FULL PRESCRIBING INFORMATION
LEVAQUIN® is a synthetic broad-spectrum antibacterial agent for oral and intravenous administration. Chemically, levofloxacin, a chiral fluorinated carboxyquinolone, is the pure (-)-(S)-enantiomer of the racemic drug substance ofloxacin. The chemical name is (-)-(S)-9-fluoro-2,3-dihydro-3-methyl-10-(4-methyl-1-piperazinyl)-7-oxo-7H-pyrido[1,2,3-de]-1,4-benzoxazine-6-carboxylic acid hemihydrate.
Figure 1: The Chemical Structure of Levofloxacin
The empirical formula is C18H20FN3O4 •½ H2O and the molecular weight is 370.38. Levofloxacin is a light yellowish-white to yellow-white crystal or crystalline powder. The molecule exists as a zwitterion at the pH conditions in the small intestine.
The data demonstrate that from pH 0.6 to 5.8, the solubility of levofloxacin is essentially constant (approximately 100 mg/mL). Levofloxacin is considered soluble to freely soluble in this pH range, as defined by USP nomenclature. Above pH 5.8, the solubility increases rapidly to its maximum at pH 6.7 (272 mg/mL) and is considered freely soluble in this range. Above pH 6.7, the solubility decreases and reaches a minimum value (about 50 mg/mL) at a pH of approximately 6.9.
Levofloxacin has the potential to form stable coordination compounds with many metal ions. This in vitro chelation potential has the following formation order: Al+3>Cu+2>Zn+2>Mg+2>Ca+2.
Excipients and Description of Dosage Forms
LEVAQUIN® Tablets are available as film-coated tablets and contain the following inactive ingredients:
- 250 mg (as expressed in the anhydrous form): hypromellose, crospovidone, microcrystalline cellulose, magnesium stearate, polyethylene glycol, titanium dioxide, polysorbate 80 and synthetic red iron oxide.
- 500 mg (as expressed in the anhydrous form): hypromellose, crospovidone, microcrystalline cellulose, magnesium stearate, polyethylene glycol, titanium dioxide, polysorbate 80 and synthetic red and yellow iron oxides.
- 750 mg (as expressed in the anhydrous form): hypromellose, crospovidone, microcrystalline cellulose, magnesium stearate, polyethylene glycol, titanium dioxide, polysorbate 80.
LEVAQUIN® Oral Solution
LEVAQUIN® Oral Solution, 25 mg/mL, is a multi-use self-preserving aqueous solution of levofloxacin with pH ranging from 5.0 – 6.0. The appearance of LEVAQUIN® Oral Solution may range from clear yellow to clear greenish-yellow. This does not adversely affect product potency.
LEVAQUIN® Oral Solution contains the following inactive ingredients: sucrose, glycerin, sucralose, hydrochloric acid, purified water, propylene glycol, artificial and natural flavors, benzyl alcohol, ascorbic acid, and caramel color. It may also contain a solution of sodium hydroxide for pH adjustment.
The appearance of LEVAQUIN® Injection may range from a clear yellow to a clear greenish-yellow solution. This does not adversely affect product potency.
LEVAQUIN ® Injection in Single-Use Vials is a sterile, preservative-free aqueous solution of levofloxacin in Water for Injection, with pH ranging from 3.8 to 5.8.
LEVAQUIN ® Injection Premix in Single-Use Flexible Containers is a sterile, preservative-free aqueous solution of levofloxacin with pH ranging from 3.8 to 5.8. This is a dilute, non-pyrogenic, nearly isotonic premixed solution that contains levofloxacin in 5% Dextrose (D5W). Solutions of hydrochloric acid and sodium hydroxide may have been added to adjust the pH.
The flexible container is fabricated from a specially formulated non-plasticized, thermoplastic copolyester (CR3). The amount of water that can permeate from the container into the overwrap is insufficient to affect the solution significantly. Solutions in contact with the flexible container can leach out certain of the container's chemical components in very small amounts within the expiration period. The suitability of the container material has been confirmed by tests in animals according to USP biological tests for plastic containers.
