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Noroxin

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Noroxin

CLINICAL PHARMACOLOGY

In fasting healthy volunteers, at least 30-40% of an oral dose of NOROXIN is absorbed. Absorption is rapid following single doses of 200 mg, 400 mg and 800 mg. At the respective doses, mean peak serum and plasma concentrations of 0.8, 1.5 and 2.4 μg/mL are attained approximately one hour after dosing. The presence of food and/or dairy products may decrease absorption. The effective half-life of norfloxacin in serum and plasma is 3-4 hours. Steady-state concentrations of norfloxacin will be attained within two days of dosing.

In healthy elderly volunteers (65-75 years of age with normal renal function for their age), norfloxacin is eliminated more slowly because of their slightly decreased renal function. Following a single 400-mg dose of norfloxacin, the mean (± SD) AUC and Cmax of 9.8 (2.83) μg•hr/mL and 2.02 (0.77) μg/mL, respectively, were observed in healthy elderly volunteers. The extent of systemic exposure was slightly higher than that seen in younger adults (AUC 6.4 μg•hr/mL and Cmax 1.5 μg/mL). Drug absorption appears unaffected. However, the effective half-life of norfloxacin in these elderly subjects is 4 hours.

There is no information on accumulation of norfloxacin with repeated administration in elderly patients. However, no dosage adjustment is required based on age alone. In elderly patients with reduced renal function, the dosage should be adjusted as for other patients with renal impairment (see DOSAGE AND ADMINISTRATION, Renal Impairment).

The disposition of norfloxacin in patients with creatinine clearance rates greater than 30 mL/min/1.73 m² is similar to that in healthy volunteers. In patients with creatinine clearance rates equal to or less than 30 mL/min/1.73 m², the renal elimination of norfloxacin decreases so that the effective serum half-life is 6.5 hours. In these patients, alteration of dosage is necessary (see DOSAGE AND ADMINISTRATION). Drug absorption appears unaffected by decreasing renal function.

Norfloxacin is eliminated through metabolism, biliary excretion, and renal excretion. After a single 400-mg dose of NOROXIN, mean antimicrobial activities equivalent to 278, 773, and 82 μg of norfloxacin/g of feces were obtained at 12, 24, and 48 hours, respectively. Renal excretion occurs by both glomerular filtration and tubular secretion as evidenced by the high rate of renal clearance (approximately 275 mL/min). Within 24 hours of drug administration, 26 to 32% of the administered dose is recovered in the urine as norfloxacin with an additional 5-8% being recovered in the urine as six active metabolites of lesser antimicrobial potency. Only a small percentage (less than 1%) of the dose is recovered thereafter. Fecal recovery accounts for another 30% of the administered dose. In elderly subjects (average creatinine clearance 91 mL/min/1.73 m²) approximately 22% of the administered dose was recovered in urine and renal clearance averaged 154 mL/min.

Two to three hours after a single 400-mg dose, urinary concentrations of 200 μg/mL or more are attained in the urine. In healthy volunteers, mean urinary concentrations of norfloxacin remain above 30 μg/mL for at least 12 hours following a 400-mg dose. The urinary pH may affect the solubility of norfloxacin. Norfloxacin is least soluble at urinary pH of 7.5 with greater solubility occurring at pHs above and below this value. The serum protein binding of norfloxacin is between 10 and 15%.

The following are mean concentrations of norfloxacin in various fluids and tissues measured 1 to 4 hours post-dose after two 400-mg doses, unless otherwise indicated:

Renal Parenchyma 7.3 μg/g
Prostate 2.5 μg/g
Seminal Fluid 2.7 μg/mL
Testicle 1.6 μg/g
Uterus/Cervix 3.0 μg/g
Vagina 4.3 μg/g
Fallopian Tube 1.9 μg/g
Bile 6.9 μg/mL (after two 200-mg doses)

Microbiology

Mechanism of Action

Norfloxacin inhibits bacterial deoxyribonucleic acid synthesis and is bactericidal. At the molecular level, three specific events are attributed to norfloxacin in E. coli cells:

  1. inhibition of the ATP-dependent DNA supercoiling reaction catalyzed by DNA gyrase,
  2. inhibition of the relaxation of supercoiled DNA,
  3. promotion of double-stranded DNA breakage.

The fluorine atom at the 6 position provides increased potency against gram-negative organisms, and the piperazine moiety at the 7 position is responsible for antipseudomonal activity.

Drug Resistance

Resistance to norfloxacin due to spontaneous mutation in vitro is a rare occurrence (range: 10-9 to 10-12 cells). Resistant organisms have emerged during therapy with norfloxacin in less than 1% of patients treated. Organisms in which development of resistance is greatest are the following:

Pseudomonas aeruginosa
Klebsiella pneumoniae

Acinetobacter
spp.
Enterococcus
spp.

For this reason, when there is a lack of satisfactory clinical response, repeat culture and susceptibility testing should be done. Nalidixic acid-resistant organisms are generally susceptible to norfloxacin in vitro; however, these organisms may have higher minimum inhibitory concentrations (MICs) to norfloxacin than nalidixic acid-susceptible strains. There is generally no cross-resistance between norfloxacin and other classes of antibacterial agents. Therefore, norfloxacin may demonstrate activity against indicated organisms resistant to some other antimicrobial agents including the aminoglycosides, penicillins, cephalosporins, tetracyclines, macrolides, and sulfonamides, including combinations of sulfamethoxazole and trimethoprim. Antagonism has been demonstrated in vitro between norfloxacin and nitrofurantoin.

