Label: NITROFURANTOIN capsule

To reduce the development of drug-resistant bacteria and maintain the effectiveness of nitrofurantoin capsules, USP (macrocrystals)and other antibacterial drugs, nitrofurantoin capsules, USP (macrocrystals)should be used only to treat or prevent infections that are proven or strongly suspected to be caused by bacteria.

Nitrofurantoin macrocrystals, USP is a synthetic chemical of controlled crystal size. It is a stable, brown yellow, macrocrystalline compound. Nitrofurantoin macrocrystals, USP is an antibacterial agent for specific urinary tract infections. It is available in 25 mg, 50 mg, and 100 mg capsules for oral administration.

 
1-[[(5-NITRO-2-FURANYL)METHYLENE]AMINO]-2,4-IMIDAZOLIDINEDIONE

Inactive Ingredients: Lactose monohydrate, maize starch, corn starch and talc. The hard gelatin capsules contain gelatin, titanium dioxide, D&C Red No. 33 (50 mg and 100 mg capsules only) and D&C Yellow No. 10 (50 mg and 100 mg capsules only). The capsules are printed with edible black ink containing shellac, propylene glycol, potassium hydroxide and ferrosoferric oxide.

Nitrofurantoin Capsules, USP (Macrocrystals) meets USP Dissolution Test 9.

Nitrofurantoin macrocrystals are a larger crystal form of nitrofurantoin. The absorption of nitrofurantoin macrocrystals is slower and its excretion somewhat less when compared to nitrofurantoin. 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. for 7 days, average urinary drug recoveries (0 to 24 hours) on day 1 and day 7 were 37.9% and 35%.

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

MICROBIOLOGY 

Nitrofurantoin is a nitrofuran antimicrobial agent with activity against certain Gram-positive and Gram-negative bacteria. 

Mechanism of Action 

The mechanism of the antimicrobial action of nitrofurantoin is unusual among antibacterials. Nitrofurantoin is reduced by bacterial flavoproteins to reactive intermediates which inactivate or alter bacterial ribosomal proteins and other acromolecules. As a result of such inactivations, the vital biochemical processes of protein synthesis, aerobic energy metabolism, DNA synthesis, RNA synthesis, and cell wall synthesis are inhibited. Nitrofurantoin is bactericidal in urine at therapeutic doses. The broad-based nature of this mode of action may explain the lack of acquired bacterial resistance to nitrofurantoin, as the necessary multiple and simultaneous mutations of the target macromolecules would likely be lethal to the bacteria. 

Interactions with Other Antibiotics 

Antagonism has been demonstrated in vitro between nitrofurantoin and quinolone antimicrobials. The clinical significance of this finding is unknown.

 Development of Resistance 

Development of resistance to nitrofurantoin has not been a significant problem since its introduction in 1953. Cross-resistance with antibiotics and sulfonamides has not been observed, and transferable resistance is, at most, a very rare phenomenon. 

Nitrofurantoin has been shown to be active against most strains of the following bacteria both in vitro and in clinical infections (see INDICATIONS AND USAGE):

 Aerobic and facultative Gram-positive microorganisms: 

Staphylococcus aureus 

Enterococci (e.g. Enterococcus faecalis) 

Aerobic and facultative Gram-negative microorganisms: 

Escherichia coli 

NOTE: While nitrofurantoin has excellent activity against Enterococcus faecalis, the majority of Enterococcus faecium isolates are not susceptible to nitrofurantoin. 

At least 90 percent of the following microorganisms exhibit an in vitro minimum inhibitory concentration (MIC) less than or equal to the susceptible breakpoint for nitrofurantoin. However, the efficacy of nitrofurantoin in treating clinical infections due to these microorganisms has not been established in adequate and well-controlled trials.