Mechanism of Action
Levofloxacin is a member of the fluoroquinolone class of antibacterial agents [see Clinical Pharmacology].
The mean ±SD pharmacokinetic parameters of levofloxacin determined under single and steady-state conditions following oral tablet, oral solution, or intravenous (IV) doses of LEVAQUIN® are summarized in Table 10.
Table 10: Mean ±SD Levofloxacin PK Parameters
|2 volume of distribution/bioavailability|
|3 healthy males 18–53 years of age|
|4 60 min infusion for 250 mg and 500 mg doses, 90 min infusion for 750 mg dose|
|5 healthy male and female subjects 18–54 years of age|
|6 500 mg every 48h for patients with moderate renal impairment (CLCR 20–50 mL/min) and infections of the respiratory tract or skin|
|7 dose-normalized values (to 500 mg dose), estimated by population pharmacokinetic modeling|
|8 healthy males 22–75 years of age|
|9 healthy females 18–80 years of age|
|10 young healthy male and female subjects 18–36 years of age|
|11 healthy elderly male and female subjects 66–80 years of age|
|12 healthy males and females 19–55 years of age.|
|*Absolute bioavailability; F=0.99 ± 0.08 from a 500 mg tablet and F=0.99 ± 0.06 from a 750 mg tablet;|
| Single dose |
|250 mg oral tablet3||2.8 ± 0.4||1.6 ± 1.0||27.2 ± 3.9||156 ± 20||ND||7.3 ± 0.9||142 ± 21|
|500 mg oral tablet3*||5.1 ± 0.8||1.3 ± 0.6||47.9 ± 6.8||178 ± 28||ND||6.3 ± 0.6||103 ± 30|
|500 mg oral solution12||5.8 ± 1.8||0.8 ± 0.7||47.8 ± 10.8||183 ± 40||112 ± 37.2||7.0 ± 1.4||ND|
|500 mg IV3||6.2 ± 1.0||1.0 ± 0.1||48.3 ± 5.4||175 ± 20||90 ± 11||6.4 ± 0.7||112 ± 25|
|750 mg oral tablet5*||9.3 ± 1.6||1.6 ± 0.8||101 ± 20||129 ± 24||83 ± 17||7.5 ± 0.9||ND|
|750 mg IV5||11.5 ±4.04||ND||110 ±40||126 ±39||75 ± 13||7.5 ± 1.6||ND|
| Multiple dose |
|500 mg every 24h oral tablet3||5.7 ± 1.4||1.1 ± 0.4||47.5 ± 6.7||175 ± 25||102 ± 22||7.6 ± 1.6||116 ± 31|
|500 mg every 24h IV3||6.4 ± 0.8||ND||54.6 ± 11.1||158 ± 29||91 ± 12||7.0 ± 0.8||99 ± 28|
|500 mg or 250 mg every 24h IV, patients with bacterial infection6||8.7± 4.07||ND||72.5 ± 51.27||154 ± 72||111 ± 58||ND||ND|
|750 mg every 24h oral tablet5||8.6 ± 1.9||1.4 ± 0.5||90.7 ± 17.6||143 ± 29||100 ± 16||8.8 ± 1.5||116 ± 28|
|750 mg every 24h IV5||12.1 ± 4.14||ND||108 ± 34||126 ± 37||80 ± 27||7.9 ± 1.9||ND|
| 500 mg oral tablet single dose, effects of gender and age: |
|Male8||5.5 ± 1.1||1.2 ± 0.4||54.4 ± 18.9||166 ± 44||89 ± 13||7.5 ± 2.1||126 ± 38|
|Female9||7.0 ± 1.6||1.7 ± 0.5||67.7 ± 24.2||136 ± 44||62 ± 16||6.1 ± 0.8||106 ± 40|
|Young10||5.5 ± 1.0||1.5 ± 0.6||47.5 ± 9.8||182 ± 35||83 ± 18||6.0 ± 0.9||140 ± 33|
|Elderly11||7.0 ± 1.6||1.4 ± 0.5||74.7 ± 23.3||121 ± 33||67 ± 19||7.6 ± 2.0||91 ± 29|
| 500 mg oral single dose tablet, patients with renal insufficiency: |
|CLCR 50–80 mL/min||7.5 ± 1.8||1.5 ± 0.5||95.6 ± 11.8||88 ± 10||ND||9.1 ± 0.9||57 ± 8|
|CLCR 20–49 mL/min||7.1 ± 3.1||2.1 ± 1.3||182.1 ± 62.6||51 ± 19||ND||27 ± 10||26 ± 13|
|CLCR <20 mL/min||8.2 ± 2.6||1.1 ± 1.0||263.5 ± 72.5||33 ± 8||ND||35 ± 5||13 ± 3|
|Hemodialysis||5.7 ± 1.0||2.8 ± 2.2||ND||ND||ND||76 ± 42||ND|
|CAPD||6.9 ± 2.3||1.4 ± 1.1||ND||ND||ND||51 ± 24||ND|
