Nitrofurantoin Information
Nitrofurantoin ()
Nitrofurantoin () Description
Nitrofurantoin () is an antibacterial agent specific for urinary tract infections. Nitrofurantoin () monohydrate/macrocrystals is a hard gelatincapsule containing the equivalent of 100 mg of Nitrofurantoin () in the form of 25 mg of Nitrofurantoin () macrocrystals, USP and 75 mg of Nitrofurantoin () monohydrate, USP.
The chemical name of Nitrofurantoin () macrocrystals is 1-[[[5-nitro-2-furanyl] methylene]amino]-2,4-imidazolidinedione. The chemical structure is the following:
The molecular formula is CHNO and the molecular weight is 238.16.
The chemical name of Nitrofurantoin () monohydrate is 1-[[[5-nitro-2-furanyl] methylene]amino]-2,4-imidazolidinedione monohydrate. The chemical structure is the following:
The molecular formula is CHNO•HO and the molecular weight is 256.17.
Nitrofurantoin () Clinical Pharmacology
Each Nitrofurantoin () monohydrate/macrocrystals capsule contains two forms of Nitrofurantoin () . Twenty-five percent is macrocrystalline Nitrofurantoin () , which has slower dissolution and absorption than Nitrofurantoin () monohydrate. The remaining 75% is Nitrofurantoin () monohydrate contained in a powder blend which, upon exposure to gastric and intestinal fluids, forms a gel matrix that releases Nitrofurantoin () over time. Based on urinary pharmacokinetic data, the extent and rate of urinary excretion of Nitrofurantoin () from the 100 mg Nitrofurantoin () monohydrate/macrocrystalscapsule are similar to those of the 50 mg or 100 mg Nitrofurantoin () macrocrystals capsule. Approximately 20 to 25% of a single dose of Nitrofurantoin () is recovered from the urine unchanged over 24 hours.
Plasma Nitrofurantoin () concentrations after a single oral dose of the 100 mg Nitrofurantoin () monohydrate/macrocrystals capsule are low, with peak levels usually less than 1 mcg/mL. Nitrofurantoin () is highly soluble in urine, to which it may impart a brown color. When Nitrofurantoin () monohydrate/macrocrystals is administered with food, the bioavailability of Nitrofurantoin () is increased by approximately 40%.
Nitrofurantoin () , in the form of Nitrofurantoin () monohydrate/macrocrystals, has been shown to be active against most strains of the following bacteria both and in clinical infections: (See ).
Nitrofurantoin () also demonstrates activity against the following microorganisms, although the clinical significance of these data with respect to treatment with nitrofu-rantoin monohydrate/macrocrystals is unknown:
Coagulase-negative staphylococci
(including )
Group D streptococci
Viridans group streptococci
Nitrofurantoin () is not active against most strains of species or species. It has no activity against species.
Antagonism has been demonstrated between Nitrofurantoin () and quinolone antimicrobials. The clinical significance of this finding is unknown.
Dilution techniques:
Quantitative methods are used to determine antimicrobial minimal inhibitory concentrations (MIC’s). These MIC’s provide estimates of the susceptibility of bacteria to antimicrobial compounds. The MIC’s should be determined using a standardized procedure. Standardized procedures are based on a dilution method (broth or agar) or equivalent with standardized inoculum concentrations and standardized concentrations of Nitrofurantoin () powder. The MIC values should be interpreted according to the following criteria:
A report of "Susceptible" indicates that the pathogen is likely to be inhibited if the antimicrobial compound in the urine reaches the concentrations usually achievable. A report of "Intermediate" indicates that the result should be considered equivocal, and, if the microorganism is not fully susceptible to alternative, clinically feasible drugs, the test should be repeated. This category implies possible clinical applicability in body sites where the drug is physiologically concentrated or in situations where high dosage of drug can be used. This category also provides a buffer zone which prevents small uncontrolled technical factors from causing major discrepancies in interpretation. A report of "Resistant" indicates that the pathogen is not likely to be inhibited if the antimicrobial compound in the urine reaches the concentrations usually achievable; other therapy should be selected.
Standardized susceptibility test procedures require the use of laboratory control microorganisms to control the technical aspects of the laboratory procedures. Standard Nitrofurantoin () powder should provide the following MIC values:
Diffusion techniques:
Quantitative methods that require measurement of zone diameters also provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. One such standardized procedure requires the use of standardized inoculum concentrations. This procedure uses paper disks impregnated with 300 mcg Nitrofurantoin () to test the susceptibility of microorganisms to Nitrofurantoin () .
Reports from the laboratory providing results of the standard single-disk susceptibility test with a 300 mcg Nitrofurantoin () disk should be interpreted according to the following criteria:
Interpretation should be as stated above for results using dilution techniques. Interpretation involves correlation of the diameter obtained in the disk test with the MIC for Nitrofurantoin () .
