2.1 Recommended Dosage and Administration in Adult Patients

The recommended dosage is 50 mg to 100 mg of nitrofurantoin oral suspension four times a day.

For long-term suppressive therapy in adults, a reduction of dosage to 50 mg to 100 mg at bedtime may be adequate. The benefits of long-term suppressive therapy should be balanced against the increased potential for systemic toxicity and for the development of antibacterial resistance [see Warnings and Precautions (5.2, 5.4, 5.6)].

Administer nitrofurantoin oral suspension with food to improve drug absorption [see Clinical Pharmacology (12.3)] and, in some patients, tolerance.

2.2 Recommended Dosage and Administration in Pediatric Patients (1 month of age and older)

The recommended dosage of nitrofurantoin oral suspension is 5 mg/kg to 7 mg/kg of body weight per 24 hours, given in four divided doses in pediatric patients aged 1 month and older. Administer nitrofurantoin oral suspension with food to improve drug absorption [see Clinical Pharmacology (12.3)] and, in some patients, tolerance.

Table 1 lists individual dosage volumes of  nitrofurantoin oral suspension 25 mg/5 mL based on body weight for pediatric patients.

Table 1: Nitrofurantoin oral suspension Pediatric Dosing Table for Pediatric Patients 1 month of Age and Older

To measure the correct pediatric doses, it is important to administer nitrofurantoin oral suspension with an appropriate size oral dosing syringe with graduations that align with the volume prescribed in Table 1 above.

Continue therapy for one week or for at least 3 days after sterility of the urine is obtained. Continued infection indicates the need for reevaluation.

For long-term suppressive therapy in pediatric patients, doses as low as 1 mg/kg per 24 hours, given in a single dose or in two divided doses, may be adequate [see Warnings and Precautions (5.2,5.4, 5.6)].

5.1 Hypersensitivity Reactions

Serious and occasionally fatal hypersensitivity (anaphylactic) reactions have been reported in patients receiving nitrofurantoin oral suspension [see Adverse Reactions (6)]. If signs and symptoms of a hypersensitivity reaction occurs, immediately discontinue nitrofurantoin oral suspension and initiate appropriate medications and/or supportive care. Nitrofurantoin oral suspension is contraindicated in patients with known hypersensitivity to nitrofurantoin.

5.2 Pulmonary Reactions

Acute, subacute, or chronic pulmonary reactions have been reported in patients treated with nitrofurantoin oral suspension. If these reactions occur, discontinue nitrofurantoin oral suspension and take appropriate measures. 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 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 [seeAdverse Reactions (6)].

5.3 Hepatotoxicity

Hepatic reactions, including hepatitis, cholestatic jaundice, chronic active hepatitis, and hepatic necrosis, has  occurred. Fatalities  have been  reported. The  onset  of chronic  active hepatitis may be  insidious. Monitor patients  periodically  for  changes  in  biochemical tests  that  would indicate liver injury.  If  hepatitis  occurs, discontinue  nitrofurantoin oral suspension  immediately, and  take  appropriate measures.

5.4 Neuropathy

Peripheral neuropathy, 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. Monitor patients receiving long-term therapy periodically for changes in renal function.

Optic neuritis has been reported with nitrofurantoin formulations [see Adverse Reactions (6)].

5.5 Hemolytic Anemia

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. If hemolysis occurs, discontinue nitrofurantoin oral suspension immediately; hemolysis ceases when the drug is withdrawn.

5.6 Clostridioides difficile-associated Diarrhea

Clostridioides difficile-associated Diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including nitrofurantoin oral suspension, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile.

C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antibacterial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibacterial use. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents.

If CDAD is suspected or confirmed, ongoing antibacterial use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibacterial treatment of C. difficile, and institute surgical evaluation as clinically indicated.

5.7 Persistence or Reappearance of Bacteriuria

Nitrofurantoin lacks the broader tissue distribution of other therapeutic agents approved for urinary tract infections. Consequently, many patients who are treated with nitrofurantoin oral suspension are predisposed to persistence or reappearance of bacteriuria. If persistence or reappearance of bacteriuria occurs with symptoms of urinary tract infection, after treatment with nitrofurantoin oral suspension, other therapeutic agents with broader tissue distribution should be selected. In considering the use of nitrofurantoin oral suspension, lower eradication rates should be balanced against the increased potential for systemic toxicity and for the development of antibacterial resistance when agents with broader tissue distribution are utilized.