Levofloxacin 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 levofloxacin from a 500 mg tablet and a 750 mg tablet of LEVAQUIN® are both approximately 99%, demonstrating complete oral absorption of levofloxacin. Following a single intravenous dose of LEVAQUIN® 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. LEVAQUIN® Oral Solution and Tablet formulations are bioequivalent.
Levofloxacin 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 LEVAQUIN® 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, LEVAQUIN® Tablets can be administered without regard to food. It is recommended that LEVAQUIN® Oral Solution be taken 1 hour before, or 2 hours after eating.
The plasma concentration profile of levofloxacin after IV administration is similar and comparable in extent of exposure (AUC) to that observed for LEVAQUIN® Tablets when equal doses (mg/mg) are administered. Therefore, the oral and IV routes of administration can be considered interchangeable (see Figure 2 and Figure 3).
Figure 2: Mean Levofloxacin Plasma Concentration vs. Time Profile: 750 mg
Figure 3: Mean Levofloxacin Plasma Concentration vs. Time Profile: 500 mg
The mean volume of distribution of levofloxacin generally ranges from 74 to 112 L after single and multiple 500 mg or 750 mg doses, indicating widespread distribution into body tissues. Levofloxacin 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 LEVAQUIN®, respectively, to healthy subjects. Levofloxacin 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 levofloxacin concentrations, levofloxacin is approximately 24 to 38% bound to serum proteins across all species studied, as determined by the equilibrium dialysis method. Levofloxacin is mainly bound to serum albumin in humans. Levofloxacin binding to serum proteins is independent of the drug concentration.
Levofloxacin is stereochemically stable in plasma and urine and does not invert metabolically to its enantiomer, D-ofloxacin. Levofloxacin 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.
Levofloxacin is excreted largely as unchanged drug in the urine. The mean terminal plasma elimination half-life of levofloxacin ranges from approximately 6 to 8 hours following single or multiple doses of levofloxacin 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 levofloxacin occurs in addition to its glomerular filtration. Concomitant administration of either cimetidine or probenecid results in approximately 24% and 35% reduction in the levofloxacin renal clearance, respectively, indicating that secretion of levofloxacin occurs in the renal proximal tubule. No levofloxacin crystals were found in any of the urine samples freshly collected from subjects receiving LEVAQUIN®.
There are no significant differences in levofloxacin pharmacokinetics between young and elderly subjects when the subjects' differences in creatinine clearance are taken into consideration. Following a 500 mg oral dose of LEVAQUIN® to healthy elderly subjects (66 – 80 years of age), the mean terminal plasma elimination half-life of levofloxacin 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. LEVAQUIN® dose adjustment based on age alone is not necessary [See Use in Specific Populations].
