Nitrofurantoin, USP, a synthetic chemical, is a stable, yellow, crystalline compound. Nitrofurantoin, USP is an antibacterial agent for specific urinary tract infections. Nitrofurantoin, USP is available in 25 mg/5 mL liquid suspension for oral administration.

Inactive Ingredients

Nitrofurantoin Oral Suspension USP contains carboxymethylcellulose sodium, anhydrous citric acid, glycerin, magnesium aluminum silicate, methylparaben, natural and artificial flavor (peach), propylparaben, purified water, saccharin sodium, sodium citrate, and sorbitol solution.

Orally administered nitrofurantoin is readily absorbed and rapidly excreted in urine. Blood concentrations at therapeutic dosage are usually low. It is highly soluble in urine, to which it may impart a brown color.

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

Unlike many drugs, the presence of food or agents delaying gastric emptying can increase the bioavailability of nitrofurantoin, presumably by allowing better dissolution in gastric juices.

Microbiology

Mode 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.

Cross-Resistance

Although cross-resistance with other antimicrobials may occur, cross resistance with sulfonamides has not been observed.

Interaction with Other Antimicrobials

Antagonism has been demonstrated in vitro between nitrofurantoin and quinolone antimicrobial agents. Nitrofurantoin, in the form of nitrofurantoin oral suspension, has been shown to be active against most of the following bacteria both in vitro and in clinical infections: (See INDICATIONS AND USAGE).

Gram-positive Aerobes

Staphylococcus aureus

Enterococcus species

Gram-Negative Aerobes

Escherichia coli

NOTE: Some strains of Enterobacter species and Klebsiella species are resistant to nitrofurantoin.

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 effectiveness of nitrofurantoin in treating clinical infections due to these bacteria have not been established in adequate and well controlled clinical trials.

Gram-Positive Aerobes Coagulase-negative staphylococci (including Staphylococcus epidermidis and Staphylococcus saprophyticus)

Streptococcus agalactiae

Viridans group streptococci

Gram-Negative Aerobes

Citrobacter koseri

Citrobacter freundii

Klebsiella oxytoca

Nitrofurantoin is not active against most strains of Proteus species or Serratia species. It has no activity against Pseudomonas species.

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: https://www.fda.gov/STIC.

Nitrofurantoin oral suspension is specifically indicated for the treatment of urinary tract infections when due to susceptible strains of Escherichia coli, enterococci, Staphylococcus aureus, and certain susceptible strains of Klebsiella and Enterobacter species.

Nitrofurantoin is not indicated for the treatment of pyelonephritis or perinephric abscesses.

Nitrofurantoins lack the broader tissue distribution of other therapeutic agents approved for urinary tract infections. Consequently, many patients who are treated with nitrofurantoin are predisposed to persistence or reappearance of bacteriuria. Urine specimens for culture and susceptibility testing should be obtained before and after completion of therapy. If persistence or reappearance of bacteriuria occurs after treatment with nitrofurantoin, other therapeutic agents with broader tissue distribution should be selected. In considering the use of nitrofurantoin, lower eradication rates should be balanced against the increased potential for systemic toxicity and for the development of antimicrobial resistance when agents with broader tissue distribution are utilized.

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 to 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 contraindicated in patients with a previous history of cholestatic jaundice/hepatic dysfunction associated with nitrofurantoin. Nitrofurantoin is also contraindicated in those patients with known hypersensitivity to nitrofurantoin.

Pulmonary Reactions

ACUTE, SUBACUTE, OR CHRONIC PULMONARY REACTIONS HAVE BEEN OBSERVED IN PATIENTS TREATED WITH NITROFURANTOIN. IF THESE REACTIONS OCCUR, NITROFURANTOIN 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).

Hepatotoxicity

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 biochemical tests that would indicate liver injury. If hepatitis occurs, the drug should be withdrawn immediately and appropriate measures should be taken.

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. Patients receiving long-term therapy should be monitored periodically for changes in renal function.

Optic neuritis has been reported rarely in postmarketing experience with nitrofurantoin formulations.

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. Hemolysis is an indication for discontinuing nitrofurantoin; hemolysis ceases when the drug is withdrawn.

Clostridium Difficile-Associated Diarrhea

Clostridium 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 antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibiotic 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 antibiotic use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibiotic treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated.

