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Maxaquin

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CLINICAL PHARMACOLOGY

Pharmacokinetics in healthy volunteers

In 6 fasting healthy male volunteers, approximately 95% to 98% of a single oral dose of lomefloxacin was absorbed. Absorption was rapid following single doses of 200 and 400 mg (Tmax 0.8 to 1.4 hours). Mean plasma concentration increased proportionally between 100 and 400 mg as shown below:

Dose (mg) Mean Peak Plasma Concentration (Mg/mL) Area Under Curve (AUC) (Mgh/mL)
100 0.8 5.6
200 1.4 10.9
400 3.2 26.1

In 6 healthy male volunteers administered 400 mg of lomefloxacin on an empty stomach qd for 7 days, the following mean pharmacokinetic parameter values were obtained:

C max 2.8 μg/mL
Cmin 0.27 μg/mL
AUC0-24 h 25.9 μg-h/mL
Tmax 1.5 h
7.75 h

The elimination half-life in 8 subjects with normal renal function was approximately 8 hours. At 24 hours postdose, subjects with normal renal function receiving single doses of 200 or 400 mg had mean plasma lomefloxacin concentrations of 0.10 and 0.24 μ g/mL, respectively. Steady-state concentrations were achieved within 48 hours of initiating therapy with one-a-day dosing. There was no drug accumulation with single-daily dosing in patients with normal renal function.

Approximately 65% of an orally administered dose was excreted in the urine as unchanged drug in patients with normal renal function. Following a 400-mg dose of lomefloxacin administered qd for 7 days, the mean urine concentration 4 hours postdose was in excess of 300 μ g/mL. The mean urine concentration exceeded 35 μ g/mL for at least 24 hours after dosing.

Following a single 400-mg dose, the solubility of lomefloxacin in urine usually exceeded its peak urinary concentration 2- to 6-fold. In this study, urine pH affected the solubility of lomefloxacin with solubilities ranging from 7.8 mg/mL at pH 5.2, to 2.4 mg/mL at pH 6.5, and 3.03 mg/mL at pH 8.12.

The urinary excretion of lomefloxacin was virtually complete within 72 hours after cessation of dosing, with approximately 65% of the dose being recovered as parent drug and 9% as its glucuronide metabolite. The mean renal clearance was 145 mL/min in subjects with normal renal function (GFR = 120 mL/min). This may indicate tubular secretion.

Food effect

When lomefloxacin and food were administered concomitantly, the rate of drug absorption was delayed (Tmax increased to 2 hours [delayed by 41%], Cmax decreased by 18%), and the extent of absorption (AUC) was decreased by 12%.

Pharmacokinetics in the geriatric population

In 16 healthy elderly volunteers (61 to 76 years of age) with normal renal function for their age, the half-life of lomefloxacin (mean of 8 hours) and its peak plasma concentration (mean of 4.2 μ g/mL) following a single 400-mg dose were similar to those in 8 younger subjects dosed with a single 400-mg dose. Thus, drug absorption appears unaffected in the elderly. Plasma clearance was, however, reduced in this elderly population by approximately 25%, and the AUC was increased by approximately 33%. This slower elimination most likely reflects the decreased renal function normally observed in the geriatric population.

Pharmacokinetics in renally impaired patients

In 8 patients with creatinine clearance (ClCr) between 10 and 40 mL/min/1.73 m², the mean AUC after a single 400-mg dose of lomefloxacin increased 335% over the AUC demonstrated in patients with a ClCr > 80 mL/min/1.73 m². Also, in these patients, the mean t½ increased to 21 hours. In 8 patients with ClCr < 10 mL/min/1.73 m², the mean AUC after a single 400-mg dose of lomefloxacin increased 700% over the AUC demonstrated in patients with a ClCr > 80 mL/min/1.73 m². In these patients with ClCr < 10 mL/min/1.73 m², the mean t½ increased to 45 hours. The plasma clearance of lomefloxacin was closely correlated with creatinine clearance, ranging from 31 mL/min/1.73 m² when creatinine clearance was zero to 271 mL/min/1.73 m² at a normal creatinine clearance of 110 mL/min/1.73 m². Peak lomefloxacin concentrations were not affected by the degree of renal function when single doses of lomefloxacin were administered. Adjustment of dosage schedules for patients with such decreases in renal function is warranted. (See DOSAGE AND ADMINISTRATION.)