The pharmacokinetics of levofloxacin 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 levofloxacin 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 levofloxacin once every 24 hours.
There are no significant differences in levofloxacin pharmacokinetics between male and female subjects when subjects' differences in creatinine clearance are taken into consideration. Following a 500 mg oral dose of LEVAQUIN® to healthy male subjects, the mean terminal plasma elimination half-life of levofloxacin 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.
The effect of race on levofloxacin 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.
Clearance of levofloxacin 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 levofloxacin from the body, indicating that supplemental doses of LEVAQUIN® are not required following hemodialysis or CAPD [see Dosage and Administration, Use in Specific Populations].
Pharmacokinetic studies in hepatically impaired patients have not been conducted. Due to the limited extent of levofloxacin metabolism, the pharmacokinetics of levofloxacin are not expected to be affected by hepatic impairment [See Use in Specific Populations].
The pharmacokinetics of levofloxacin in patients with serious community-acquired bacterial infections are comparable to those observed in healthy subjects.
The potential for pharmacokinetic drug interactions between LEVAQUIN® and antacids warfarin, theophylline, cyclosporine, digoxin, probenecid, and cimetidine has been evaluated [see Drug Interactions (7) ].
Mechanism of Action
Levofloxacin 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 levofloxacin 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.
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 levofloxacin, differ in chemical structure and mode of action from aminoglycosides, macrolides and β-lactam antibiotics, including penicillins. Fluoroquinolones may, therefore, be active against bacteria resistant to these antimicrobials.
Resistance to levofloxacin due to spontaneous mutation in vitro is a rare occurrence (range: 10-9 to 10-10). Although cross-resistance has been observed between levofloxacin and some other fluoroquinolones, some microorganisms resistant to other fluoroquinolones may be susceptible to levofloxacin.
Activity in vitro and in vivo
Levofloxacin has in vitro activity against a wide range of Gram-negative and Gram-positive microorganisms.
Levofloxacin is often bactericidal at concentrations equal to or slightly greater than inhibitory concentrations.
Levofloxacin has been shown to be active against most strains of the following microorganisms both in vitro and in clinical infections as described in Indications and Usage (1):
- Aerobic Gram-Positive Microorganisms
- Enterococcus faecalis (many strains are only moderately susceptible)
- Staphylococcus aureus (methicillin-susceptible strains)
- Staphylococcus epidermidis (methicillin-susceptible strains)
- Staphylococcus saprophyticus
- Streptococcus pneumoniae (including multi-drug resistant strains [MDRSP]MDRSP (Multi-drug resistant Streptococcus pneumoniae) isolates are strains 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.)
- Streptococcus pyogenes
- Aerobic Gram-Negative Microorganisms
- Enterobacter cloacae
- Escherichia coli
- Haemophilus influenzae
- Haemophilus parainfluenzae
- Klebsiella pneumoniae
- Legionella pneumophila
- Moraxella catarrhalis
- Proteus mirabilis
- Pseudomonas aeruginosaAs with other drugs in this class, some strains of Pseudomonas aeruginosa may develop resistance fairly rapidly during treatment with LEVAQUIN®.
- Serratia marcescens
- Other Microorganisms
- Chlamydophila pneumoniae
- Mycoplasma pneumoniae
Levofloxacin has been shown to be active against Bacillus anthracis both in vitro and by use of plasma levels as a surrogate marker in a rhesus monkey model for anthrax (post-exposure) [see Indications and Usage, Clinical Studies].
The following in vitro data are available, but their clinical significance is unknown : Levofloxacin exhibits in vitro minimum inhibitory concentrations (MIC values) of 2 mcg/mL or less against most (≥90%) strains of the following microorganisms; however, the safety and effectiveness of LEVAQUIN® in treating clinical infections due to these microorganisms have not been established in adequate and well-controlled trials.
