Macrobid
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Macrobid - Scientific Information

Manufacture: Actavis
Country: Canada
Condition: Bladder Infection, Prevention of Bladder infection (Cystitis Prophylaxis), Urinary Tract Infection
Class: Urinary anti-infectives
Form: Capsules
Ingredients: nitrofurantoin, carbomer 934P, corn starch, compressible sugar, D&C Yellow No. 10, edible gray ink, FD&C Blue No. 1, FD&C Red No. 40, gelatin, lactose, magnesium stearate, povidone, talc, and titanium dioxide

Pharmaceutical Information

Drug Substance

Proper Name
Nitrofurantoin Macrocrystals Nitrofurantoin Monohydrate
Chemical Name
1-[[(5-nitro-2-furanyl)
methylene]amino] -2,4
imidazolidinedione
1-[[(5-nitro-2-furanyl)
methylene]amino] -2,4 imidazolidinedione
monohydrate
Structural Formula





Molecular Formula
C8H6N4O5 C8H6N4O5.H2O\
Molecular Weight
238.16 256.17
Description
Each 100 mg hard shell gelatin MacroBID capsule contains the equivalent of 100 mg of
nitrofurantoin in the form of nitrofurantoin macrocrystals and nitrofurantoin monohydrate.
Nitrofurantoin is a stable, yellow, odourless, crystalline compound; very slightly soluble in
water and alcohol and soluble in dimethylformamide and DMSO. Aqueous solubility of
nitrofurantoin is a function of both pH and temperature. Nitrofurantoin melts with
decomposition at 270-272°C.

Composition

Each capsule contains the following inactive ingredients: carbomer 934P, corn starch, compressible sugar, D&C Yellow No. 10, edible gray ink, FD&C Blue No. 1, FD&C Red No. 40, gelatin, lactose, magnesium stearate, povidone, talc, and titanium dioxide.

Storage

Store at controlled room temperature (20°C to 25°).

Availability

MacroBID 100 mg is available for oral administration as opaque black and yellow capsules, imprinted "Macrobid" on the black portion and "Norwich Eaton" on the yellow portion in bottles of 100.

Information for the Consumer

Patients should be instructed as follows, before taking MacroBID (SEE PRECAUTIONS).

  1. Take MacroBID with food (ideally breakfast and dinner) to enhance tolerance and improve drug absorption.
  2. Complete the full course of therapy and contact their physician if any unusual symptoms occur during therapy.
  3. Do not use antacid preparations containing magnesium trisilicate while using MacroBID.
  4. With some glucose test tablets, a false positive result may be noted when taking MacroBID.

Microbiology

The in vitro antibacterial activity of nitrofurantoin against clinical isolates is given below.

Minimal Inhibitory Concentration
(mcg/mL)
Organism (# strains tested) MIC50 MIC90 Range
Citrobacter freundii (97) 32 32 16 - >128
Enterobacter aerogenes (75) 64 128 32-128
Enterobacter cloacae (135) 64 128 4-128
Escherichia coli (1792) 16 32 8-128
Klebsiella oxytoca (52) 32 64 ≤16 - >128
Klebsiella pneumoniae (410) 64 128 32 - >128
Staphylococcus aureus (84) 16 32 16-32
Staphylococcus epidermidis (25) 16 16 8-32
Staphylococcus saprophyticus (25) 16 16 8-32
Enterococcus faecalis (598) 16 16 8-64

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

Nitrofurantoin is bactericidal in urine at levels equal to one or two times the MIC. Nitrofurantoin exhibits concentration dependent killing of bacteria.

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

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.

Susceptibility Tests - Quantitative methods that require measurement of zone diameters give the most precise estimates of antimicrobial susceptibility. One recommended procedure, (National Committee for Clinical Laboratory Standards, Performance Standards for Antimicrobial Disc Susceptibility Tests, Approved Standard: M2-A4, Vol. 10, Number 7, 1990), uses a disc containing 300 mcg nitrofurantoin for testing susceptibility.

Reports from the laboratory should be interpreted according to the following criteria:

  • Susceptible organisms produce zones of 17 mm or greater indicating that the tested organism is likely to respond to therapy.
  • Organisms of intermediate susceptibility produce zones of 15 to 16 mm, indicating that the tested organism may or may not be susceptible.
  • Resistant organisms produce zones of 14 mm or less, indicating that other therapy should be selected.

