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Norfloxacin is authorised in the world under the following brand names: Chibroxin, Noroxin.

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Norfloxacin

Norfloxacin is a fluoroquinolone anti-infective agent.

Dosage and Administration

Administration

Norfloxacin is administered orally. The drug should be given with a glass of water at least 1 hour before or at least 2 hours after a meal or ingestion of milk or other dairy products. Patients receiving norfloxacin should be well hydrated and should be instructed to drink fluids liberally. To minimize the possibility of interference with the GI absorption of norfloxacin, patients should be instructed not to ingest antacids containing magnesium or aluminum, sucralfate, metal cations such as iron or zinc (including multivitamin preparations containing zinc), or buffered didanosine preparations concomitantly with or within 2 hours of a norfloxacin dose.

Dosage

Because of the risk of crystalluria, the manufacturer recommends that the usual dosage of 400 mg twice daily not be exceeded in adults with normal renal function.

Urinary Tract Infections and Prostatitis

For the treatment of complicated or uncomplicated urinary tract infections caused by susceptible organisms, the usual adult dosage of norfloxacin is 400 mg twice daily. Therapy generally should be continued for 3 days for the treatment of uncomplicated urinary tract infections caused by susceptible E. coli, K. pneumoniae, or P. mirabilis; therapy should be continued for 7-10 days for the treatment of uncomplicated urinary tract infections caused by other susceptible organisms.

For the treatment of complicated urinary tract infections caused by susceptible organisms, oral norfloxacin therapy should be continued for at least 10-21 days. For the treatment of acute or chronic prostatitis caused by E. coli, the usual adult dosage of norfloxacin is 400 mg every 12 hours for 28 days.

Gonorrhea

For the treatment of uncomplicated urethral, endocervical, or rectal gonorrhea caused by susceptible Neisseria gonorrhoeae, adults should receive a single 800-mg dose of oral norfloxacin. Unless the presence of coexisting chlamydial infection has been excluded by appropriate testing, patients receiving norfloxacin for the treatment of gonorrhea should also receive an anti-infective regimen effective for presumptive treatment of chlamydia (e.g., a single oral dose of azithromycin or a 7-day regimen of oral doxycycline).

GI Infections

For the treatment of gastroenteritis caused by susceptible organisms, the usual adult dosage of norfloxacin is 400 mg twice daily for 5 days. For the treatment of shigellosis or GI infections caused by E. coli, some clinicians recommend that norfloxacin be given in a dosage of 400 mg twice daily for 3 days.

For the treatment of travelers' diarrhea that is severe or associated with fever or bloody stools, some clinicians recommend that 400 mg of norfloxacin be given twice daily for up to 3 days until symptoms resolve.

Although the use of anti-infectives for prophylaxis of travelers' diarrhea is generally discouraged, if norfloxacin is used, the recommended adult oral dosage of the drug is 400 mg once daily during the period of risk (for up to 3 weeks) beginning the day of travel and continuing for 1 or 2 days after leaving the area of risk.

Dosage in Renal Impairment

In patients with impaired renal function, doses and/or frequency of administration of norfloxacin should be modified in response to the degree of renal impairment. Adults (including geriatric patients) with creatinine clearances greater than 30 mL/minute per 1.73 m may receive the usual adult dosage of norfloxacin. Adults with creatinine clearance of 30 mL/minute per 1.73 m or less should receive 400 mg once daily. At this dosage, norfloxacin concentrations in urine exceed the MICs of the drug for most susceptible urinary pathogens, even when the patient's creatinine clearance is less than 10 mL/minute per 1.73 m.

Acute Toxcicity

Limited information is available on the acute toxicity of norfloxacin. The oral LD50 of the drug is greater than 4 g/kg in mice and rats. If acute overdosage of norfloxacin occurs, the stomach should be emptied by inducing emesis or by gastric lavage.

Supportive and symptomatic treatment should be initiated, and the patient should be observed carefully; adequate hydration must be maintained to minimize the risk of crystalluria.

Mechanism of Action

Norfloxacin usually is bactericidal in action. Like other fluoroquinolone anti-infectives, norfloxacin inhibits DNA synthesis in susceptible organisms via inhibition of type II DNA topoisomerases (DNA gyrase, topoisomerase IV). In vitro studies, particularly those involving in vitro susceptibility tests, indicate that the antibacterial activity of norfloxacin is decreased in the presence of urine, especially acidic urine.

