Prolevox Actions

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• Actions of Prolevox in details
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• Prolevox pharmacology
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Actions of Prolevox in details

Pharmacology: Mechanism of Action: The main mechanism of action of Prolevox is the inhibition of DNA gyrase. It is 2-fold stronger than that of ofloxacin. There is not much difference between the minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC). The activity of Prolevox is bactericidal. In the observation of bacterial morphology, bacteriolysis can be seen in the concentration around MIC.

Pharmacokinetics: Absorption:

Orally administered Prolevox is rapidly and almost completely absorbed with peak plasma concentrations being obtained within 1 hr. The absolute bioavailability is approximately 100%. Food has little effect on the absorption of Prolevox.

Distribution in Plasma: Approximately 30-40% of Prolevox is bound to serum protein. Multiple dosing with Prolevox 500 mg once daily showed neglible accumulation. There is modest but predictable accumulation of Prolevox after doses of 500 mg twice daily. Steady state is achieved within 3 days.

Penetration into Tissues and Body Fluids: Penetration into Bronchial Mucosa, Epithelial Lining Fluid (ELF): Maximum Prolevox concentrations in bronchial mucosa and ELF were 8.3 mcg/mL and 10.8 mcg/mL, respectively. These were reached approximately 1 hr after administration.

Penetration into Lung Tissue: Maximum Prolevox concentrations in lung tissues were approximately 11.3 mcg/mL and were reached between 4-6 hrs after administration.

Metabolism: Prolevox is metabolised to a very small extent, the metabolites being desmethyl-Prolevox and Prolevox N-oxide. These metabolites account for <5% of the dose excretion in urine. Prolevox is stereochemically stable and does not undergo chiral inversion.

Elimination: Following oral and IV administration, Prolevox is eliminated relatively slowly from the plasma (half-life: 6-8 hrs). Excretion is primarily by the renal route (>85% of the administered dose).

Microbiology: Prolevox is a broad-spectrum antibacterial agent against gram-positive and gram-negative bacteria including anaerobes. Prolevox has shown strong antibacterial activities against Staphylococcus spp, Streptococcus pneumoniae, Streptococcus pyogenes, Streptococcus hemolyticus, Enterobacter spp, Escherichia coli, Klebsiella spp, Serratia spp, Enterococcus spp, Proteus spp and other glucose nonfermentative gram-negative rods, Pseudomonas aeruginosa, Haemophilus influenzae and Neisseria gonorrhoeae. Morever, Prolevox has shown antibacterial activity against Chlamydia trachomatis. Prolevox has an excellent protective and treatment effects in mice.

How should I take Prolevox?

Take Prolevox only as directed by your doctor. Do not take more of it, do not take it more often, and do not take it for a longer time than your doctor ordered.

Prolevox comes with a Medication Guide. Read and follow the instructions carefully. Ask your doctor if you have any questions.

Prolevox oral liquid should be taken 1 hour before or 2 hours after eating. You may measure your dose with a marked measuring spoon, oral syringe, or medicine cup.

Prolevox tablets may be taken with meals or on an empty stomach.

Prolevox is best taken with a full glass (8 ounces) of water. Several additional glasses of water should be taken every day, unless otherwise directed by your doctor. Drinking extra water will help to prevent some unwanted effects of Prolevox.

Prolevox works best when there is a constant amount in the blood. To help keep the amount constant, do not miss any doses. Also, it is best to take the doses at evenly spaced times, day and night. For example, if you are to take one dose a day, try to take it at the same time each day.

If you need to take Prolevox for anthrax infection or plague, your doctor will want you to begin taking it as soon as possible after you are exposed to anthrax or bacteria causing the plague.

If you are taking aluminum or magnesium-containing antacids, iron supplements, multivitamins, didanosine (Videx®), sucralfate (Carafate®), or zinc, do not take them at the same time that you take Prolevox. It is best to take these medicines at least 2 hours before or 2 hours after taking Prolevox. These medicines may keep Prolevox from working properly.

Keep using Prolevox for the full treatment time, even if you feel better after the first few doses. Your infection may not clear up if you stop using the medicine too soon.