 Aerobic and facultative Gram-positive microorganisms: 

Coagulase-negative staphylococci (including Staphylococcus epidermidis and Staphylococcus saprophyticus)

 Streptococcus agalactiae  

Group D streptococci

Viridans group streptococci

 Aerobic and facultative Gram-negative microorganisms:

 Citrobacter amalonaticus

 Citrobacter diversus

 Citrobacter freundii

 Klebsiella oxytoca

 Klebsiella ozaenae

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

 Susceptibility Test:

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 capsules, USP (macrocrystals) 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.

To reduce the development of drug-resistant bacteria and maintain the effectiveness of nitrofurantoin capsules, USP (macrocrystals) and other antibacterial drugs, nitrofurantoin capsules, USP (macrocrystals) 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.

Nitrofurantoins lack the broader tissue distribution of other therapeutic agents approved for urinary tract infections. Consequently, many patients who are treated with nitrofurantoin capsules, USP (macrocrystals) 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 capsules, USP (macrocrystals), other therapeutic agents with broader tissue distribution should be selected. In considering the use of nitrofurantoin capsules, USP (macrocrystals), 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 capsules, (macrocrystals) are contraindicated in patients with a previous history of cholestatic jaundice/ hepatic dysfunction associated with nitrofurantoin.

Nitrofurantoin capsules, (macrocrystals) are 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 MACROCRYSTALS 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 capsules (macrocrystals); 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, 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 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 DEGREE 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 or 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 necrosis, 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 also have 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; chills; and vasculitis (sometimes associated with pulmonary reactions) have been reported. Hypersensitivity reactions represent the most frequent spontaneously-reported adverse events in worldwide 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, superinfections caused by resistant organisms, e.g., Pseudomonas species or Candida species, can occur.

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.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

Occasional incidents of acute overdosage of nitrofurantoin capsules (macrocrystals) 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 capsules (macrocrystals) 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).

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 Capsules, USP (Macrocrystals), 25 mg are white opaque cap / white opaque body, size 4, hard gelatin capsules imprinted with “A219” on cap in black ink, filled with light yellow to yellow, free flowing powder.

NDC 62332-389-31                Bottle of 100 capsules

NDC 62332-389-91                Bottle of 1000 capsules

Nitrofurantoin Capsules, USP (Macrocrystals), 50 mg are yellow opaque cap / white opaque body, size 3, hard gelatin capsules imprinted with “A220” on cap in black ink, filled with light yellow to yellow, free flowing powder.

NDC 62332-390-31                Bottle of 100 capsules

NDC 62332-390-91                Bottle of 1000 capsules

Nitrofurantoin Capsules, USP (Macrocrystals), 100 mg are yellow opaque cap / yellow  opaque body, size 2, hard gelatin capsules imprinted with “A221” on cap in black ink, filled with light yellow to yellow, free flowing powder.

NDC 62332-391-31                Bottle of 100 capsules

NDC 62332-391-91                Bottle of 1000 capsules

Store at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature].

Dispense in a tight, light-resistant container as defined in the USP using a child-resistant closure.

For more information call Alembic Pharmaceuticals Limited at 1-866-210-9797.

Manufactured by:

Alembic Pharmaceuticals Limited

(Formulation Division),

Panelav 389350, Gujarat, India

Manufactured for:

Alembic Pharmaceuticals, Inc.

Bedminster, NJ 07921, USA

Revised: 05/2023

NDC 62332-389-31
Nitrofurantoin Capsules,
USP (Macrocrystals) 
25 mg
URINARY TRACT ANTIBACTERIAL
Rx only
100 Capsules

Alembic

NDC 62332-390-31
Nitrofurantoin Capsules,
USP (Macrocrystals) 
50 mg
URINARY TRACT ANTIBACTERIAL
Rx only
100 Capsules

Alembic

NDC 62332-391-31
Nitrofurantoin Capsules,
USP (Macrocrystals) 
100 mg
URINARY TRACT ANTIBACTERIAL
Rx only
100 Capsules

Alembic