Nitrofurantoin

RECENT MAJOR CHANGES Dosage and Administration (2) 1/2024

1 INDICATIONS AND USAGE Nitrofurantoin oral suspension is indicated in adults and pediatric patients 1 month of age and older for the treatment of urinary tract infections due to susceptible strains of Escherichia coli , Enterococcus species, Staphylococcus aureus , Klebsiella species and Enterobacter species. Limitations of Use Nitrofurantoin oral suspension is not indicated for the treatment of pyelonephritis or perinephric abscesses [see Warnings and Precautions (5.7) ]. Usage To reduce the development of drug-resistant bacteria and maintain the effectiveness of nitrofurantoin oral suspension and other antibacterial drugs, nitrofurantoin oral suspension should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy. Nitrofurantoin oral suspension is a nitrofuran antibacterial indicated in adults and pediatric patients 1 month of age and older for the treatment of urinary tract infections caused by susceptible bacteria. ( 1 ) Limitations of Use Nitrofurantoin oral suspension is not indicated for the treatment of pyelonephritis or perinephric abscesses. ( 1 ) Usage To reduce the development of drug-resistant bacteria and maintain the effectiveness of nitrofurantoin oral suspension and other antibacterial drugs nitrofurantoin oral suspension should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria. ( 1 )

2 DOSAGE AND ADMINISTRATION Adult Patients: 50 mg to 100 mg four times a day - the lower dosage level is recommended for uncomplicated urinary tract infections. (2.2) Pediatric Patients: 5 mg/kg to 7 mg/kg of body weight per 24 hours, given in four divided doses (contraindicated under one month of age). (2.3) 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 [ s ee Clinical Pharmacology ( 12.3 )] and, in some patients, tolerance. Table 1 lists individual dosage volumes for two different strengths of nitrofurantoin oral suspension (25 mg/5 mL and 50 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 Weight in Kilograms (kg) Pediatric Doses (mL), Frequency: Four times Daily 25 mg/5 mL oral suspension 50 mg/5 mL oral suspension 4 kg or lower 1 0.5 Greater than 4 kg to 5 kg 1.4 0.7 Greater than 5 kg to 7 kg 1.8 0.9 Greater than 7 kg to 10 kg 2.5 1.25 Greater than 10 kg to 14 kg 3.5 1.75 Greater than 14 kg to 20 kg 5 2.5 Greater than 20 kg to 25 kg 7 3.5 Greater than 25 kg to 30 kg 8.5 4.25 Greater than 30 kg to 40 kg 10 5 40 kg or greater See Adult Dose See Adult Dose 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 ) ].

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 [ s ee Clinical Pharmacology ( 12.3 )] and, in some patients, tolerance. Table 1 lists individual dosage volumes for two different strengths of nitrofurantoin oral suspension (25 mg/5 mL and 50 mg/5 mL) based on body weight for pediatric patients. Table 1: Nitrofurantoin Oral Suspensio …

3 DOSAGE FORMS & STRENGTHS Nitrofurantoin Oral Suspension, USP is available as a lemon-yellow liquid with cherry flavor, free from extraneous particles for oral suspension containing 25 mg/5 mL of nitrofurantoin. Oral Suspension: 25 mg/5 mL. (3)

4 CONTRAINDICATIONS Nitrofurantoin oral suspension is contraindicated in: • patients with known hypersensitivity to nitrofurantoin [see Warnings and Precautions ( 5.1 )]. • patients with a previous history of cholestatic jaundice/hepatic dysfunction associated with nitrofurantoin [see Warnings and Precautions ( 5.3 )]. • patients who have anuria, oliguria, or significant impairment of renal function (creatinine clearance under 60 mL per minute or clinically significant elevated serum creatinine) due to an increased risk of toxicity resulting from impaired excretion of the drug [see Warnings and Precautions ( 5.4 )]. • pregnant patients at term (38 weeks to 42 weeks gestation), during labor and delivery, or when the onset of labor is imminent and 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 Warnings and Precautions ( 5.5 ) and Use in Specific Populations ( 8.1 and 8.4 )]. • Known hypersensitivity to nitrofurantoin. ( 4 ) • History of cholestatic jaundice/hepatic dysfunction associated with nitrofurantoin. ( 4 ) • Patients who have anuria, oliguria, or significant impairment of renal function (creatinine clearance under 60 mL per minute or clinically significant elevated serum creatinine). ( 4 ) • Pregnant patients at term (38 weeks to 42 weeks gestation), during labor and delivery, or when the onset of labor is imminent. ( 4 ) • Pediatric Patients under one month of age. ( 4 )

