Nitrofurantoin (monohydrate/macrocrystals)

NITROFURANTOIN (MONOHYDRATE/MACROCRYSTALS)- nitrofurantoin monohydrate and nitrofurantoin capsule
Quality Care Products, LLC

(Twice-a-day Dosage)

Rx Only

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 bacteria.

DESCRIPTION

Nitrofurantoin is an antibacterial agent specific for urinary tract infections. Nitrofurantoin capsules, USP (monohydrate/macrocrystals) are hard gelatin capsule shells 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 USP is 1-[[[5-nitro-2-furanyl]methylene]amino]-2,4-imidazolidinedione. The chemical structure is the following:

Chemical Structure 1

Molecular Weight: 238.16

The chemical name of nitrofurantoin monohydrate USP is 1-[[[5-nitro-2-furanyl]methylene]amino]-2,4-imidazolidinedione monohydrate. The chemical structure is the following:

Chemical Structure 2

Molecular Weight: 256.17

Inactive Ingredients

Each capsule contains carbomer 934P, colloidal silicon dioxide, corn starch, compressible sugar, D&C yellow No. 10, edible white ink, FD&C blue No. 1, FD&C red No. 40, gelatin, lactose monohydrate, magnesium stearate, povidone, talc, and titanium dioxide.

Meets USP Dissolution Test 5

CLINICAL PHARMACOLOGY

Each nitrofurantoin capsule (monohydrate/macrocrystals) 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 capsules (monohydrate/macrocrystals) are similar to those of the 50 mg or 100 mg nitrofurantoin (macrocrystals) capsules. 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 capsules (monohydrate/macrocrystals) 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%.

Microbiology

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

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

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

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

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

Aerobic and Facultative Gram-Positive Microorganisms

Staphylococcus saprophyticus

Aerobic and Facultative Gram-Negative Microorganisms

Escherichia coli

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

Aerobic and Facultative Gram-Positive Microorganisms

Coagulase-negative staphylococci (including Staphylococcus epidermidis)

Enterococcus faecalis

Staphylococcus aureus

Streptococcus agalactiae

Group D streptococci

Viridans group streptococci

Aerobic and Facultative Gram-Negative Microorganisms

Citrobacter amalonaticus

Citrobacter diversus

Citrobacter freundii

Klebsiella oxytoca

Klebsiella ozaenae

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

Susceptibility Test Methods: When available, the clinical microbiology laboratory should provide cumulative results of the in vitro susceptibility test results for antimicrobial drugs used in resident hospitals 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 the most effective antimicrobial.

Dilution Techniques: Quantitative methods are used to determine antimicrobial minimum inhibitory concentrations (MICs). These MICs provide estimates of the susceptibility of bacteria to antimicrobial compounds. The MICs should be determined using a standardized procedure. Standardized procedures are based on a dilution method (broth or agar) (1) or equivalent with standardized inoculum concentrations and standardized concentrations of nitrofurantoin powder. The MIC values should be interpreted according to the criteria provided in Table 1.

Diffusion Technique: Quantitative methods that require measurement of zone diameters also provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. One such standardized procedure (2) requires the use of standardized inoculum concentrations. This procedure uses paper disks impregnated with 300 mcg of nitrofurantoin to test the susceptibility of microorganisms to nitrofurantoin. The disk diffusion interpretive criteria are provided in Table 1.

Table 1. Susceptibility Interpretive Criteria for Nitrofurantoin

Pathogen

Susceptibility Interpretive Criteria

Minimum Inhibitory Concentrations (mcg/mL)

Disk Diffusion

(Zone diameter in mm)

S

I

R

S

I

R

Enterobacteriaceae

≤32

64

≥128

≥17

15 to 16

≤14

Staphylococcus spp.

≤32

64

≥128

≥17

15 to 16

≤14

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 a 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.

Quality Control: Standardized susceptibility test procedures require the use of quality control microorganisms to control the technical aspects of the test procedures (3). Standard nitrofurantoin powder should provide the following range of values noted in Table 2.

Table 2. Acceptable Quality Control Ranges for Nitrofurantoin
*
Not applicable

QC Strain

Acceptable Quality Control Ranges

Minimum Inhibitory Concentration (mcg/mL)

Disk Diffusion

(zone diameter in mm)

Escherichia coli ATCC 25922

4 to 16

20 to 25

Enterococcus faecalis ATCC 29212

4 to 16

NA *

Staphylococcus aureus ATCC 29213

8 to 32

NA *

Staphylococcus aureus ATCC 25923

NAa

18 to 22

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