The clinical importance of this in vitro effect has not been determined to date; however, because norfloxacin concentrations attained in urine are usually substantially higher than norfloxacin MICs for most urinary tract pathogens, the effect probably is not clinically important. Spectrum Norfloxacin has a spectrum of activity similar to that of many other fluoroquinolones (e.g., ciprofloxacin, ofloxacin). Norfloxacin is active in vitro against most gram-negative aerobic bacteria, including Enterobacteriaceae and Pseudomonas aeruginosa.

The drug also is active in vitro against many gram-positive aerobic bacteria, including penicillinase-producing, nonpenicillinase-producing, and oxacillin-resistant staphylococci (previously known as methicillin-resistant staphylococci), although many strains of streptococci are relatively resistant to the drug. Obligately anaerobic bacteria are generally resistant to norfloxacin.

The drug has some activity in vitro against Chlamydia, Mycoplasma, and some Mycobacterium, but is inactive against fungi and viruses.

In Vitro Susceptibility Testing

Like those of other fluoroquinolones, results of norfloxacin in vitro susceptibility tests are affected by the pH of the media and the presence of certain cations (e.g., calcium, magnesium). When in vitro susceptibility tests are performed in media with pH less than 7, MICs of norfloxacin are generally 2-100 times greater than those obtained when the tests are performed in media with pH 7-8. In a study using Mueller-Hinton broth with pH 6.5, 7.2, or 8, the MICs of norfloxacin for Ps. aeruginosa were 1.8, 0.7, or 0.5 mcg/mL, respectively.

 

Norfloxacin MICs may be increased when high concentrations of calcium or magnesium are present in the media; it has been suggested that these cations may form complexes with the drug and interfere with its mechanism of action. MICs of norfloxacin may be 4-100 times higher when susceptibility tests are performed in pooled urine or urine agar rather than in nutrient broth or Mueller-Hinton media.

The decreased antibacterial activity in the presence of urine probably occurs because of low pH and because urine contains a higher concentration of magnesium ions than nutrient broth or Mueller-Hinton media. Inoculum size generally does not affect susceptibility to norfloxacin, and MICs for most organisms are only 2-4 times greater when the size of the inoculum is increased from 103 to 107 colony-forming units (CFU) per mL.

Results of norfloxacin susceptibility tests are generally unaffected by the presence of serum. The National Committee for Clinical Laboratory Standards (NCCLS) states that, if results of in vitro susceptibility testing indicate that a clinical isolate is susceptible to norfloxacin, then an infection caused by this strain may be appropriately treated with dosages of the drug recommended for that type of infection and infecting species, unless otherwise contraindicated.

If results indicate that a clinical isolate has intermediate susceptibility to norfloxacin, then the strain has a minimum inhibitory concentration (MIC) that approaches usually attainable blood and tissue concentrations and response rates may be lower than for strains identified as susceptible.

Therefore, the intermediate category implies clinical applicability in body sites where the drug is physiologically concentrated or when high dosage can be used.

This intermediate category also includes a buffer zone which should prevent small, uncontrolled technical factors from causing major discrepancies in interpretation, especially for drugs with narrow pharmacotoxicity margins. If results of in vitro susceptibility testing indicate that a clinical isolate is resistant to norfloxacin, the strain is not inhibited by systemic concentrations of the drug achievable with normal dosage schedules and/or MICs fall in the range where specific microbial resistance mechanisms are likely and efficacy has not been reliable in clinical studies.

Norfloxacin

Becauase of differences in spectra of activity, norfloxacin susceptibility tests should not be used to predict susceptibility to other fluoroquinolones.

Disk Susceptibility Tests

When the disk-diffusion procedure is used to test susceptibility to norfloxacin, a disk containing 10 mcg of norfloxacin should be used. When the disk-diffusion procedure is performed according to NCCLS standardized procedures, urinary isolates of Enterobacteriaceae, Pseudomonas aeruginosa, Acinetobacter, Staphylococcus, or Enterococcus with growth inhibition zones of 17 mm or greater are susceptible to norfloxacin, those with zones of 13-16 mm have intermediate susceptibility, and those with zones of 12 mm or less are resistant to the drug.