Pharmacokinetics in patients with cirrhosis

In 12 patients with histologically confirmed cirrhosis, no significant changes in rate or extent of lomefloxacin exposure (Cmax, Tmax, t½, or AUC) were observed when they were administered 400 mg of lomefloxacin as a single dose. No data are available in cirrhotic patients treated with multiple doses of lomefloxacin. Cirrhosis does not appear to reduce the nonrenal clearance of lomefloxacin.

There does not appear to be a need for a dosage reduction in cirrhotic patients, provided adequate renal function is present.

Metabolism and pharmacodynamics of lomefloxacin

Lomefloxacin is minimally metabolized although 5 metabolites have been identified in human urine. The glucuronide metabolite is found in the highest concentration and accounts for approximately 9% of the administered dose. The other 4 metabolites together account for < 0.5% of the dose.

Approximately 10% of an oral dose was recovered as unchanged drug in the feces.

Serum protein binding of lomefloxacin is approximately 10%.

The following are mean tissue- or fluid-to-plasma ratios of lomefloxacin following oral administration. Studies have not been conducted to assess the penetration of lomefloxacin into human cerebrospinal fluid.

Tissue or Body Fluid Mean Tissue- or Fluid-to-Plasma Ratio
Bronchial mucosa 2.1
Bronchial secretions 0.6
Prostatic tissue 2.0
Sputum 1.3
Urine 140.0

In two studies including 74 healthy volunteers, the minimal dose of UVA light needed to cause erythema (MED-UVA) was inversely proportional to plasma lomefloxacin concentration. The MED-UVA values (16 hours and 12 hours postdose) were significantly higher than the MED-UVA values 2 hours postdose at steady state. Increasing the interval between lomefloxacin dosing and exposure to UVA light increased the amount of light energy needed for photoreaction. In a study of 27 healthy volunteers, the steady state AUC values and Cmin values were equivalent whether the drug was administered in the morning or in the evening.

Microbiology

Lomefloxacin is a bactericidal agent with in vitro activity against a wide range of gram-negative and gram-positive organisms. The bactericidal action of lomefloxacin results from interference with the activity of the bacterial enzyme DNA gyrase, which is needed for the transcription and replication of bacterial DNA. The minimum bactericidal concentration (MBC) generally does not exceed the minimum inhibitory concentration (MIC) by more than a factor of 2, except for staphylococci, which usually have MBCs 2 to 4 times the MIC.

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

Gram-positive aerobes

Staphylococcus saprophyticus

Gram-negative aerobes

Citrobacter diversus
Enterobacter cloacae

Escherichia coli

Haemophilus influenzae

Klebsiella pneumoniae

Moraxella catarrhalis

Proteus mirabilis

Pseudomonas aeruginosa
(urinary tract only—See INDICATIONS AND USAGE and WARNINGS)

The following in vitro data are available; however, their clinical significance is unknown. Lomefloxacin exhibits in vitro MICs of 2 μ g/mL or less against most strains of the following organisms; however, the safety and effectiveness of lomefloxacin in treating clinical infections due to these organisms have not been established in adequate and well controlled trials:

Gram-positive aerobes

Staphylococcus aureus (including methicillin-resistant strains)
Staphylococcus epidermidis (including methicillin-resistant strains)

Gram-negative aerobes

Aeromonas hydrophila
Citrobacter freundii

Enterobacter aerogenes

Enterobacter agglomerans

Haemophilus parainfluenzae

Hafnia alvei

Klebsiella oxytoca

Klebsiella ozaenae

Morganella morganii

Proteus vulgaris

Providencia alcalifaciens

Providencia rettgeri

Serratia liquefaciens

Serratia marcescens

Other organisms

Legionella pneumophila

Beta-lactamase production should have no effect on the in vitro activity of lomefloxacin.