- Aerobic Gram-Positive Microorganisms
- Staphylococcus haemolyticus
- β-hemolytic Streptococcus (Group C/F)
- β-hemolytic Streptococcus (Group G)
- Streptococcus agalactiae
- Streptococcus milleri
- Viridans group streptococci
- Aerobic Gram-Negative Microorganisms
- 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
- Anaerobic Gram-Positive Microorganisms
- Clostridium perfringens
Susceptibility testing for levofloxacin should be performed, as it is the optimal predictor of activity.
- Dilution techniques:
Quantitative methods are used to determine antimicrobial minimal inhibitory concentrations (MIC values). These MIC values 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 (broth or agar) or equivalent with standardized inoculum concentrations and standardized concentrations of levofloxacin powder. The MIC values should be interpreted according to the criteria outlined in Table 11.
- 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 5 mcg levofloxacin to test the susceptibility of microorganisms to levofloxacin.
Reports from the laboratory providing results of the standard single-disk susceptibility test with a 5 mcg levofloxacin disk should be interpreted according the criteria outlined in Table 11. Interpretation involves correlation of the diameter obtained in the disk test with the MIC for levofloxacin.
Table 11: Susceptibility Interpretive Criteria for LEVAQUIN®
(zone diameter in mm)
|S = Susceptible, I = Intermediate, R = Resistant|
| Pathogen || S || I || R || S || I || R |
| Enterobacteriaceae ||≤2||4||≥8||≥17||14–16||≤13|
| Enterococcus faecalis ||≤2||4||≥8||≥17||14–16||≤13|
| Pseudomonas aeruginosa ||≤2||4||≥8||≥17||14–16||≤13|
| Haemophilus influenzae ||≤2
| Haemophilus parainfluenzae ||≤2||--||--||≥17||--||--|
| Streptococcus pneumoniae ||≤2
| Streptococcus pyogenes ||≤2||4||≥8||≥17||14–16||≤13|
Adult patients with clinically and radiologically documented nosocomial pneumonia were enrolled in a multicenter, randomized, open-label study comparing intravenous LEVAQUIN® (750 mg once daily) followed by oral LEVAQUIN® (750 mg once daily) for a total of 7–15 days to intravenous imipenem/cilastatin (500–1000 mg every 6–8 hours daily) followed by oral ciprofloxacin (750 mg every 12 hours daily) for a total of 7–15 days. LEVAQUIN®-treated patients received an average of 7 days of intravenous therapy (range: 1–16 days); comparator-treated patients received an average of 8 days of intravenous therapy (range: 1–19 days).
Overall, in the clinically and microbiologically evaluable population, adjunctive therapy was empirically initiated at study entry in 56 of 93 (60.2%) patients in the LEVAQUIN® arm and 53 of 94 (56.4%) patients in the comparator arm. The average duration of adjunctive therapy was 7 days in the LEVAQUIN® arm and 7 days in the comparator. In clinically and microbiologically evaluable patients with documented Pseudomonas aeruginosa infection, 15 of 17 (88.2%) received ceftazidime (N=11) or piperacillin/tazobactam (N=4) in the LEVAQUIN® arm and 16 of 17 (94.1%) received an aminoglycoside in the comparator arm. Overall, in clinically and microbiologically evaluable patients, vancomycin was added to the treatment regimen of 37 of 93 (39.8%) patients in the LEVAQUIN® arm and 28 of 94 (29.8%) patients in the comparator arm for suspected methicillin-resistant S. aureus infection.
Clinical success rates in clinically and microbiologically evaluable patients at the posttherapy visit (primary study endpoint assessed on day 3–15 after completing therapy) were 58.1% for LEVAQUIN® and 60.6% for comparator. The 95% CI for the difference of response rates (LEVAQUIN® minus comparator) was [-17.2, 12.0]. The microbiological eradication rates at the posttherapy visit were 66.7% for LEVAQUIN® and 60.6% for comparator. The 95% CI for the difference of eradication rates (LEVAQUIN® minus comparator) was [-8.3, 20.3]. Clinical success and microbiological eradication rates by pathogen are detailed in Table 13.