Dosing

The dose of Prolevox will be different for different patients. Follow your doctor's orders or the directions on the label. The following information includes only the average doses of Prolevox. If your dose is different, do not change it unless your doctor tells you to do so.

The amount of medicine that you take depends on the strength of the medicine. Also, the number of doses you take each day, the time allowed between doses, and the length of time you take the medicine depend on the medical problem for which you are using the medicine.

• For oral dosage forms (oral solution or tablets):
  • For treatment of an infection:
    • Adults—250 to 750 milligrams (mg) once a day.
    • Children—Use and dose must be determined by your doctor.
  • For preventing anthrax infection:
    • Adults—500 milligrams (mg) once a day.
    • Children 6 months of age and older and weighing more than 50 kilograms (kg)—500 mg once a day.
    • Children 6 months of age and older and weighing less than 50 kg—Dose is based on body weight and must be determined by your doctor. The dose is usually 8 mg per kg of body weight per dose, given two times a day. However, the dose is usually not more than 250 mg.
    • Infants younger than 6 months of age—Use and dose must be determined by your doctor.
  • For treatment and prevention of plague:
    • Adults—500 milligrams (mg) once a day.
    • Children 6 months of age and older, weighing more than 50 kilograms (kg)—500 mg once a day.
    • Children 6 months of age and older, weighing less than 50 kg—Dose is based on body weight and must be determined by your doctor. The dose is usually 8 mg per kg of body weight per dose, given two times a day. However, the dose is usually not more than 250 mg.
    • Infants younger than 6 months of age—Use and dose must be determined by your doctor.

Missed Dose

If you miss a dose of Prolevox, take it as soon as possible. However, if it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. Do not double doses.

Storage

Store the medicine in a closed container at room temperature, away from heat, moisture, and direct light. Keep from freezing.

Keep out of the reach of children.

Do not keep outdated medicine or medicine no longer needed.

Ask your healthcare professional how you should dispose of any medicine you do not use.

Prolevox administration

Oral: Tablets may be administered without regard to meals.

Oral solution should be administered at least 1 hour before or 2 hours after meals. Maintain adequate hydration of patient to prevent crystalluria. Administer at least 2 hours before or 2 hours after antacids containing magnesium or aluminum, sucralfate, metal cations (eg, iron), multivitamin preparations with zinc, or didanosine chewable/buffered tablets or the pediatric powder for solution.

IV: Infuse 250 to 500 mg IV solution over 60 minutes; infuse 750 mg IV solution over 90 minutes. Too rapid of infusion can lead to hypotension. Avoid administration through an intravenous line with a solution containing multivalent cations (eg, magnesium, calcium). Maintain adequate hydration of patient to prevent crystalluria or cylindruria.

Prolevox pharmacology

Mechanism of Action

Prolevox is a member of the fluoroquinolone class of antibacterial agents.

Pharmacokinetics

The mean ± SD pharmacokinetic parameters of Prolevox determined under single and steady-state conditions following oral tablet, oral solution, or intravenous (IV) doses of Prolevox are summarized in Table 8.

ND = not determined

Absorption

Prolevox is rapidly and essentially completely absorbed after oral administration. Peak plasma concentrations are usually attained one to two hours after oral dosing. The absolute bioavailability of Prolevox from a 500 mg tablet and a 750 mg tablet of Prolevox are both approximately 99%, demonstrating complete oral absorption of Prolevox. Following a single intravenous dose of Prolevox to healthy volunteers, the mean ± SD peak plasma concentration attained was 6.2 ± 1.0 mcg/mL after a 500 mg dose infused over 60 minutes and 11.5 ± 4.0 mcg/mL after a 750 mg dose infused over 90 minutes. Prolevox

Oral Solution and Tablet formulations are bioequivalent.

Prolevox pharmacokinetics are linear and predictable after single and multiple oral or IV dosing regimens. Steady-state conditions are reached within 48 hours following a 500 mg or 750 mg once-daily dosage regimen. The mean ± SD peak and trough plasma concentrations attained following multiple once-daily oral dosage regimens were approximately 5.7 ± 1.4 and 0.5 ± 0.2 mcg/mL after the 500 mg doses, and 8.6 ± 1.9 and 1.1 ± 0.4 mcg/mL after the 750 mg doses, respectively. The mean ± SD peak and trough plasma concentrations attained following multiple once-daily IV regimens were approximately 6.4 ± 0.8 and 0.6 ± 0.2 mcg/mL after the 500 mg doses, and 12.1 ± 4.1 and 1.3 ± 0.71 mcg/mL after the 750 mg doses, respectively.