Most group A, B, D, and G streptococci, Streptococcus pneumoniae, Pseudomonas cepacia, Ureaplasma urealyticum, Mycoplasma hominis, and anaerobic bacteria are resistant to lomefloxacin.

Lomefloxacin appears slightly less active in vitro when tested at acidic pH. An increase in inoculum size has little effect on the in vitro activity of lomefloxacin. In vitro resistance to lomefloxacin develops slowly (multiple-step mutation). Rapid one-step development of resistance occurs only rarely ( < 10–9) in vitro.

Cross-resistance between lomefloxacin and other quinolone-class antimicrobial agents has been reported; however, cross-resistance between lomefloxacin and members of other classes of antimicrobial agents, such as aminoglycosides, penicillins, tetracyclines, cephalosporins, or sulfonamides has not yet been reported. Lomefloxacin is active in vitro against some strains of cephalosporin- and aminoglycoside-resistant gram-negative bacteria.

Susceptibility tests

Diffusion techniques

Quantitative methods that require measurement of zone diameters give the most precise estimate of the susceptibility of bacteria to antimicrobial agents. One such standardized procedure1 that has been recommended for use with disks to test the susceptibility of organisms to lomefloxacin uses the 10-μ g lomefloxacin disk. Interpretation involves correlation of the diameter obtained in the disk test with the MIC for lomefloxacin.

Reports from the laboratory giving results of the standard single-disk susceptibility test with a 10-μ g lomefloxacin disk should be interpreted according to the following criteria:

Zone Diameter (mm) Interpretation
≥ 22 Susceptible (S)
19-21 Intermediate (I)
≤ 18 Resistant (R)

A report of “susceptible” indicates that the pathogen is likely to be inhibited by generally achievable drug concentrations. A report of “intermediate” indicates that the result should be considered equivocal, and, if the organism is not fully susceptible to alternative clinically feasible drugs, the test should be repeated. This category provides a buffer zone that prevents small uncontrolled technical factors from causing major discrepancies in interpretation. A report of “resistant” indicates that achievable drug concentrations are unlikely to be inhibitory, and other therapy should be selected.

Standardized susceptibility test procedures require the use of laboratory control organisms. The 10-μ g lomefloxacin disk should give the following zone diameters:

Organism Zone Diameter (mm)
S aureus (ATCC 25923) 23-29
E coli (ATCC 25922) 27-33
P aeruginosa (ATCC 27853) 22-28

Dilution techniques

Use a standardized dilution method2 (broth, agar, or microdilution) or equivalent with lomefloxacin powder. The MIC values obtained should be interpreted according to the following criteria:

MIC (μg/mL) Interpretation
≤ 2 Susceptible (S)
4 Intermediate (I)
≥ 8 Resistant (R)

As with standard diffusion techniques, dilution methods require the use of laboratory control organisms. Standard lomefloxacin powder should provide the following MIC values:

Organism MIC (μg/mL)
S aureus (ATCC 29213) 0.25-2.0
E coli (ATCC 25922) 0.03-0.12
P aeruginosa (ATCC 27853) 1.0-4.0

Clinical Studies—Uncomplicated Cystitis

In three controlled clinical studies of uncomplicated cystitis in females, two performed in the United States and one in Canada, lomefloxacin was compared to other oral antimicrobial agents. In these studies, using very strict evaluability criteria and microbiological criteria at 5–9 days posttherapy follow-up, the following bacterial eradication outcomes were obtained:

