Nitrofurantoin - Nitrofurantoin suspension
(Nitrofurantoin)Nitrofurantoin - Nitrofurantoin suspension Prescribing Information
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
Nitrofurantoin oral suspension is not indicated for the treatment of pyelonephritis or perinephric abscesses
5.7 Persistence or Reappearance of BacteriuriaNitrofurantoin 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.
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.
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
12.3 PharmacokineticsOrally administered nitrofurantoin oral suspension is readily absorbed. Blood concentrations at therapeutic dosage are usually low.
Effect of Food
The presence of food or agents delaying gastric emptying can increase the bioavailability of nitrofurantoin oral suspension.
Nitrofurantoin is highly soluble in urine. Nitrofurantoin lacks the broader tissue distribution of other therapeutic agents approved for urinary tract infections.
Nitrofurantoin is rapidly excreted in urine, to which it may impart a brown color.
Following a dose regimen of 100 mg four times a day for 7 days, average urinary drug recoveries (0 hour to 24 hours) on Day 1 and Day 7 were 42.7% and 43.6%.
Nitrofurantoin is dialyzable.
The pharmacokinetics of nitrofurantoin oral suspension are unknown for the geriatric patients, pediatric patients, patients with hepatic impairment, or pregnant women. Differences between male and female patients, and racial or ethnic groups are unknown.
The reported urinary recoveries of nitrofurantoin after a single 100 mg oral dose and 100 mg four times a day in patients with varying renal function showed approximate linear relationship between the amount of nitrofurantoin recovered and creatinine clearance.
In a cross-over study, the
In a crossover study, the
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.
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
5.2 Pulmonary ReactionsAcute, 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
5.4 NeuropathyPeripheral 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
5.6If CDAD is suspected or confirmed, ongoing antibacterial use not directed against
5.6If CDAD is suspected or confirmed, ongoing antibacterial use not directed against
Nitrofurantoin oral suspension, USP is available as an opaque, yellow liquid oral suspension containing 25 mg/5 mL of nitrofurantoin.
Nitrofurantoin oral suspension is contraindicated in:
- patients with known hypersensitivity to nitrofurantoin [see Warnings and Precautions (
5.1 Hypersensitivity ReactionsSerious and occasionally fatal hypersensitivity (anaphylactic) reactions have been reported in patients receiving nitrofurantoin oral suspension
[see Adverse Reactions (6)].If signs and symptoms of a hypersensitivity reaction occurs, immediately discontinue nitrofurantoin oral suspension and initiate appropriate medications and/or supportive care. Nitrofurantoin oral suspension is contraindicated in patients with known hypersensitivity to nitrofurantoin.)]. - patients with a previous history of cholestatic jaundice/hepatic dysfunction associated with nitrofurantoin [see Warnings and Precautions (
5.3 HepatotoxicityHepatic 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.
)]. - 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 NeuropathyPeripheral neuropathy, which may become severe or irreversible, has occurred. Fatalities have been reported. Conditions such as renal impairment (creatinine clearance under 60 mL per minute or clinically significant elevated serum creatinine), anemia, diabetes mellitus, electrolyte imbalance, vitamin B deficiency, and debilitating disease may enhance the occurrence of peripheral neuropathy. Monitor patients receiving long-term therapy periodically for changes in renal function.
Optic neuritis has been reported with nitrofurantoin formulations
[see Adverse Reactions (6)].)]. - 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 Hemolytic AnemiaCases 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.
) and Use in Specific Populations (and8.1 PregnancyRisk SummaryNitrofurantoin 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 ConsiderationsFetal/Neonatal Adverse ReactionsNitrofurantoin 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)].DataAnimal DataSeveral 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.
8.4 Pediatric UseNitrofurantoin oral suspension is contraindicated in pediatric patients younger than 1 month of age because of the possibility of hemolytic anemia due to immature erythrocyte enzyme systems (glutathione instability).
[see Contraindications (4) and Warnings and Precautions (5.4)].The safety and effectiveness of nitrofurantoin oral suspension in pediatric patients aged 1 month of age and older for the treatment of urinary tract infections have been established.
)].
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.
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 Hypersensitivity ReactionsSerious and occasionally fatal hypersensitivity (anaphylactic) reactions have been reported in patients receiving nitrofurantoin oral suspension
[see Adverse Reactions (6)].If signs and symptoms of a hypersensitivity reaction occurs, immediately discontinue nitrofurantoin oral suspension and initiate appropriate medications and/or supportive care. Nitrofurantoin oral suspension is contraindicated in patients with known hypersensitivity to nitrofurantoin.)] - Pulmonary Reactions [see Warnings and Precautions (
5.2 Pulmonary ReactionsAcute, 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
[see Adverse Reactions (6)].)] - Hepatotoxicity [see Warnings and Precautions (
5.3 HepatotoxicityHepatic 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.
)] - Neuropathy [see Warnings and Precautions (
5.4 NeuropathyPeripheral neuropathy, which may become severe or irreversible, has occurred. Fatalities have been reported. Conditions such as renal impairment (creatinine clearance under 60 mL per minute or clinically significant elevated serum creatinine), anemia, diabetes mellitus, electrolyte imbalance, vitamin B deficiency, and debilitating disease may enhance the occurrence of peripheral neuropathy. Monitor patients receiving long-term therapy periodically for changes in renal function.
Optic neuritis has been reported with nitrofurantoin formulations
[see Adverse Reactions (6)].)] - Hemolytic anemia [see Warnings and Precautions (
5.5 Hemolytic AnemiaCases 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.
)] - Clostridioides difficile-associated Diarrhea[see Warnings and Precautions (
5.6Clostridioides difficile-associated DiarrheaClostridioides 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 ofC. difficile.C. difficileproduces toxins A and B which contribute to the development of CDAD. Hypertoxin producing strains ofC. difficilecause 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. difficilemay need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibacterial treatment ofC. difficile, and institute surgical evaluation as clinically indicated.)] - Persistence or Reappearance of Bacteriuria [see Warnings and Precautions (
5.7 Persistence or Reappearance of BacteriuriaNitrofurantoin 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.
)]
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.
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 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.
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.
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.