6 ADVERSE REACTIONS The following clinically significant adverse reactions are discussed in more detail in other sections of the labeling: • Hypersensitivity Reactions [see Warnings and Precautions (5.1) ] • Pulmonary Reactions [see Warnings and Precautions (5.2) ] • Hepatotoxicity [see Warnings and Precautions (5.3) ] • Neuropathy [see Warnings and Precautions (5.4) ] • Hemolytic anemia [see Warnings and Precautions (5.5) ] • Clostridioides difficile -associated Diarrhea [see Warnings and Precautions (5.6) ] • Persistence or Reappearance of Bacteriuria [see Warnings and Precautions (5.7) ] The following adverse reactions associated with the use of nitrofurantoin formulations, including, nitrofurantoin oral suspension were identified in clinical studies or post-marketing reports. Because some of these reactions were reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Respiratory : chronic, subacute, or acute pulmonary hypersensitivity reactions have occurred. Chronic pulmonary reactions have occurred generally in patients who have received continuous treatment for six months or longer. Malaise, dyspnea on exertion, cough, and altered pulmonary function are common manifestations which can occur insidiously. Radiologic and histologic findings of diffuse interstitial pneumonitis or fibrosis, or both, are also common manifestations of the chronic pulmonary reaction. Fever is prominent. The severity of chronic pulmonary reactions and their degrees of resolution appear to be related to the duration of therapy after the first clinical signs appear. Pulmonary function may be impaired permanently, even after cessation of therapy. The risk is greater when chronic pulmonary reactions are not recognized early. In subacute pulmonary reactions, fever and eosinophilia occur less often than in the acute form. Upon cessation of therapy, recovery may require several months. If the symptoms are not recognized as being drug-related and nitrofurantoin oral suspension therapy is not stopped, the symptoms may become more severe. Acute pulmonary reactions are commonly manifested by fever, chills, cough, chest pain, dyspnea, pulmonary infiltration with consolidation of pleural effusion on x-ray, and eosinophilia. Acute reactions usually occur within the first week of treatment and are reversible with cessation of therapy. Resolution often is dramatic. Changes in EKG (e.g., non-specific ST/T wave changes, bundle branch block) have been reported in association with pulmonary reactions. Cyanosis has been reported. Hepatic : Hepatic reactions, including hepatitis, cholestatic jaundice, chronic active hepatitis, and hepatic necrosis, have occurred. Neurologic : 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 diseases may increase the possibility of peripheral neuropathy. Asthenia, vertigo, nystagmus, dizziness, headache, and drowsiness also have been reported with the use of nitrofurantoin. Benign intracranial hypertension (pseudotumor cerebri), confusion, depression, optic neuritis, and psychotic reactions have been reported. Bulging fontanels, as a sign of benign intracranial hypertension in infants, have been reported rarely. Dermatologic : Exfoliative dermatitis and erythema multiforme (including Stevens-Johnson syndrome) have been reported. Alopecia also has been reported. Allergic : A lupus-like syndrome associated with pulmonary reactions to nitrofurantoin has been reported. Also, angioedema; maculopapular, erythematous, or eczematous eruptions; pruritus; urticaria; anaphylaxis; arthralgia; myalgia; drug fever; and vasculitis (sometimes associated wi …

7 DRUG INTERACTIONS • Antacids: Decreased absorption of nitrofurantoin. ( 7.1 ) • Uricosuric drugs: Inhibit renal tubular secretion of nitrofurantoin. ( 7.2 ) 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 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 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.

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 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 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 USE IN SPECIFIC POPULATIONS • Lactation: Breastfeeding is not recommended in infants under one month of age or with glucose-6-phosphate dehydrogenase (G6PD) deficiency. (8.2) • Pediatric Use: Nitrofurantoin oral suspension is contraindicated in pediatric patients under one month of age. (8.4) 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 …

12.1 Mechanism of Action Nitrofurantoin is an antibacterial drug [ see Microbiology (12.4) ] .

11 DESCRIPTION Nitrofurantoin oral suspension, USP contains nitrofurantoin monohydrate USP, a synthetic nitrofuran antibacterial agent specific for urinary tract infections. The chemical name is 2,4-Imidazolidinedione,1-[[(5-nitro-2-furanyl) methylene] amino]-;monohydrate. The molecular formula is C 8 H 6 N 4 O 5 ꞏH 2 O and the molecular weight is 256.18. The structural formula is: Nitrofurantoin monohydrate USP is a lemon yellow crystalline powder. Nitrofurantoin oral suspension, USP is available as a opaque yellow color suspension for oral administration containing 25 mg/5 mL nitrofurantoin. Nitrofurantoin oral suspension, USP also contains the following inactive ingredients: banana flavor (contains flavouring ingredients and propylene glycol), carboxymethylcellulose sodium, citric acid monohydrate, glycerin, magnesium aluminum silicate, methylparaben, microcrystalline cellulose & carboxymethylcellulose sodium, natural peppermint flavour (contains flavouring ingredients, propylene glycol and benzyl alcohol), non-crystalline sorbitol solution, propylparaben, purified water, raspberry flavour (contains natural & artificial flavour and propylene glycol), trisodium citrate dihydrate powder. nitrofurantionchemicalstructure

OVERDOSAGE Occasional incidents of acute overdosage of Nitrofurantoin Oral Suspension, USP have not resulted in any specific symptoms other than vomiting. Induction of emesis is recommended. There is no specific antidote, but a high fluid intake should be maintained to promote urinary excretion of the drug. It is dialyzable.

HOW SUPPLIED Nitrofurantoin oral suspension, USP (a clear, yellow colored, tutti frutti flavored suspension) containing 25 mg nitrofurantoin, USP in each teaspoonful (5 mL) is available as follows: 230 mL in an 8 oz amber bottle. NDC 65162-689-88 Avoid exposure to strong light which may darken the drug. It is stable when stored between 20° to 25°C (68° to 77°F); excursions permitted between 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature]. Protect from freezing. Shake vigorously. Dispense in tight, light-resistant, amber glass bottles. Use within 30 days. Keep out of reach of children. Rx only Distributed by: Amneal Pharmaceuticals LLC Bridgewater, NJ 08807 Rev. 08-2021-04