Studies 1, 2, and 3

U.S. AND CANADIAN STUDIES
  Lomefloxacin 3-Day Treatment Norfloxacin 3-Day Treatment Ofloxacin 3-Day Treatment Trimethoprim/ sulfamethoxazole 10-Day Treatment
E coli 133/135 (99%) 36/39 (92%) 65/67 (97%) 33/34 (97%)
K pneumoniae 7/7 (100%) 2/2 (100%) 4/4 (100%) 2/2 (100%)
P mirabilis 8/8 (100%) 1/1 (100%) 2/2 (100%) 1/1 (100%)
S saprophyticus 11/11 (100%) 3/3 (100%) 1/1 (100%) 0/0

Study 4

In a controlled clinical study of uncomplicated cystitis performed in Sweden, lomefloxacin 3-day treatment was compared with lomefloxacin 7-day treatment and norfloxacin 7-day treatment. In this study, using very strict evaluability criteria and microbiological criteria at 5–9 days post-therapy follow-up, the following bacterial eradication outcomes were obtained:

SWEDISH STUDY
  Lomefloxacin 3-Day Treatment Lomefloxacin 7-Day Treatment Norfloxacin 7-Day Treatment
E coli 101/109 (93%) 102/104 (98%) 108/110 (98%)
K pneumoniae 2/2 (100%) 5/5 (100%) 1/1 (100%)
P mirabilis 0/0 6/6 (100%) 4/4 (100%)
S saprophyticus 11/17 (65%) 23/23 (100%) 16/16 (100%)

Animal Pharmacology

Lomefloxacin and other quinolones have been shown to cause arthropathy in juvenile animals. Arthropathy, involving multiple diarthrodial joints, was observed in juvenile dogs administered lomefloxacin at doses as low as 4.5 mg/kg for 7 to 8 days (0.3 times the recommended human dose based on mg/m² or 0.6 times the recommended human dose based on mg/kg). In juvenile rats, no changes were observed in the joints with doses up to 91 mg/kg for 7 days (2 times the recommended human dose based on mg/m² or 11 times the recommended human dose based on mg/kg). (See WARNINGS.)

In a 13-week oral rat study, gamma globulin decreased when lomefloxacin was administered at less than the recommended human exposure. Beta globulin decreased when lomefloxacin was administered at 0.6 to 2 times the recommended human dose based on mg/m². The A/G ratio increased when lomefloxacin was administered at 6 to 20 times the human dose. Following a 4-week recovery period, beta globulins in the females and A/G ratios in the females returned to control values. Gamma globulin values in the females and beta and gamma globulins and A/G ratios in the males were still statistically significantly different from control values. No effects on globulins were seen in oral studies in dogs or monkeys in the limited number of specimens collected.

Twenty-seven NSAIDs, administered concomitantly with lomefloxacin, were tested for seizure induction in mice at approximately 2 times the recommended human dose based on mg/m². At a dose of lomefloxacin equivalent to the recommended human exposure based on mg/m² (10 times the human dose based on mg/kg), only fenbufen, when coadministered, produced an increase in seizures. Crystalluria and ocular toxicity, seen with some related quinolones, were not observed in any lomefloxacin-treated animals, either in studies designed to look for these effects specifically or in subchronic and chronic toxicity studies in rats, dogs, and monkeys.

Long-term, high-dose systemic use of other quinolones in experimental animals has caused lenticular opacities; however, this finding was not observed with lomefloxacin.

REFERENCES

1. National Committee for Clinical Laboratory Standards, Performance Standards for Antimicrobial Disk Susceptibility Tests—4th ed. Approved Standard NCCLS Document M2–A4, vol 10, No. 7, NCCLS, Villanova, Pa, 1990.

2. National Committee for Clinical Laboratory Standards. Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria that Grow Aerobically—2nd ed. Approved Standard NCCLS Document M7–A2, vol 10, No. 8, NCCLS, Villanova, Pa, 1990.

Last reviewed on RxList: 6/11/2012
This monograph has been modified to include the generic and brand name in many instances.

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