Activity in vitro and in vivo

Norfloxacin has in vitro activity against a broad range of gram-positive and gram-negative aerobic bacteria.

Norfloxacin has been shown to be active against most strains of the following microorganisms both in vitro and in clinical infections as described in the INDICATIONS AND USAGE section.

Gram-positive aerobes

Enterococcus faecalis
Staphylococcus aureus

Staphylococcus epidermidis

Staphylococcus saprophyticus

Streptococcus agalactiae

Gram-negative aerobes

Citrobacter freundii
Enterobacter aerogenes

Enterobacter cloacae

Escherichia coli

Klebsiella pneumoniae

Neisseria gonorrhoeae

Proteus mirabilis

Proteus vulgaris

Pseudomonas aeruginosa

Serratia marcescens

The following in vitro data are available, but their clinical significance is unknown.

Norfloxacin exhibits in vitro MICs of ≤ 4 μg/mL against most ( ≥ 90%) strains of the following microorganisms; however, the safety and effectiveness of norfloxacin in treating clinical infections due to these microorganisms have not been established in adequate and well-controlled clinical trials.

Gram-negative aerobes

Citrobacter diversus
Edwardsiella tarda

Enterobacter agglomerans

Haemophilus ducreyi

Klebsiella oxytoca

Morganella morganii

Providencia alcalifaciens

Providencia rettgeri

Providencia stuartii

Pseudomonas fluorescens

Pseudomonas stutzeri

Other

Ureaplasma urealyticum

NOROXIN is not generally active against obligate anaerobes.

Norfloxacin has not been shown to be active against Treponema pallidum (see WARNINGS).

Susceptibility Tests

Dilution Techniques

Quantitative methods are used to determine antimicrobial 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 method1 (broth, agar, or microdilution) or equivalent with standardized inoculum concentrations and standardized concentrations of norfloxacin powder. The MIC values should be interpreted according to the criteria outlined 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. One such standardized procedure2 requires the use of standardized inoculum concentrations. This procedure uses paper disks impregnated with 10-μg norfloxacin to test the susceptibility of microorganisms to norfloxacin. Reports from the laboratory providing results of the standard single-disk susceptibility test with a 10-μg norfloxacin disk should be interpreted according to the criteria outlined in Table 1. Interpretation involves correlation of the diameter obtained in the disk test with the MIC for norfloxacin.

Table 1: Susceptibility Interpretive Criteria for Norfloxacin

MIC (μg/mL) Zone Diameter (mm)
S I R S I R
≤ 4 8 ≥ 16 ≥ 17 13-16 ≤ 12
These interpretative criteria apply only to isolates from urinary tract infections. There are no established norfloxacin interpretive criteria for Neisseria gonorrhoeae or organisms isolated from other infection sites.
S=Susceptible, I=Intermediate, and R=Resistant

A report of “Susceptible” indicates that the pathogen is likely to be inhibited if the antimicrobial compound in the blood 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 blood reaches the concentrations usually achievable; other therapy should be selected.

Quality Control

Standardized susceptibility test procedures require the use of laboratory control microorganisms to control the technical aspects of the laboratory procedures. Standard norfloxacin powder should provide the MIC values outlined in Table 2. For the diffusion techniques, the 10-μg norfloxacin disk should provide the zone diameters outlined in Table 2.

Table 2: Quality Control for Susceptibility Testing

Strains MIC Range (μg/mL) Zone Diameter (mm)
Enterococcus faecalis (ATCC 29212) 2 – 8 Not applicable
Escherichia coli (ATCC 25922) 0.03 – 0.12 28 – 35
P. aeruginosa (ATCC 27853) 1 – 4 22 – 29
Staphylococcus aureus (ATCC 29213) 0.5 – 2 Not applicable
Staphylococcus aureus (ATCC 25923) Not applicable 17 – 28

Animal Pharmacology

Norfloxacin and related drugs have been shown to cause arthropathy in immature animals of most species tested (see WARNINGS).

Crystalluria has occurred in laboratory animals tested with norfloxacin. In dogs, needle-shaped drug crystals were seen in the urine at doses of 50 mg/kg/day. In rats, crystals were reported following doses of 200 mg/kg/day.

Embryo lethality and slight maternotoxicity (vomiting and anorexia) were observed in cynomolgus monkeys at doses of 150 mg/kg/day or higher.

Ocular toxicity, seen with some related drugs, was not observed in any norfloxacin-treated animals. 13

REFERENCES

1. Clinical and Laboratory Standards Institute, Methods for dilution antimicrobial susceptibility tests for bacteria that grow aerobically - Eighth edition, Approved Standard CLSI Document M7-A8, Vol. 29, No. 2, CLSI, Wayne, PA, 2009.

2. Clinical and Laboratory Standards Institute, Performance standards for antimicrobial disk susceptibility tests - Tenth edition, Approved Standard CLSI Document M2-A10, Vol. 29, No. 1, CLSI, Wayne, PA, 2009.

Last reviewed on RxList: 8/26/2013
This monograph has been modified to include the generic and brand name in many instances.

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