NITROFURANTOIN: 5,073 Adverse Event Reports & Safety Profile

DESCRIPTION Nitrofurantoin, USP is an antibacterial agent specific for urinary tract infections. Nitrofurantoin capsules, USP (monohydrate/macrocrystals) are a hard gelatin capsule shell containing the equivalent of 100 mg of nitrofurantoin, USP in the form of 25 mg of nitrofurantoin macrocrystals and 75 mg of nitrofurantoin monohydrate. The chemical name of nitrofurantoin macrocrystals is 1-[[[5-nitro-2-furanyl]methylene]amino]-2,4-imidazolidinedione. The chemical structure is the following: The chemical name of nitrofurantoin monohydrate is 1-[[[5-nitro-2-furanyl]methylene]amino]-2,4- imidazolidinedione monohydrate. The chemical structure is the following: Inactive Ingredients: Each capsule contains carbomer 934P, carboxymethylcellulose, corn starch, D&C Yellow No. 10, FD&C Red No. 40, gelatin, iron oxide black, iron oxide yellow, lactose, magnesium stearate, maltodextrin, povidone, sodium lauryl sulfate, sugar, talc and titanium dioxide. The black monogramming ink contains butyl alcohol, dehydrated alcohol, iron oxide black, isopropyl alcohol, potassium hydroxide, propylene glycol, purified water, shellac and strong ammonia solution. The white monogramming ink contains butyl alcohol, dehydrated alcohol, isopropyl alcohol, povidone, propylene glycol, shellac, sodium hydroxide and titanium dioxide. Meets USP Dissolution Test 7.

Nitrofurantoin Macrocrystals Structural Formula Nitrofurantoin

Monohydrate Structural Formula

INDICATIONS AND USAGE: Nitrofurantoin Capsules, USP (monohydrate/ macrocrystals) are indicated only for the treatment of acute uncomplicated urinary tract infections (acute cystitis) caused by susceptible strains of Escherichia coli or Staphylococcus saprophyticus . 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 (monohydrate/ macrocrystals) and other antibacterial drugs,Nitrofurantoin Capsules, USP (monohydrate/ 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 (monohydrate/ macrocrystals) are predisposed to persistence or reappearance of bacteriuria. (see Error! Hyperlink reference not valid. ). 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 (monohydrate/ macrocrystals), other therapeutic agents with broader tissue distribution should be selected. In considering the use of Nitrofurantoin Capsules, USP (monohydrate/ 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.

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 <span class="opacity-50 text-xs">[see Warnings and Precautions ( 5.2, 5.4, 5.6 ) ]</span>. Administer nitrofurantoin oral suspension with food to improve drug absorption <span class="opacity-50 text-xs">[see Clinical Pharmacology ( 12.3 )]</span> 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 <span class="opacity-50 text-xs">[see Warnings and Precautions ( 5.2, 5.4, 5.6 ) ]</span>.

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 <span class="opacity-50 text-xs">[see Warnings and Precautions ( 5.2, 5.4, 5.6 ) ]</span>. Administer nitrofurantoin oral suspension with food to improve drug absorption <span class="opacity-50 text-xs">[see Clinical Pharmacology ( 12.3 )]</span> 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 <span class="opacity-50 text-xs">[see Warnings and Precautions ( 5.2, 5.4, 5.6 ) ]</span>.

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 )

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 with pulmonary reactions) have been reported. Hypersensitivity reactions present the most frequent spontaneously-reported adverse reactions in worldwide post marketing experience with nitrofurantoin formulations, including nitrofurantoin oral suspension. 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 antibacterial treatment. Hematologic : Cyanosis secondary to methemoglobinemia has been reported. Miscellaneous : As with other antibacterial agents, superinfections caused by resistant organisms, e.g., Pseudomonas species or Candida species, can occur. There are sporadic reports of Clostridioides difficile superinfections, or pseudomembranous colitis, with the use of nitrofurantoin, including nitrofurantoin oral suspension.

Laboratory Adverse Reactions

The following laboratory adverse reactions have been reported with the use of nitrofurantoin formulations, including nitrofurantoin oral suspension; increased AST (SGOT), increased ALT (SGPT), decreased hemoglobin, increased serum phosphorus, eosinophilia, glucose-6-phosphate dehydrogenase deficiency anemia, agranulocytosis, leukopenia, granulocytopenia, hemolytic anemia, thrombocytopenia, megaloblastic anemia. In most cases, these hematologic abnormalities resolved following cessation of therapy. Aplastic anemia has been reported. The most common adverse reactions occurring in patients are nausea, vomiting, anorexia, vertigo, nystagmus, dizziness, headache, angioedema, rash, urticaria, pulmonary hypersensitivity reactions, hepatic reactions, peripheral neuropathy, increased aspartate aminotransferase, increased alanine aminotransferase, decreased hemoglobin, increased serum phosphorus, and eosinophilia ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Rising Pharma Holdings, Inc. at 1(844)874–7464 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