Dilution Susceptibility Tests

When dilution susceptibility testing (agar or broth dilution) is performed according to NCCLS standardized procedures, urinary isolates of Enterobacteriaceae, Ps. aeruginosa, and other non-Enterobacteriaceae gram-negative bacilli (e.g., Acinetobacter, Stenotrophomonas maltophilia, other Pseudomonas spp), Staphylococcus, or Enterococcus with norfloxacin MICs of 4 mcg/mL or less are susceptible to norfloxacin, those with MICs of 8 mcg/mL have intermediate susceptibility, and those with MICs of 16 mcg/mL or greater are resistant to the drug.

Gram-positive Aerobic Bacteria

Gram-positive Aerobic Cocci

Norfloxacin is active in vitro against most strains of Staphylococcus aureus, S. epidermidis. and S. saprophyticus. The drug is active against both penicillinase-producing and nonpenicillinase-producing staphylococci and is also active in vitro against oxacillin-resistant strains.

Although some strains of Streptococcus pneumoniae, group A b-hemolytic streptococci (S. pyogenes), group B streptococci (S. agalactiae), groups C and G streptococci, viridans streptococci, and nonenterococcal group D streptococci are inhibited in vitro by norfloxacin concentrations of 16 mcg/mL or less, many strains of these organisms require high concentrations of the drug for in vitro inhibition and are generally considered relatively resistant.

Norfloxacin is active in vitro against some strains of enterococci, including some E. faecalis (formerly S. faecalis) and E. faecium (formerly S. faecium). Norfloxacin is bactericidal in vitro against enterococci and is active against some strains of E. faecalis resistant to penicillin-aminoglycoside drug combinations. The following table includes MIC50s (minimum inhibitory concentrations of the drug at which 50% of strains tested are inhibited) and MIC90s (minimum inhibitory concentrations of the drug at which 90% of strains tested are inhibited) of norfloxacin reported for gram-positive aerobic cocci: Organism MIC50 (mcg/mL) MIC90 (mcg/mL) Staphylococcus aureus 0.5-2 1-6. S. epidermidis 0.25-1.6 0.5-3.1 S. saprophyticus 0.8-2 1.6-4 Oxacillin-resistant S. 0.1-4 1-12.5 aureus Streptococcus pneumoniae 2-8 8-16 Group A streptococci 1-6.25 2-32 Group B streptococci 1.6-16 4-32 Groups C and G 0.8-8 3.1-32 streptococci Viridans streptococci 4-8 8-32 Nonenterococcal group D 4 8-16 streptococci Enterococci 2-8 2-32

Gram-positive Aerobic Bacilli

Norfloxacin is active in vitro against Listeria monocytogenes, and the MIC90 of the drug reported for this organism is 2-16 mcg/mL. Norfloxacin is also active in vitro against Bacillus cereus and some strains of Corynebacterium. In studies that used a limited number of isolates, the MIC90 of norfloxacin was 4-8 mcg/mL for Corynebacterium jeikeium (JK strains of Corynebacterium) and 2-4 mcg/mL for Corynebacterium D2. Although some strains of Nocardia asteroides are inhibited in vitro by norfloxacin concentrations of 4 mcg/mL, the MIC90 of the drug for this organism is 64 mcg/mL.

Gram-negative Aerobic Bacteria

Neisseria Norfloxacin is active in vitro against Neisseria meningitidis and most strains of penicillinase- and nonpenicillinase-producing N. gonorrhoeae. The MIC90 of norfloxacin is 0.03-0.06 mcg/mL for N. meningitidis and 0.01-0. mcg/mL for penicillinase- or nonpenicillinase-producing N. gonorrhoeae.

Haemophilus

Norfloxacin is active in vitro against most b-lactamase- and non-b-lactamase-producing Haemophilus influenzae, and the MIC90 of the drug reported for these organisms is 0.02-1. mcg/mL. Norfloxacin is also active in vitro against H. ducreyi, and the MIC90 of the drug for this organism is 0.06 mcg/mL.

Moraxella catarrhalis

Norfloxacin is active in vitro against both b-lactamase- and non-b-lactamase-producing strains of Moraxella catarrhalis. The MIC90 of the drug for these organisms is generally 0.12-0. mcg/mL, although an MIC90 of 4 mcg/mL has been reported.