Oral administration of a 500 mg dose of Prolevox with food prolongs the time to peak concentration by approximately 1 hour and decreases the peak concentration by approximately 14% following tablet and approximately 25% following oral solution administration. Therefore, Prolevox Tablets can be administered without regard to food. It is recommended that Prolevox

Oral Solution be taken 1 hour before or 2 hours after eating.

The plasma concentration profile of Prolevox after IV administration is similar and comparable in extent of exposure (AUC) to that observed for Prolevox Tablets when equal doses (mg/mg) are administered. Therefore, the oral and IV routes of administration can be considered interchangeable.

Figure 2: Mean Prolevox Plasma Concentration vs. Time Profile: 750 mg

Figure 3: Mean Prolevox Plasma Concentration vs. Time Profile: 500 mg

Distribution

The mean volume of distribution of Prolevox generally ranges from 74 to 112 L after single and multiple 500 mg or 750 mg doses, indicating widespread distribution into body tissues. Prolevox reaches its peak levels in skin tissues and in blister fluid of healthy subjects at approximately 3 hours after dosing. The skin tissue biopsy to plasma AUC ratio is approximately 2 and the blister fluid to plasma AUC ratio is approximately 1 following multiple once-daily oral administration of 750 mg and 500 mg doses of Prolevox respectively, to healthy subjects. Prolevox also penetrates well into lung tissues. Lung tissue concentrations were generally 2- to 5-fold higher than plasma concentrations and ranged from approximately 2.4 to 11.3 mcg/g over a 24-hour period after a single 500 mg oral dose.

In vitro, over a clinically relevant range (1 to 10 mcg/mL) of serum/plasma Prolevox concentrations, Prolevox is approximately 24 to 38% bound to serum proteins across all species studied, as determined by the equilibrium dialysis method. Prolevox is mainly bound to serum albumin in humans. Prolevox binding to serum proteins is independent of the drug concentration.

Metabolism

Prolevox is stereochemically stable in plasma and urine and does not invert metabolically to its enantiomer, D-ofloxacin. Prolevox undergoes limited metabolism in humans and is primarily excreted as unchanged drug in the urine. Following oral administration, approximately 87% of an administered dose was recovered as unchanged drug in urine within 48 hours, whereas less than 4% of the dose was recovered in feces in 72 hours. Less than 5% of an administered dose was recovered in the urine as the desmethyl and N-oxide metabolites, the only metabolites identified in humans. These metabolites have little relevant pharmacological activity.

Excretion

Prolevox is excreted largely as unchanged drug in the urine. The mean terminal plasma elimination half-life of Prolevox ranges from approximately 6 to 8 hours following single or multiple doses of Prolevox given orally or intravenously. The mean apparent total body clearance and renal clearance range from approximately 144 to 226 mL/min and 96 to 142 mL/min, respectively. Renal clearance in excess of the glomerular filtration rate suggests that tubular secretion of Prolevox occurs in addition to its glomerular filtration. Concomitant administration of either cimetidine or probenecid results in approximately 24% and 35% reduction in the Prolevox renal clearance, respectively, indicating that secretion of Prolevox occurs in the renal proximal tubule. No Prolevox crystals were found in any of the urine samples freshly collected from subjects receiving Prolevox.

Geriatric

There are no significant differences in Prolevox pharmacokinetics between young and elderly subjects when the subjects' differences in creatinine clearance are taken into consideration. Following a 500 mg oral dose of Prolevox to healthy elderly subjects (66 – 80 years of age), the mean terminal plasma elimination half-life of Prolevox was about 7.6 hours, as compared to approximately 6 hours in younger adults. The difference was attributable to the variation in renal function status of the subjects and was not believed to be clinically significant. Drug absorption appears to be unaffected by age. Prolevox dose adjustment based on age alone is not necessary.