Alternatively, a bacterial isolate may be considered susceptible if the MIC value for nitrofurantoin is not more than 32 mcg/mL. A MIC of 64 mcg/mL indicates intermediate susceptibility. Organisms are considered resistant if the MIC is equal to or greater than 128 mcg/mL.

Dilution and diffusion susceptibility tests should give MICs and zone diameters within the ranges listed below for the following quality control organisms.

Organism MIC (mcg/mL) Zone Size
Range (mm)
E. coli (ATCC 25922) 4-16 20-25
S. aureus (ATCC 29213) 8-32 18-22
E. faecalis (ATCC 29212) 4-16 -

Pharmacology

Human

Nitrofurantoin taken orally is rapidly absorbed from the gastrointestinal tract and appears to be widely distributed. Based upon urine recovery levels its bioavailability may be increased by as much as 40% when administered with food. In one study in which healthy male adults were provided a single 100 mg capsule of MacroBID with food the Cmax, tmax, AUC and elimination t1/2 were respectively 0.6 μg/mL, 5 hrs and 1.8 μg/mLxhrs and 0.8 hrs in plasma. In urine Cmax, tmax and elimination t1/2 were respectively 144 μg/mL, 5.1 hrs and 1.1 hrs. Plasma levels do not normally exceed 1 μg/mL following therapeutic administration of MacroBID to subjects with normal kidney function. Levels far exceeding those in plasma have been reported for human bile, seminal fluid and kidney. About 20-25% of a single dose of MacroBID is recovered in the urine and about 1.5% of urine contents are metabolized. Little is known about nitrofurantoin metabolism and the rate or extent of its excretion by other routes in humans.

Animal

In Sprague-Dawley rats nitrofurantoin was rapidly and completely absorbed from the gastrointestinal tract and was widely distributed. Following administration of 0.5 mg/kg of a suspension by gavage it was excreted primarily in the feces (58%, all of which was metabolized) and urine (35%, three quarters of which was metabolized). A Cmax of 0.05 μg/mL was attained at 0.5 hrs. Admixed to food in long term toxicity studies at average doses of 96 mg/kg/day plasma levels of 0.39 and 1.1 μg/mL were recorded in males and females respectively. The maximal plasma levels attained in rats appear low relative to those attained in humans.

Toxicology

Chronic Toxicity and Carcinogenicity Studies

Nitrofurantoin was not considered carcinogenic when administered for 22 months to male and female Swiss mice at dietary doses up to 181 and 224 mg/kg/day respectively and in male and female BDF1 mice at dietary doses (estimated from feed consumption of Swiss and B6C3F1 mice historical controls) of up to 550 and 560 mg/kg/day respectively for 24 months. There was an increase in mortality in the high dosed males and changes in the urinary system and gonads (increase in ovarian cysts and testicular degeneration/atrophy) observed in Swiss mice. No neoplastic lesions were attributed to the administration of nitrofurantoin for either strain of mouse.

In a chronic study, nitrofurantoin was consumed in the diet for two years by male and female Sprague-Dawley rats in doses of up to 81 and 116 mg/kg/day respectively. In a carcinogenicity study Sprague-Dawley male and female rats consumed dietary nitrofurantoin for 2 years in doses of up to 43 and 56 mg/kg/day respectively. No evidence of carcinogenicity was observed in these studies. In the higher dose groups, increased mortality, testicular degeneration, epididymal fibrosis and sciatic nerve fibrosis was seen in males and an increase in bile duct hyperplasia and sciatic nerve demyelination was seen in females.

In a large carcinogenicity study conducted by the U.S. Department of Health and Human Services F344/N rats consumed dietary nitrofurantoin for 2 years in average amounts equivalent to 59 or 111 mg/kg/day for males and 29 or 62 mg/kg/day for females. B6C3F1 mice consumed dietary nitrofurantoin for 2 years in average amounts equivalent to 295 or 567 mg/kg/day for males and 277 or 577 mg/kg/day for females. Evidence of tumorigenicity and carcinogenicity was noted. (SEE WARNINGS)

Carcinogenesis, Mutagenesis and Impairment of Fertility

(SEE WARNINGS)

General Reproductive Studies

(SEE PRECAUTIONS)