Enterobacteriaceae

Norfloxacin is active in vitro against most clinically important Enterobacteriaceae, and the MIC90 of the drug for susceptible Enterobacteriaceae is usually 4 mcg/mL or less. Norfloxacin is active in vitro against some Enterobacteriaceae resistant to aminoglycosides and/or b-lactam antibiotics. The following table includes MIC50s and MIC90s of norfloxacin reported for Enterobacteriaceae: Organism MIC50 (mcg/mL) MIC90 (mcg/mL) Citrobacter spp. 0.03-0.4 0.12-1. C. diversus 0.03-0.15 0.05-0.5 C. freundii 0.02-0.4 0.06-6.25 Edwardsiella tarda 0.06 0.06 Enterobacter spp. 0.03-0.25 0.10-1 E. agglomerans 0.06-0.2 0.20-4 E. cloacae 0.05-0. 0.06-3.1 E. aerogenes 0.06-0. 0.12-0.5 Escherichia coli 0.02-0.13 0.03-1 Hafnia alvei 0.03 0.06 Klebsiella spp. 0.06-0.5 0.50-1.6 K. oxytoca 0.05-0.2 0.06-0.4 K. pneumoniae 0.06-0.25 0.25-1.6 Morganella morganii 0.02-0.13 0.02-1 Proteus mirabilis 0.02-0.25 0.06-3.1 P. vulgaris 0.03-0.13 0.03-2 Providencia spp. 0.06-0.5 0.25-2.5 P. rettgeri 0.03-0.13 0.06-4 P. stuartii 0.05-1 0.06-4 Serratia spp. 0.13-1 0.50-16 S. marcescens 0.06-3.1 0.50-4 Salmonella spp. 0.01-0.5 0.06-1 S. enteritidis 0.03-0.13 0.06-0.25 S. typhi 0.03-0. 0.06-0.12 Shigella spp. 0.02-0.5 0.03-0.13 Yersinia enterocolitica 0.02-0.1 0.03-0.13

Pseudomonas

Norfloxacin is active in vitro against most strains of Pseudomonas aeruginosa, including some aminoglycoside-resistant strains. The MIC50 and MIC90 of norfloxacin reported for Ps. aeruginosa are 0.25-2 and 0.5-8 mcg/mL, respectively. Norfloxacin is also active in vitro against some Pseudomonas other than Ps. aeruginosa. The MIC90 of norfloxacin for Ps. acidovorans, Ps. fluorescens, Ps. putida, and Ps. stutzeri is 0.5-4 mcg/mL. Although some strains of Ps. cepacia and Xanthomonas maltophilia (Ps. maltophilia) are inhibited in vitro by norfloxacin concentrations of 3.1-16 mcg/mL, the MIC90 for these organisms is generally greater than 16 mcg/mL and most strains are considered resistant to the drug.

Vibrio

Norfloxacin is active in vitro against most pathogenic strains of Vibrio. The MIC90 of the drug reported for V. cholerae and V. parahaemolyticus is 0.015-0.5 mcg/mL. In a study that used a limited number of isolates, V. alginolyticus, V. damsela, V. fluvialis, V. furnissii, V. hollisae, V. mimicus, and V. vulnificus were inhibited in vitro by norfloxacin concentrations of 0.03-0.25 mcg/mL.

Other Gram-negative Aerobic Bacteria

Norfloxacin has some activity in vitro against Acinetobacter. The MIC90 of the drug is usually 4-16 mcg/mL for A. lwoffii (A. calcoaceticus subsp. lwoffii) and 4-32 mcg/mL for A. baumannii (A. calcoaceticus subsp. anitratus).

Aeromonas hydrophila and Plesiomonas shigelloides are generally inhibited in vitro by norfloxacin concentrations of 0.015-0.5 mcg/mL. Some strains of Alcaligenes faecalis are inhibited in vitro by norfloxacin concentrations of 3.13-4 mcg/mL. Norfloxacin is active in vitro against some strains of Campylobacter fetus subsp. jejuni, an organism that can be microaerophilic or anaerobic; the MIC90 of the drug for this organism is 0.25-4 mcg/mL. The MIC90 of norfloxacin for Helicobacter pylori (formerly C. pylori or C. pyloridis) reportedly is 1 mcg/mL.

Norfloxacin has some in vitro activity against Bordetella pertussis, and the MIC90 of the drug reported for this organism is 8 mcg/mL. Brucella melitensis is inhibited in vitro by norfloxacin concentrations of 8 mcg/mL. The MIC90 of norfloxacin for Eikenella corrodens is reportedly 0.06 mcg/mL.

