
solutions but not with the glucose enzymatic test.
Carcinogenesis, Mutagenesis, and Impairment of Fertility: Nitrofurantoin was not
carcinogenic when fed to female Holtzman rats for 44.5 weeks or to female Sprague-Dawley rats
for 75 weeks. Two chronic rodent bioassays utilizing male and female Sprague-Dawley rats and
two chronic bioassays in Swiss mice and in BDF1 mice revealed no evidence of carcinogenicity.
Nitrofurantoin presented evidence of carcinogenic activity in female B6C3F1 mice as shown by
increased incidences of tubular adenomas, benign mixed tumors, and granulosa cell tumors of the
ovary. In male F344/N rats, there were increased incidences of uncommon kidney tubular cell
neoplasms, osteosarcomas of the bone, and neoplasms of the subcutaneous tissue. In one study
involving subcutaneous administration of 75 mg/kg nitrofurantoin to pregnant female mice, lung
papillary adenomas of unknown significance were observed in the F1 generation.
Nitrofurantoin has been shown to induce point mutations in certain strains of Salmonella
typhimurium and forward mutations in L5178Y mouse lymphoma cells. Nitrofurantoin induced
increased numbers of sister chromatid exchanges and chromosomal aberrations in Chinese hamster
ovary cells but not in human cells in culture. Results of the sex-linked recessive lethal assay in
Drosophila were negative after administration of nitrofurantoin by feeding or by injection.
Nitrofurantoin did not induce heritable mutation in the rodent models examined.
The significance of the carcinogenicity and mutagenicity findings relative to the therapeutic use of
nitrofurantoin in humans is unknown.
The administration of high doses of nitrofurantoin to rats causes temporary spermatogenic arrest;
this is reversible on discontinuing the drug. Doses of 10 mg/kg/day or greater in healthy human
males may, in certain unpredictable instances, produce a slight to moderate spermatogenic arrest
with a decrease in sperm count.
Pregnancy, Teratogenic Effects: Pregnancy Category B. Several reproduction studies have been
performed in rabbits and rats at doses up to six times the human dose and have revealed no
evidence of impaired fertility or harm to the fetus due to nitrofurantoin. In a single published study
conducted in mice at 68 times the human dose (based on mg/kg administered to the dam), growth
retardation and a low incidence of minor and common malformations were observed. However, at
25 times the human dose, fetal malformations were not observed; the relevance of these findings to
humans is uncertain. There are, however, no adequate and well-controlled studies in pregnant
women. Because animal reproduction studies are not always predictive of human response, this
drug should be used during pregnancy only if clearly needed.
Non-teratogenic Effects: Nitrofurantoin has been shown in one published transplacental
carcinogenicity study to induce lung papillary adenomas in the F1 generation mice at doses 19 times
the human dose on a mg/kg basis. The relationship of this finding to potential human carcinogenesis
is presently unknown. Because of the uncertainty regarding the human implications of these animal
data, this drug should be used during pregnancy only if clearly needed.
Labor and Delivery: See CONTRAINDICATIONS.
Nursing Mothers: Nitrofurantoin has been detected in breast milk in trace amounts. Because of
the potential for serious adverse reactions from nitrofurantoin in nursing infants under one month of
age, 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. (See CONTRAINDICATIONS.)
Pediatric Use: Nitrofurantoin is contraindicated in infants below the age of one month. (See
CONTRAINDICATIONS.)