Pediatrics

The pharmacokinetics of Prolevox following a single 7 mg/kg intravenous dose were investigated in pediatric patients ranging in age from 6 months to 16 years. Pediatric patients cleared Prolevox faster than adult patients, resulting in lower plasma exposures than adults for a given mg/kg dose. Subsequent pharmacokinetic analyses predicted that a dosage regimen of 8 mg/kg every 12 hours (not to exceed 250 mg per dose) for pediatric patients 6 months to 17 years of age would achieve comparable steady state plasma exposures (AUC0-24 and Cmax) to those observed in adult patients administered 500 mg of Prolevox once every 24 hours.

Gender

There are no significant differences in Prolevox pharmacokinetics between male and female subjects when subjects' differences in creatinine clearance are taken into consideration. Following a 500 mg oral dose of Prolevox to healthy male subjects, the mean terminal plasma elimination half-life of Prolevox was about 7.5 hours, as compared to approximately 6.1 hours in female subjects. This difference was attributable to the variation in renal function status of the male and female subjects and was not believed to be clinically significant. Drug absorption appears to be unaffected by the gender of the subjects. Dose adjustment based on gender alone is not necessary.

Race

The effect of race on Prolevox pharmacokinetics was examined through a covariate analysis performed on data from 72 subjects: 48 white and 24 non-white. The apparent total body clearance and apparent volume of distribution were not affected by the race of the subjects.

Renal Impairment

Clearance of Prolevox is substantially reduced and plasma elimination half-life is substantially prolonged in adult patients with impaired renal function (creatinine clearance < 50 mL/min), requiring dosage adjustment in such patients to avoid accumulation. Neither hemodialysis nor continuous ambulatory peritoneal dialysis (CAPD) is effective in removal of Prolevox from the body, indicating that supplemental doses of Prolevox are not required following hemodialysis or CAPD.

Hepatic Impairment

Pharmacokinetic studies in hepatically impaired patients have not been conducted. Due to the limited extent of Prolevox metabolism, the pharmacokinetics of Prolevox are not expected to be affected by hepatic impairment.

Bacterial Infection

The pharmacokinetics of Prolevox in patients with serious community-acquired bacterial infections are comparable to those observed in healthy subjects.

Drug-Drug Interactions

The potential for pharmacokinetic drug interactions between Prolevox and antacids warfarin, theophylline, cyclosporine, digoxin, probenecid, and cimetidine has been evaluated.

Microbiology

Mechanism of Action

Prolevox is the L-isomer of the racemate, ofloxacin, a quinolone antimicrobial agent. The antibacterial activity of ofloxacin resides primarily in the L-isomer. The mechanism of action of Prolevox and other fluoroquinolone antimicrobials involves inhibition of bacterial topoisomerase IV and DNA gyrase (both of which are type II topoisomerases), enzymes required for DNA replication, transcription, repair and recombination.

Mechanism of Resistance

Fluoroquinolone resistance can arise through mutations in defined regions of DNA gyrase or topoisomerase IV, termed the Quinolone-Resistance Determining Regions (QRDRs), or through altered efflux.

Fluoroquinolones, including Prolevox, differ in chemical structure and mode of action from aminoglycosides, macrolides and ß-lactam antibiotics, including penicillins. Fluoroquinolones may, therefore, be active against bacteria resistant to these antimicrobials.

Resistance to Prolevox due to spontaneous mutation in vitro is a rare occurrence (range: 10-9 to 10-10). Cross-resistance has been observed between Prolevox and some other fluoroquinolones, some microorganisms resistant to other fluoroquinolones may be susceptible to Prolevox.

Activity in vitro and in vivo

Prolevox has in vitro activity against Gram-negative and Gram-positive bacteria.

Prolevox has been shown to be active against most isolates of the following bacteria both in vitro and in clinical infections as described in :

Gram-Positive Bacteria

Enterococcus faecalis

Staphylococcus aureus (methicillin-susceptible isolates)

Staphylococcus epidermidis (methicillin-susceptible isolates)

Staphylococcus saprophyticus

Streptococcus pneumoniae (including multi-drug resistant isolates [MDRSP])1

Streptococcus pyogenes

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1 MDRSP (Multi-drug resistant Streptococcus pneumoniae) isolates are isolates resistant to two or more of the following antibiotics: penicillin (MIC ≥ 2 mcg/mL), 2nd generation cephalosporins, e.g., cefuroxime; macrolides, tetracyclines and trimethoprim/sulfamethoxazole.