Norfloxacin also has some activity in vitro against Flavobacterium. Some strains of Gardnerella vaginalis (formerly Haemophilus vaginalis) are inhibited in vitro by norfloxacin concentrations of 2-16 mcg/mL. In vitro, norfloxacin concentrations of 0.125-2 mcg/mL generally inhibit Legionella pneumophila, and concentrations of 0.04-0.25 mcg/mL generally inhibit L. bozemanii, L. dumoffii, L. gormanii, L. jordanis, L. micdadei (the Pittsburgh pneumonia agent), and L. wadsworthii. Norfloxacin is active in vitro against Moraxella and Pasteurella multocida, and these organisms are usually inhibited by concentrations of 0.016-2 and 0.06-0.13 mcg/mL, respectively.

Anaerobic Bacteria

Norfloxacin has only limited activity against gram-positive or gram-negative anaerobic bacteria. The MIC90 of norfloxacin reported for Peptococcus and Peptostreptococcus is 4-16 mcg/mL. Some strains of Clostridium perfringens are inhibited in vitro by norfloxacin concentrations of 1-2 mcg/mL, but other Clostridium, including C. difficile, are generally resistant to the drug. Eubacterium are generally resistant to norfloxacin. The MIC90 of norfloxacin reported for Veillonella is 1-8 mcg/mL. Although some strains of Fusobacterium may be inhibited in vitro by norfloxacin concentrations of 6.25-16 mcg/mL, most strains are resistant to the drug. Bacteroides, including B. fragilis, are generally resistant to norfloxacin.

Chlamydia and Mycoplasma

Norfloxacin has some activity in vitro against Chlamydia trachomatis, but the drug may not be effective clinically. C. trachomatis are generally inhibited in vitro by norfloxacin concentrations of 8-32 mcg/mL; however, in one study, both the MIC and minimum lethal concentration (MLC) of norfloxacin for this organism were 50 mcg/mL. Norfloxacin has some activity in vitro against Mycoplasma hominis and M. pneumoniae. In one study, the initial MIC90 of norfloxacin for M. pneumoniae was 12. mcg/mL and the final MIC90 (measured 14-20 days later) was 25 mcg/mL. Ureaplasma urealyticum is generally inhibited in vitro by norfloxacin concentrations of 8-32 mcg/mL, but the minimum bactericidal concentration (MBC) of the drug for this organism is greater than 64 mcg/mL.

Mycobacterium

Although the clinical importance has not been determined, norfloxacin is active in vitro against some Mycobacterium. The MIC90 of norfloxacin reported for M. tuberculosis and for M. fortuitum is 2-8 mcg/mL. The MIC90 of norfloxacin for M. kansasii is 4 to greater than 16 mcg/mL, and for M. chelonei and M. avium complex is usually greater than 16 mcg/mL. Resistance Resistance to norfloxacin can be produced in vitro in some strains of Enterobacteriaceae and Pseudomonas aeruginosa by serial passage in the presence of increasing concentrations of the drug or other fluoroquinolones (e.g., ciprofloxacin).

Norfloxacin resistance resulting from spontaneous mutation occurs rarely in vitro (i.e., with a frequency of 10-12 to 10-9). Resistance to norfloxacin has developed during therapy with the drug in less than 1% of patients. The development of norfloxacin resistance during therapy has been reported most frequently in Acinetobacter, enterococci, Klebsiella pneumoniae, and Ps. aeruginosa.

Strains of Neisseria gonorrhoeae with decreased susceptibility to norfloxacin and other fluoroquinolones have been reported within the last several years. 336 Strains of N. gonorrhoeae with decreased susceptibility to fluoroquinolones are endemic in many Asian countries and have been reported sporadically in other parts of the world, including North America, Australia, Africa, and Great Britain. In the US, strains with decreased susceptibility to fluoroquinolones have been isolated from patients in Hawaii, Ohio, Oregon, California, and Washington. In some cases, these isolates appeared to have been introduced into the US by travelers returning from the Philippines; however, in Ohio, these strains appeared to have been transmitted locally and were not linked to travel outside the US. The recent increase in fluoroquinolone-resistant N. gonorrhoeae in Hawaii also appears to be the result of endemic spread.