As with standardized dilution techniques, diffusion methods require the use of laboratory control microorganisms that are used to control the technical aspects of the laboratory procedures. For the diffusion technique, the 300 mcg Nitrofurantoin () disk should provide the following zone diameters in these laboratory test quality control strains:
Nitrofurantoin () Indications And Usage
Nitrofurantoin () monohydrate/macrocrystals capsules, USP is indicated only for the treatment of acute uncomplicated urinary tract infections (acute cystitis) caused by susceptible strains of or
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 () monohydrate/macrocrystals capsules, USP and other antibacterial drugs, Nitrofurantoin () monohydrate/macrocrystals capsules, USP should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy.
Nitrofurantoin () s lack the broader tissue distribution of other therapeutic agents approved for urinary tract infections. Consequently, many patients who are treated with Nitrofurantoin () monohydrate/macrocrystals capsules, USP, are predisposed to persistence or reappearance of bacteriuria. (See .) 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 () monohydrate/macrocrystals capsules, USP, other therapeutic agents with broader tissue distribution should be selected. In considering the use of Nitrofurantoin () monohydrate/macrocrystals capsules, USP, 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.
Nitrofurantoin () Contraindications
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.
Beause 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 () monohydrate/macrocrystals is contraindicated in patients with a previous history of cholestatic jaundice/hepatic dysfunction associated with Nitrofurantoin () .
Nitrofurantoin () monohydrate/macrocrystals is also contraindicated in those patients with known hypersensitivity to Nitrofurantoin () .
Nitrofurantoin () Warnings
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.
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.
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 () monohydrate/macrocrystals; hemolysis ceases when the drug is withdrawn.
If CDAD is suspected or confirmed, ongoing antibiotic use not directed against may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibiotic treatment of , and surgical evaluation should be instituted as clinically indicated.
Nitrofurantoin () Precautions
Patients should be advised to take Nitrofurantoin () 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 () monohydrate/ macrocrystals.
Patients should be counseled that antibacterial drugs including Nitrofurantoin () monohydrate/ macrocrystals capsules should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When Nitrofurantoin () monohydrate/macrocrystals capsules are 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 () monohydrate/macrocrystals capsules 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.
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.
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 mice revealed no evidence of carcinogenicity.
Nitrofurantoin () presented evidence of carcinogenic activity in female B6C3F 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 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.
Teratogenic effects:
Non-teratogenic effects:
Clinical studies of Nitrofurantoin () monohydrate/macrocrystals capsules 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 ). Spontaneous reports also suggest an increased proportion of severe hepatic reactions, including fatalities, in elderly patients (See ).
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 () 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 ). Because elderly patients are more likely to have decreased renal function, it may be useful to monitor renal function.
Nitrofurantoin () Adverse Reactions
In clinical trials of Nitrofurantoin () monohydrate/macrocrystals, the most frequent clinical adverse events that were reported as possibly or probably drug-related were nausea (8%), headache (6%), and flatulence (1.5%). Additional clinical adverse events reported as possibly or probably drug-related occurred in less than 1% of patients studied and are listed below within each body system in order of decreasing frequency:
The following additional clinical adverse events have been reported with the use of Nitrofurantoin () :
Asthenia, vertigo, and nystagmus 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.
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 ).
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.
In clinical trials of Nitrofurantoin () monohydrate/macrocrystals, the most frequent laboratory adverse events (1 to 5%), without regard to drug relationship, were as follows: eosinophilia, increased AST (SGOT), increased ALT (SGPT), decreased hemoglobin, increased serum phosphorus. The following laboratory adverse events also have been reported with the use of Nitrofurantoin () : glucose-6-phosphate dehydrogenase deficiency anemia (See ), 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.
Nitrofurantoin () Overdosage
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. Nitrofurantoin () is dialyzable.
Nitrofurantoin () Dosage And Administration
Nitrofurantoin () monohydrate/macrocrystals capsules, USP should be taken with food.
Nitrofurantoin () How Supplied
Nitrofurantoin () monohydrate/macrocrystals capsules, USP is available as 100 mg opaque black cap and yellow body, size”0” hard gelatin capsules printed with ‘ in white ink on cap and in black ink on body containing off-white to light yellow powder and a yellow tablet debossed with ‘ on one side and plain on the other side.
Store at 20 - 25° C (68 - 77° F) [See USP Controlled Room Temperature].
Dispense in a tight, light resistant container.
Call your doctor for medical advice about side effects. You may report side effects to FDA at .
Nitrofurantoin () Clinical Studies
Controlled clinical trials comparing Nitrofurantoin () monohydrate/macrocrystals100 mg p.o. q12h and Nitrofurantoin () macrocrystals 50 mg p.o. q6h in the treatment of acute uncomplicated urinary tract infections demonstrated approximately 75% microbiologic eradication of susceptible pathogens in each treatment group.
Manufactured for:
Ranbaxy Pharmaceuticals Inc.
Jacksonville, FL 32257 USA
by: Ranbaxy Laboratories Ltd.
New Delhi – 110 019, India
April 2009