AND PRECAUTIONS Hypersensitivity Reactions: Serious and occasionally fatal hypersensitivity (anaphylactic) reactions have been reported in patients receiving nitrofurantoin oral suspension. If signs and symptoms of a hypersensitivity reaction occurs, immediately discontinue nitrofurantoin oral suspension. ( 5.1 )

Pulmonary

Reactions: Discontinue if sign and symptoms of pulmonary reactions occur and take appropriate measures. ( 5.2 ) Hepatotoxicity: Discontinue if signs/symptoms of hepatitis occur. Monitor liver function tests. (5.3) Neuropathy: Peripheral neuropathy has occurred. ( 5.4 )

Hemolytic

Anemia: Discontinue if sign and symptoms of hemolysis occur. ( 5.5 ) Clostridioides difficile -associated diarrhea: Evaluate patients if diarrhea occurs. ( 5.6 )

5.1 Hypersensitivity Reactions Serious and occasionally fatal hypersensitivity (anaphylactic) reactions have been reported in patients receiving nitrofurantoin oral suspension <span class="opacity-50 text-xs">[see Adverse Reactions ( 6 )]</span>. 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 <span class="opacity-50 text-xs">[see Adverse Reactions ( 6 )]</span>.

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 <span class="opacity-50 text-xs">[see Adverse Reactions ( 6 )]</span> .

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, 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.

5.1 Hypersensitivity Reactions Serious and occasionally fatal hypersensitivity (anaphylactic) reactions have been reported in patients receiving nitrofurantoin oral suspension <span class="opacity-50 text-xs">[see Adverse Reactions ( 6 )]</span>. 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 <span class="opacity-50 text-xs">[see Adverse Reactions ( 6 )]</span>.

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 <span class="opacity-50 text-xs">[see Adverse Reactions ( 6 )]</span> .

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, 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.

PRECAUTIONS: Information for Patients: Patients should be advised to take Nitrofurantoin Capsules, USP (Monohydrate/Macrocrystals) with food (ideally breakfast and dinner) 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. Patients should be advised not to use antacid preparations containing magnesium trisilicate while taking Nitrofurantoin Capsules, USP (monohydrate/macrocrystals). Patients should be counseled that antibacterial drugs including Nitrofurantoin Capsules, USP (monohydrate/macrocrystals) should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold).

When Nitrofurantoin

Capsules, USP (monohydrate/macrocrystals) is prescribed to treat a bacterial infection, patients should be told that although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed. Skipping doses or not completing the full course of therapy may (1) decrease the effectiveness of the immediate treatment and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by Nitrofurantoin Capsules, USP (monohydrate/macrocrystals) or other antibacterial drugs in the future. Diarrhea is a common problem caused by antibiotics which usually ends when the antibiotic is discontinued. Sometimes after starting treatment with antibiotics, patients can develop watery and bloody stools (with or without stomach cramps and fever) even as late as two or more months after having taken the last dose of the antibiotic. If this occurs, patients should contact their physician as soon as possible. General: Prescribing Nitrofurantoin Capsules, USP (monohydrate/macrocrystals) in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria.

Drug

Interactions: 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. 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.

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, 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 BDF 1 mice revealed no evidence of carcinogenicity. Nitrofurantoin presented evidence of carcinogenic activity in female B6C3F 1 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 Error! Hyperlink reference not valid..

Nursing

Mothers: Nitrofurantoin has been detected in human 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 Error! Hyperlink reference not valid. ).

Pediatric

Use: Nitrofurantoin Capsules, USP (monohydrate/macrocrystals) is contraindicated in infants below the age of one month. (see Error! Hyperlink reference not valid. ). Safety and effectiveness in pediatric patients below the age of twelve years have not been established.

Geriatric

Use: Clinical studies of Nitrofurantoin Capsules, USP (monohydrate/macrocrystals) did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. Spontaneous reports suggest a higher proportion of pulmonary reactions, including fatalities, in elderly patients; these differences appear to be related to the higher proportion of elderly patients receiving long- term nitrofurantoin therapy. As in younger patients, chronic pulmonary reactions generally are observed in patients receiving therapy for six months or longer (see Error! Hyperlink reference not valid. ). Spontaneous reports also suggest an increased proportion of severe hepatic reactions, including fatalities, in elderly patients (see Error! Hyperlink reference not valid. ). In general, the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy in elderly patients should be considered when prescribing Nitrofurantoin Capsules, USP (monohydrate/macrocrystals). This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Anuria, oliguria, or significant impairment of renal function (creatinine clearance under 60 mL per minute or clinically significant elevated serum creatinine) are contraindications (see Error! Hyperlink reference not valid. ). Because elderly patients are more likely to have decreased renal function, it may be useful to monitor renal function.

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 <span class="opacity-50 text-xs">[see Clinical Pharmacology ( 12.3 )]</span> .

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&apos;s or Fehling&apos;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 <span class="opacity-50 text-xs">[see Clinical Pharmacology ( 12.3 )]</span> .

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&apos;s or Fehling&apos;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.