The clinical importance of reduced susceptibility to fluoroquinolones has not been fully determined, and it is unclear whether uncomplicated gonococcal infections caused by these strains respond to currently recommended single-dose fluoroquinolone regimens. Treatment failures have been reported with the currently recommended single-dose regimens.Strains of N. gonorrhoeae with decreased susceptibility to one fluoroquinolone also have decreased susceptibility to other fluoroquinolones (e.g., ciprofloxacin, lomefloxacin, norfloxacin, ofloxacin), but may be susceptible to ceftriaxone, cefixime, and spectinomycin.)

The mechanism(s) of resistance to norfloxacin has not been fully elucidated. Resistance to the drug in some organisms (e.g., Serratia) appears to result from mutations that alter the A subunits of DNA gyrase. Resistance in other organisms (e.g., Escherichia coli, Ps. aeruginosa) also may be related to alterations in outer-membrane porin proteins and/or other factors that affect permeability of the organism to the drug. There is no evidence that resistance to norfloxacin is plasmid mediated.

Cross-resistance can occur between norfloxacin and other fluoroquinolones. Cross-resistance generally does not occur between norfloxacin and other anti-infectives, including aminoglycosides, b-lactam antibiotics, sulfonamides (including co-trimoxazole), macrolides, and tetracyclines.

However, rare strains of Enterobacter, Klebsiella pneumoniae, and Ps. aeruginosa resistant to norfloxacin have also been resistant to b-lactam antibiotics. In addition, some strains of norfloxacin-resistant E. coli produced in vitro were also resistant to cefoxitin, chloramphenicol, and tetracycline. Resistance in these mutants appeared to result from decreased permeability of the organism to the drug, principally because of alterations in outer-membrane porin proteins; however, other mechanisms that affect permeability may also be involved.

Pharmacokinetics

Absorption

Norfloxacin is rapidly, but incompletely, absorbed from the GI tract following oral administration. Presence of food in the GI tract may decrease the rate of absorption of the drug. Absorption appears to be unaffected by decreasing renal function. Antacids containing magnesium hydroxide or aluminum hydroxide decrease the oral bioavailability of norfloxacin. In healthy, fasting adults, at least 30-50% of an oral dose of norfloxacin is absorbed from the GI tract, and peak plasma or serum concentrations of the drug are generally attained within 1-2 hours.

Following oral administration in healthy, fasting adults, peak plasma or serum norfloxacin concentrations average 0.75-1 mcg/mL following a single 200-mg dose and 1.3-1. mcg/mL following a single 400-mg dose; plasma or serum concentrations of the drug are still detectable 12 hours after the dose.

Following oral administration of a single 800-, 1200-, or 1600-mg dose of norfloxacin in healthy, fasting adults, peak serum norfloxacin concentrations average 2.4, 3.2, or 3.9 mcg/mL, respectively. Multiple-dose studies in adults with normal renal function indicate that peak serum concentrations of norfloxacin do not increase after repeated dosing and that the drug apparently does not accumulate. Steady-state serum concentrations of norfloxacin are attained by the second day of therapy.

Distribution

There is limited information on the distribution of norfloxacin. Following oral administration in adults, norfloxacin is distributed into renal parenchyma, gallbladder, liver, prostatic tissue, testicles, seminal fluid, uterus, fallopian tubes, cervical and vaginal tissue, blister fluid, tonsils, maxillary sinus mucosa, sputum, and bile.

Biliary concentrations of norfloxacin may be up to 10 times higher than concurrent serum concentrations. In cholecystectomy patients who received a single 400-mg oral dose of norfloxacin prior to surgery, concentrations of the drug ranged from 0.6-15.6 mcg/mL in gallbladder bile, from 0.4-7.5 mcg/g in gallbladder tissue, and from 0.4-1. mcg/mL in serum in specimens obtained approximately 3.5-6 hours after the dose. In adults who received 400 mg of oral norfloxacin twice daily, prostatic tissue concentrations of the drug ranged from 0.24-4.65 mcg/g in specimens obtained 1-4 hours after the second dose; concurrent serum concentrations ranged from 0.42-5.3 mcg/mL. Norfloxacin is 10-15% bound to serum proteins.

Norfloxacin crosses the placenta and is distributed into cord blood and amniotic fluid. It is not known whether the drug is distributed into milk.

Norfloxacin was not detected in the milk of lactating women following a single 200-mg oral dose of the drug, but the possibility of distribution into milk following higher doses remains to be determined. Some other quinolones (e.g., ciprofloxacin, ofloxacin, pefloxacin) are distributed into milk.