Respiratory

CHRONIC, SUBACUTE, OR ACUTE PULMONARY HYPERSENSITIVITY REACTIONS MAY OCCUR.

CHRONIC PULMONARY REACTIONS MAY OCCUR 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 RARELY 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 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. (See WARNINGS)

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 rarely.

Hepatic

Hepatic reactions, including hepatitis, cholestatic jaundice, chronic active hepatitis, and hepatic neurosis, occur rarely. (See WARNINGS)

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. (See WARNINGS)

Asthenia, vertigo, nystagmus, dizziness, headache, and drowsiness have also been reported with the use of nitrofurantoin.

Benign intracranial hypertension (pseudotumor cerebri), confusion, depression, optic neuritis, and psychotic reactions have been reported rarely. 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 rarely. Transient 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 with pulmonary reactions) have been reported. Hypersensitivity reactions present the most frequent spontaneously-reported adverse events in world-wide postmarketing experience with nitrofurantoin formulations.

Gastrointestinal

Nausea, emesis, and anorexia occur most often. Abdominal pain and diarrhea are less common gastrointestinal reactions. These dose-related reactions can be minimized by reduction of dosage. Sialadenitis and pancreatitis have been reported. There have been sporadic reports of pseudomembranous colitis with the use of nitrofurantoin. The onset of pseudomembranous colitis symptoms may occur during or after antimicrobial treatment. (See WARNINGS)

Hematologic

Cyanosis secondary to methemoglobinemia has been reported rarely.

Miscellaneous

As with other antimicrobial agents, super infections caused by resistant organisms, e.g., Pseudomonas species or Candida species, can occur. There are sporadic reports of Clostridium difficile super infections, or pseudomembranous colitis, with the use of nitrofurantoin.

Laboratory Adverse Events

The following laboratory adverse events have been reported with the use of nitrofurantoin; increased AST (SGOT), increased ALT (SGPT), decreased hemoglobin, increased serum phosphorus, eosinophilia, glucose-6-phosphate dehydrogenase deficiency anemia (see WARNINGS), agranulocytosis, leukopenia, granulocytopenia, hemolytic anemia, thrombocytopenia, megaloblastic anemia. In most cases, these hematologic abnormalities resolved following cessation of therapy. Aplastic anemia has been reported rarely.

To report SUSPECTED ADVERSE EVENTS, contact Actavis at 1-800-432-8534 or FDA at 1-800-FDA-1088 or http://www.fda.gov/ for voluntary reporting of adverse reactions.

Occasional incidents of acute overdosage of nitrofurantoin 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.

Nitrofurantoin should be given with food to improve drug absorption and, in some patients, tolerance.

Adults

50 to 100 mg four times a day -- the lower dosage level is recommended for uncomplicated urinary tract infections.

Pediatric Patients

5 to 7 mg/kg of body weight per 24 hours, given in four divided doses (contraindicated under one month of age).

The following table is based on an average weight in each range receiving 5 to 6 mg/kg of body weight per 24 hours, given in four divided doses. It can be used to calculate an average dose of nitrofurantoin oral suspension (25 mg/5 mL) for pediatric patients.

Therapy should be continued 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 adults, a reduction of dosage to 50 to 100 mg at bedtime may be adequate. 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 SECTION REGARDING RISKS ASSOCIATED WITH LONG TERM THERAPY.

Nitrofurantoin Oral Suspension USP, 25 mg/5 mL is a yellow, peach flavored liquid. It is supplied in an 8 fl. oz. amber glass bottle (NDC 0472-1992-08).

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 to 15 to 30°C (59 to 86°F) [See USP Controlled Room Temperature]. Protect from freezing.

SHAKE VIGOROUSLY.

Dispense in tight, light-resistant, plastic (PET) or glass container. Use within 30 days.

Keep out of reach of children.

Manufactured by:

G&W Laboratories, Inc.

111 Coolidge Street

South Plainfield, NJ 07080 USA

Distributed by:

Actavis Pharma, Inc.

Parsippany, NJ 07054 USA

I602-1460 GW 7066

Rev. A 10/2018

Actavis

Rx Only

NDC 0472-1992-08

Nitrofurantoin Oral Suspension, USP

25 mg/5 mL

URINARY TRACT ANTIBACTERIAL

SHAKE VIGOROUSLY

8 fl. oz. (230 mL)