Nitrofurantoin Oral Suspension

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

Inactive Ingredients

Furadantin Oral Suspension contains carboxymethylcellulose sodium, citric acid, flavors, glycerin, magnesium aluminum silicate, methylparaben, propylparaben, purified water, sodium citrate, and sorbitol.

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

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

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

Microbiology

Nitrofurantoin is reduced by a wide range of enzymes including bacterial flavoproteins to reactive intermediates which are damaging to macromolecules such as DNA and proteins.

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

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

Staphylococcus aureus
Enterococcus species

Escherichia coli

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

The following in vitro data are available, but their clinical significance is unknown. Nitrofurantoin exhibits in vitro activity against the following bacteria; however, the safety and effectiveness of nitrofurantoin in treating clinical infections due to these bacteria have not been established in adequate and well controlled clinical trials.

Coagulase-negative staphylococci (including Staphylococcus epidermidis and Staphylococcus saprophyticus)
Streptococcus agalactiae
Viridans group streptococci

Citrobacter koseri
Citrobacter freundii
Klebsiella oxytoca

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

Susceptibility Tests Methods

When available, the clinical microbiology laboratory should provide the results of in vitro susceptibility test results for antimicrobial drugs used in local hospitals and practice areas to the physician as periodic reports that describe the susceptibility profile of nosocomial and communityacquired pathogens. These reports should aid the physician in selecting an antibacterial drug product for treatment.

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 test method1,3 (broth or agar). The MIC values should be interpreted according to the criteria in Table 1.

Quantitative methods that require measurement of zone diameters also provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. The zone size provides an estimate of the susceptibility of bacteria to antimicrobial compounds. The zone size should be determined using a standardized method.2 This procedure uses paper disks impregnated with 300 mcg of nitrofurantoin to test the susceptibility of bacteria to nitrofurantoin. The disk diffusion interpretive criteria are provided in Table 1.

Table 1: Susceptibility interpretive Criteria for Nitrofurantoin

A report of "Susceptible" indicates that the antimicrobial is likely to inhibit growth of the pathogen if the antimicrobial compound reaches the concentration at the infection site necessary to inhibit growth of the pathogen. 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 site where the drug is physiologically concentrated. This category also provides a buffer zone that prevents small uncontrolled technical factors from causing major discrepancies in interpretation. A report of "Resistant" indicates that the antimicrobial is not likely to inhibit growth of the pathogen if the antimicrobial compound reaches the concentrations usually achievable at the infection site; other therapy should be selected.

Quality Control

Standardized susceptibility test procedures require the use of laboratory controls to monitor and ensure the accuracy and precision of supplies and reagents used in the assay, and the techniques of the individuals performing the test.1,2,3 Standard nitrofurantoin powder should provide the following MIC values provided in Table 2. For the diffusion technique using the 300-mcgnitrofurantoin disk the criteria provided in Table 2 should be achieved.

Table 2: Acceptable Quality Control Ranges for Susceptibility Testing

REFERENCES

1. Clinical and Laboratory Standards Institute (CLSI). Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria That Grow Aerobically; Approved Standard-Ninth Edition. CLSI document M07-A9, Clinical and Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne, Pennsylvania 19087, USA, 2012.

2. Clinical and Laboratory Standards Institute (CLSI). Performance Standards for Antimicrobial Disk Diffusion Susceptibility Tests; Approved Standard-Eleventh Edition. CLSI document M02-A11. Clinical and Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne, Pennsylvania 19087,USA, 2012

3. Clinical and Laboratory Standards Institute (CLSI). Performance Standards for Antimicrobial Susceptibility Testing; Twenty-third Informational Supplement, CLSI document M100-S23. Clinical and Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne, Pennsylvania 19087, USA, 2013.

You should not take nitrofurantoin if you are allergic to it, or if you have:

• severe kidney disease;
• a history of jaundice or liver problems caused by taking nitrofurantoin;
• if you are urinating less than usual or not at all; or
• if you are in the last 2 to 4 weeks of pregnancy.

To make sure you can safely take nitrofurantoin, tell your doctor if you have any of these other conditions:

• kidney disease;
• anemia;
• diabetes;
• an electrolyte imbalance or vitamin B deficiency;
• glucose-6-phosphate dehydrogenase (G6PD) deficiency; or
• any type of debilitating disease.

FDA pregnancy category B. This medication is not expected to be harmful to an unborn baby, unless it is used during the last 2 to 4 weeks of pregnancy. Tell your doctor if you are pregnant or plan to become pregnant during treatment.

Nitrofurantoin can pass into breast milk and may harm a nursing baby. You should not breast-feed while you are taking nitrofurantoin.

• Liver Disease

WARNING/CAUTION: Even though it may be rare, some people may have very bad and sometimes deadly side effects when taking a drug. Tell your doctor or get medical help right away if you have any of the following signs or symptoms that may be related to a very bad side effect:

• Signs of an allergic reaction, like rash; hives; itching; red, swollen, blistered, or peeling skin with or without fever; wheezing; tightness in the chest or throat; trouble breathing or talking; unusual hoarseness; or swelling of the mouth, face, lips, tongue, or throat.
• Signs of a pancreas problem (pancreatitis) like very bad stomach pain, very bad back pain, or very bad upset stomach or throwing up.
• Change in eyesight.
• Eye pain.
• Not able to control eye movements.
• Feeling confused.
• Very bad headache.
• Low mood (depression).
• Change in color of skin to a bluish color like on the lips, nail beds, fingers, or toes.
• Feeling very tired or weak.
• It is common to have diarrhea when taking this medicine. Rarely, a very bad form of diarrhea called Clostridium difficile (C diff)–associated diarrhea (CDAD) may occur. Sometimes, this has led to a deadly bowel problem (colitis). CDAD may happen while you are taking nitrofurantoin oral suspension or within a few months after you stop taking it. Call your doctor right away if you have stomach pain or cramps, very loose or watery stools, or bloody stools. Do not try to treat loose stools without first checking with your doctor.