Elimination

The effective plasma or serum half-life of norfloxacin in adults with normal renal function is 2.3-4 hours. The effective half-life of the drug averages 4 hours in geriatric individuals 65-75 years of age with renal function normal for their age. In patients with impaired renal function, serum concentrations of norfloxacin are higher and its half-life is prolonged. In adults with renal impairment, the half-life of norfloxacin averaged 4.4, 6.6, or 7.6 hours in adults with creatinine clearances of 30-80, 10-29, or less than 10 mL/minute per 1.73 m, respectively.

Limited data suggest that half-life of the drug is not substantially affected by hepatic impairment. Norfloxacin is eliminated by renal and nonrenal mechanisms. The drug is partially metabolized by modification of the piperazinyl group to 6 metabolites, designated M-1, M-2, M-3, M-4[1], M-4[2], and M-5. Although some of the metabolites are microbiologically active, they are less active than the parent drug. It has been suggested that norfloxacin undergoes first-pass metabolism in the liver, but further study is needed to fully elucidate the metabolic fate of the drug. Norfloxacin and its metabolites are excreted in urine, with unchanged norfloxacin being excreted by both glomerular filtration and tubular secretion. Norfloxacin is also excreted in feces, apparently mainly as unabsorbed drug and, to a small extent, via biliary elimination.

Following oral administration of a single 400-mg dose of norfloxacin in adults with normal renal function, approximately 25-40% of the dose is excreted in urine as unchanged drug and 5-10% as metabolites within 24-48 hours, and at least 30% (range: 10-50%) is excreted in feces within 48 hours. Renal clearance of norfloxacin averages 234-296 mL/minute in adults with normal renal function. Urinary concentrations of norfloxacin are generally 200 mcg/mL or greater 2-3 hours after a single 400-mg oral dose of the drug in adults with normal renal function; urinary concentrations remain greater than 30 mcg/mL for at least 12 hours after the dose.

Following oral administration of a single 400-mg dose in healthy adults with normal renal function, urinary norfloxacin concentrations average 417, 46.9, and 22.5 mcg/mL in urine collected over 1-2, 8-12, and 12-24 hours, respectively, after the dose. Following oral administration of a single 400-mg dose of norfloxacin, antimicrobial activity expressed in norfloxacin equivalents averaged 278, 773, and 82 mcg/g of feces at 12, 24, and 48 hours, respectively, after the dose.

Mean fecal concentrations (determined by microbiologic assay) of norfloxacin and active metabolites were 950 mg/g of feces (range: 440-1900 mg/g) following oral administration of 200 mg of the drug twice daily in healthy adults. Norfloxacin does not appear to be removed by hemodialysis, but it is not known whether the drug is removed by peritoneal dialysis.

Chemistry and Stability

Chemistry

Norfloxacin is a fluoroquinolone anti-infective agent. Like other commercially available fluoroquinolones, norfloxacin contains a fluorine atom at position 6 of the quinolone nucleus. Like some other fluoroquinolones (ciprofloxacin, gatifloxacin, levofloxacin, lomefloxacin, ofloxacin, sparfloxacin), norfloxacin contains a piperazinyl group at position 7.1, 2, 17, 18, 19, 104 The piperazinyl group in norfloxacin results in antipseudomonal activity.

Norfloxacin occurs as a white to pale yellow, crystalline powder. The drug is very slightly soluble in water and in alcohol, having solubilities of approximately 0.28 mg/mL and 1.9 mg/mL, respectively, at 25°C. Although norfloxacin is relatively insoluble in aqueous solutions with neutral pH, it is generally soluble in solutions with acidic or basic pH. Solubility of norfloxacin in urine depends on pH and temperature.

The drug is least soluble in urine at pH 7.5, having maximum solubilities of about 0.45 and 1.2 mg/mL at 25° and 37°C, respectively, at this pH. At 37°C, the solubility of the drug in urine is greater than 40 mg/mL at pH 5.5 or less and approximately 2.8, 1.5, and 1.9 mg/mL at pH 6.5, 7, and 8, respectively. Norfloxacin has pKas of 6.34 and 8.75.

Stability

Norfloxacin tablets should be stored in tight containers at 25°C, but may be exposed to temperatures ranging from 15-30°C.

Preparations

Norfloxacin Oral Tablets, film- 400 mg Noroxin®, coated Merck

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