Gram-Negative Bacteria

Enterobacter cloacae

Escherichia coli

Haemophilus influenzae

Haemophilus parainfluenzae

Klebsiella pneumoniae

Legionella pneumophila

Moraxella catarrhalis

Proteus mirabilis

Pseudomonas aeruginosa

Serratia marcescens

Other Bacteria

Chlamydophila pneumoniae

Mycoplasma pneumoniae

The following in vitro data are available, but their clinical significance is unknown: Prolevox exhibits in vitro minimum inhibitory concentrations (MIC values) of 2 mcg/mL or less against most (≥ 90%) isolates of the following microorganisms; however, the safety and effectiveness of Prolevox in treating clinical infections due to these bacteria have not been established in adequate and well-controlled clinical trials.

Gram-Positive Bacteria

Staphylococcus haemolyticus

ß-hemolytic Streptococcus (Group C/F)

ß-hemolytic Streptococcus (Group G)

Streptococcus agalactiae

Streptococcus milleri

Viridans group streptococci

Bacillus anthracis

Gram-Negative Bacteria

Acinetobacter baumannii

Acinetobacter lwoffii

Bordetella pertussis

Citrobacter koseri

Citrobacter freundii

Enterobacter aerogenes

Enterobacter sakazakii

Klebsiella oxytoca

Morganella morganii

Pantoea agglomerans

Proteus vulgaris

Providencia rettgeri

Providencia stuartii

Pseudomonas fluorescens

Yersinia pestis

Anaerobic Gram-Positive Bacteria

Clostridium perfringens

Susceptibility Tests

When available, the clinical microbiology laboratory should provide the results of in vitro susceptibility test results for antimicrobial drug products used in the 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 an antibacterial drug product for treatment.

Dilution techniques:

Quantitative methods are used to determine antimicrobial minimal inhibitory concentrations (MICs). These MICs provide estimates of the susceptibility of bacteria to antimicrobial compounds. The MIC values should be determined using a standardized procedure. Standardized procedures are based on a dilution method1, 2, 4 (broth or agar) or equivalent with standardized inoculum concentrations and standardized concentrations of Prolevox powder. The MIC values should be interpreted according to the criteria outlined in Table 9.

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, 3 requires the use of standardized inoculum concentrations. This procedure uses paper disks impregnated with 5 mcg Prolevox to test the susceptibility of bacteria to Prolevox.

Reports from the laboratory providing results of the standard single-disk susceptibility test with a 5 mcg Prolevox disk should be interpreted according to the criteria outlined in Table 9.

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 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 blood reaches the concentrations usually achievable; other therapy should be selected.

Quality Control:

Standardized susceptibility test procedures require the use of laboratory controls to monitor and ensure the accuracy and precision of supplies and reagents used in the assay, and the techniques of the individuals performing the test.1,2,3,4 Standard Prolevox powder should provide the range of MIC values noted in Table 10. For the diffusion technique using the 5 mcg disk, the criteria in Table 10 should be achieved.

References

1. DailyMed. "LEVOFLOXACIN: DailyMed provides trustworthy information about marketed drugs in the United States. DailyMed is the official provider of FDA label information (package inserts).". https://dailymed.nlm.nih.gov/dailyme... (accessed September 17, 2018).
2. NCIt. "Levofloxacin: NCI Thesaurus (NCIt) provides reference terminology for many systems. It covers vocabulary for clinical care, translational and basic research, and public information and administrative activities.". https://ncit.nci.nih.gov/ncitbrowser... (accessed September 17, 2018).
3. EPA DSStox. "Levofloxacin: DSSTox provides a high quality public chemistry resource for supporting improved predictive toxicology.". https://comptox.epa.gov/dashboard/ds... (accessed September 17, 2018).

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Information checked by Dr. Sachin Kumar, MD Pharmacology