• Store at room temperature. Do not freeze.
• Store in original container.
• Protect from light.
• Throw away any unused portion after 30 days.
• Store in a dry place. Do not store in a bathroom.
• Keep all drugs in a safe place. Keep all drugs out of the reach of children and pets.
• Check with your pharmacist about how to throw out unused drugs.

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

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

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

Mode of Action

Nitrofurantoin is reduced by a wide range of enzymes including bacterial flavoproteins to reactive intermediates which are damaging to macromolecules such as DNA and proteins.

Cross-Resistance

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

Interaction with Other Antimicrobials

Antagonism has been demonstrated in vitro between nitrofurantoin and quinolone antimicrobial agents.

Nitrofurantoin, in the form of Nitrofurantoin Oral Suspension, has been shown to be active against most strains of the following bacteria both in vitro and in clinical infections: (See INDICATIONS AND USAGE).

Gram-positive Aerobes

Staphylococcus aureus

Enterococcus Species

Gram-Negative Aerobes

Escherichia coli

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

The following in vitro data are available, but their clinical significance is unknown. Nitrofurantoin exhibits in vitro activity against the following bacteria; however, the safety and effectiveness of nitrofurantoin in treating clinical infections due to these bacteria have not been established in adequate and well controlled clinical trials.

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

Streptococcus agalactiae

Viridans group streptococci

Gram-Negative Aerobes

Citrobacter Koseri

Citrobacter freundii

Klebsiella oxytoca

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

Susceptibility Tests Methods

When available, the clinical microbiology laboratory should provide the results of in vitro susceptibility test results for antimicrobial drugs used in local hospitals and practice areas to the physician as periodic reports that describe the susceptibility profile of nosocomial and community-acquired pathogens. These reports should aid the physician in selecting an antibacterial drug product for treatment.

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 test method1,3(broth or agar).  The MIC values should be interpreted according to the criteria in Table 1.

Diffusion Techniques

Quantitative methods that require measurement of zone diameters also provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. The zone size provides an estimate of the susceptibility of bacteria to antimicrobial compounds. The zone size should be determined using a standardized method.2  This procedure uses paper disks impregnated with 300 mcg of nitrofurantoin to test the susceptibility of bacteria to nitrofurantoin. The disk diffusion interpretive criteria are provided in Table 1.

A report of "Susceptible" indicates that the antimicrobial is likely to inhibit growth of the pathogen if the antimicrobial compound reaches the concentration at the infection site necessary to inhibit growth of the pathogen. 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 site where the drug is physiologically concentrated. This category also provides a buffer zone that prevents small uncontrolled technical factors from causing major discrepancies in interpretation. A report of "Resistant" indicates that the antimicrobial is not likely to inhibit growth of the pathogen if the antimicrobial compound reaches the concentrations usually achievable at the infection site; other therapy should be selected.

Quality Control

Standardized susceptibility test procedures require the use of laboratory controls to monitor and ensure the accuracy and precision of supplies and reagents used in the assay, and the techniques of the individuals performing the test.1,2,3 Standard nitrofurantoin powder should provide the following MIC values provided in Table 2. For the diffusion technique using the 300-mcg nitrofurantoin disk the criteria provided in Table 2 should be achieved.

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 (38-42 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 Oral Suspension, USP is contraindicated in patients with a previous history of cholestatic jaundice/hepatic dysfunction associated with nitrofurantoin.  Nitrofurantoin Oral Suspension, USP is also contraindicated in those patients with known hypersensitivity to nitrofurantoin.

1. Clinical and Laboratory Standards Institute (CLSI). Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria That Grow Aerobically; Approved Standard-Ninth Edition. CLSI document M07-A9, Clinical and Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne, Pennsylvania 19087, USA, 2012.
2. Clinical and Laboratory Standards Institute (CLSI). Performance Standards for Antimicrobial Disk Diffusion Susceptibility Tests; Approved Standard-Eleventh Edition. CLSI document M02-A11. Clinical and Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne, Pennsylvania 19087,USA, 2012
3. Clinical and Laboratory Standards Institute (CLSI). Performance Standards for Antimicrobial Susceptibility Testing; Twenty-third Informational Supplement, CLSI document M100-S23. Clinical and Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne, Pennsylvania 19087, USA, 2013.

Manufactured by

Novel Laboratories, Inc.

Somerset, NJ 08873

Manufactured For:

Lupin Pharmaceuticals, Inc.

Baltimore MD, 21202

PI4501100202

Revised: 05/2016

Side effects that you should report to your doctor or health care professional as soon as possible:

• allergic reactions like skin rash or hives, swelling of the face, lips, or tongue
• chest pain
• cough
• difficulty breathing
• dizziness, drowsiness
• fever or infection
• joint aches or pains
• pale or blue-tinted skin
• redness, blistering, peeling or loosening of the skin, including inside the mouth
• tingling, burning, pain, or numbness in hands or feet
• unusual bleeding or bruising
• unusually weak or tired
• yellowing of eyes or skin

Side effects that usually do not require medical attention (report to your doctor or health care professional if they continue or are bothersome):

• dark urine
• diarrhea
• headache
• loss of appetite
• nausea or vomiting
• temporary hair loss