7.1 Antacids

Antacids containing magnesium trisilicate, when administered concomitantly with nitrofurantoin, reduce both the rate and extent of absorption. The mechanism for this interaction probably is adsorption of nitrofurantoin onto the surface of magnesium trisilicate. If coadministration of nitrofurantoin oral suspension with antacids containing magnesium trisilicate cannot be avoided, monitor for lack of efficacy [see Clinical Pharmacology (12.3)].

7.2 Uricosuric Drugs

Uricosuric drugs, such as probenecid and sulfinpyrazone, can inhibit renal tubular secretion of nitrofurantoin. The resulting increase in nitrofurantoin serum levels may increase toxicity, and the decreased urinary levels could lessen its efficacy as a urinary tract antibacterial. Therefore, monitor for nitrofurantoin adverse reactions when co-administering nitrofurantoin oral suspension with uricosuric drugs.

7.3 Drug Interference with Laboratory Tests

The presence of nitrofurantoin can cause a false-positive reaction for glucose in the urine when using Benedict's or Fehling's copper reduction reaction to determine the amount of reducing substances like glucose in the urine. Use glucose tests based on enzymatic glucose oxidase reactions to detect glucose in the urine.

8.1 Pregnancy

Risk Summary

Nitrofurantoin is contraindicated in pregnant women at term (38 weeks to 42 weeks gestation), during labor and delivery, or when the onset of labor is imminent because of the possibility of hemolytic anemia in the infant (see Clinical Considerations).

Published epidemiological studies, including cohort studies and case control studies, have reported inconsistent findings related to nitrofurantoin use during the first trimester and risk of major birth defects. These studies cannot definitively establish the presence or absence of risk due to several methodological limitations. The limited number of epidemiological studies available have not identified drug-associated risks of major birth defects, miscarriage or other adverse maternal or fetal outcomes.

In animal reproduction studies, no fetotoxicity was observed when nitrofurantoin was administered orally to pregnant rats and rabbits, during organogenesis, at up to 6 times the recommended human dose (see Data).

The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Clinical Considerations

Fetal/Neonatal Adverse Reactions

Nitrofurantoin is not recommended in pregnant women at term (38 weeks to 42 weeks gestation), during labor and delivery, or when the onset of labor is imminent because of the possibility of hemolytic anemia due to immature erythrocyte enzyme systems (glutathione instability) [see Contraindications (4) and Warnings and Precautions (5.4)].

Data

Animal Data

Several reproduction studies have been performed in rabbits and rats at doses up to six times the human dose and have revealed no 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.

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.

8.2 Lactation

Risk Summary

Nitrofurantoin is present in human breast milk following oral administration. There are insufficient data on the effect of nitrofurantoin on milk production.

Infants less than one month of age or who have glucose-6-phosphate dehydrogenase (G6PD) deficiency are at risk for hemolytic anemia from nitrofurantoin oral suspension exposure. Therefore, breastfeeding is not recommended in these infants.

In a breastfed infant over the age of one month and with normal G6PD, the developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for nitrofurantoin oral suspension and any potential adverse effects on the breastfed infant from nitrofurantoin oral suspension or from the underlying maternal condition. Monitor these infants for vomiting, diarrhea, and rash.

8.3 Females and Males of Reproductive Potential

Infertility

Male

Based on findings from a fertility study conducted in 36 healthy male volunteers and an animal fertility study, nitrofurantoin may reversibly decrease spermatogenesis [see Nonclinical Toxicology (13.1)]. Nitrofurantoin doses of 10 mg/kg/day or greater in healthy human males may produce a slight to moderate spermatogenic arrest with a decrease in sperm count. The effect on fertility is unknown.

8.4 Pediatric Use

Nitrofurantoin oral suspension is contraindicated in pediatric patients younger than 1 month of age because of the possibility of hemolytic anemia due to immature erythrocyte enzyme systems (glutathione instability). [see Contraindications (4)and Warnings and Precautions (5.4)].

The safety and effectiveness of nitrofurantoin oral suspension in pediatric patients aged 1 month of age and older for the treatment of urinary tract infections have been established.

12.1 Mechanism of Action

Nitrofurantoin is an antibacterial drug [see Microbiology (12.4)].

12.2 Pharmacodynamics

Pharmacodynamic effects of nitrofurantoin oral suspension are unknown.

12.3 Pharmacokinetics

Absorption

Orally administered nitrofurantoin oral suspension is readily absorbed. Blood concentrations at therapeutic dosage are usually low.

Effect of Food

The presence of food or agents delaying gastric emptying can increase the bioavailability of nitrofurantoin oral suspension.

Distribution

Nitrofurantoin is highly soluble in urine. Nitrofurantoin lacks the broader tissue distribution of other therapeutic agents approved for urinary tract infections.

Elimination

Excretion

Nitrofurantoin is rapidly excreted in urine, to which it may impart a brown color.

Following a dose regimen of 100 mg four times a day for 7 days, average urinary drug recoveries (0 hour to 24 hours) on Day 1 and Day 7 were 42.7% and 43.6%.

Nitrofurantoin is dialyzable.

Specific Populations

The pharmacokinetics of nitrofurantoin oral suspension are unknown for the geriatric patients, pediatric patients, patients with hepatic impairment, or pregnant women. Differences between male and female patients, and racial or ethnic groups are unknown.

Patients with Renal Impairment

The reported urinary recoveries of nitrofurantoin after a single 100 mg oral dose and 100 mg four times a day in patients with varying renal function showed approximate linear relationship between the amount of nitrofurantoin recovered and creatinine clearance.

Drug Interaction Studies

Antacids such as magnesium trisilicate

In a cross-over study, the in vivo absorption characteristics of nitrofurantoin and nitrofurantoin-magnesium trisilicate combination were evaluated in 6 healthy males. The administration of 5 g magnesium trisilicate with 100 mg nitrofurantoin reduced the rate and extent of nitrofurantoin excretion reflecting decrease in both rate and extent of its absorption [see Drug Interaction (7.1)].

Propantheline

In a crossover study, the in vivo absorption characteristics of nitrofurantoin and propantheline (an anticholinergic agent) combination were evaluated in six subjects. Administration of 30 mg of propantheline 45 min prior to nitrofurantoin 100 mg administration resulted in a statistically significant increase in nitrofurantoin excretion, however, the clinical significance of this effect is unknown.

12.4 Microbiology

Mechanism of Action

Nitrofurantoin is reduced by a wide range of enzymes including bacterial flavoproteins to reactive intermediates which are damaging to macromolecules such as DNA and proteins.

Resistance

Nitrofurantoin is not active against most strains of Proteus species or Serratia species. It has no activity against Pseudomonas species. Although cross-resistance with other antibacterials may occur, cross resistance with sulfonamides has not been observed.

Interaction with Other Antibacterials

Antagonism has been demonstrated in vitro between nitrofurantoin and quinolones.

Antibacterial Activity

Nitrofurantoin has been shown to be active against most of the following bacteria both in vitro and in clinical infections:

Aerobic bacteria

              Gram-positive bacteria

              Staphylococcus aureus

              Enterococcus species

              Gram-negative bacteria

              Escherichia coli

              Enterobacter species

              Klebsiella species

The following in vitro data are available, but their clinical significance is unknown. Nitrofurantoin exhibits in vitro activity against the following bacteria; however, the safety and efficacy of nitrofurantoin in treating clinical infections due to these bacteria have not been established in adequate and well-controlled clinical trials.

Aerobic bacteria

            Gram-positive bacteria

            Coagulase-negative staphylococci (including Staphylococcus epidermidis and

            Staphylococcus saprophyticus)

            Streptococcus agalactiae

            Viridans group streptococci

            Gram-negative bacteria

            Citrobacter koseri

            Citrobacter freundii

            Klebsiella oxytoca

Susceptibility Testing

For specific information regarding susceptibility test interpretive criteria, and associated test methods and quality control standards recognized by FDA for this drug, please see: http://www.fda.gov/STIC .

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

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.

The significance of carcinogenicity findings relative to the therapeutic use of nitrofurantoin in humans is unknown.

Mutagenesis

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 mutagenicity findings relative to the therapeutic use of nitrofurantoin in humans is unknown.

Impairment of Fertility

The administration of high doses of nitrofurantoin to rats causes temporary spermatogenic arrest; this is reversible on discontinuing the drug.