Table 13: Clinical Success Rates and Microbiological Eradication Rates (Nosocomial Pneumonia)
|Pathogen||N||LEVAQUIN® No. (%) of |
|N||Imipenem/Cilastatin No. (%)|
of Patients Microbiologic/
|MSSAMethicillin-susceptible S. aureus ||21||14 (66.7)/13 (61.9)||19||13 (68.4)/15 (78.9)|
| P. aeruginosa See above text for use of combination therapy ||17||10 (58.8)/11 (64.7)||17||5 (29.4)/7 (41.2)|
| S. marcescens ||11||9 (81.8)/7 (63.6)||7||2 (28.6)/3 (42.9)|
| E. coli ||12||10 (83.3)/7 (58.3)||11||7 (63.6)/8 (72.7)|
| K. pneumoniae The observed differences in rates for the clinical and microbiological outcomes may reflect other factors that were not accounted for in the study ||11||9 (81.8)/5 (45.5)||7||6 (85.7)/3 (42.9)|
| H. influenzae ||16||13 (81.3)/10 (62.5)||15||14 (93.3)/11 (73.3)|
| S. pneumoniae ||4 ||3 (75.0)/3 (75.0)||7||5 (71.4)/4 (57.1)|
Community-Acquired Pneumonia: 7–14 day Treatment Regimen
Adult inpatients and outpatients with a diagnosis of community-acquired bacterial pneumonia were evaluated in 2 pivotal clinical studies. In the first study, 590 patients were enrolled in a prospective, multi-center, unblinded randomized trial comparing LEVAQUIN® 500 mg once daily orally or intravenously for 7 to 14 days to ceftriaxone 1 to 2 grams intravenously once or in equally divided doses twice daily followed by cefuroxime axetil 500 mg orally twice daily for a total of 7 to 14 days. Patients assigned to treatment with the control regimen were allowed to receive erythromycin (or doxycycline if intolerant of erythromycin) if an infection due to atypical pathogens was suspected or proven. Clinical and microbiologic evaluations were performed during treatment, 5 to 7 days posttherapy, and 3 to 4 weeks posttherapy. Clinical success (cure plus improvement) with LEVAQUIN® at 5 to 7 days posttherapy, the primary efficacy variable in this study, was superior (95%) to the control group (83%). The 95% CI for the difference of response rates (LEVAQUIN® minus comparator) was [-6, 19]. In the second study, 264 patients were enrolled in a prospective, multi-center, non-comparative trial of 500 mg LEVAQUIN® administered orally or intravenously once daily for 7 to 14 days. Clinical success for clinically evaluable patients was 93%. For both studies, the clinical success rate in patients with atypical pneumonia due to Chlamydophila pneumoniae, Mycoplasma pneumoniae, and Legionella pneumophila were 96%, 96%, and 70%, respectively. Microbiologic eradication rates across both studies are presented in Table 14.
Table 14: Microbiologic Eradication Rates Across 2 Community Acquired Pneumonia Clinical Studies
|Pathogen||No. Pathogens||Microbiologic Eradication Rate (%)|
| H. influenzae ||55||98|
| S. pneumoniae ||83||95|
| S. aureus ||17||88|
| M. catarrhalis ||18||94|
| H. parainfluenzae ||19||95|
| K. pneumoniae ||10||100.0|
Community-Acquired Pneumonia Due to Multi-Drug Resistant Streptococcus pneumoniae
LEVAQUIN® was effective for the treatment of community-acquired pneumonia caused by multi-drug resistant Streptococcus pneumoniae (MDRSP). MDRSP isolates are strains resistant to two or more of the following antibacterials: penicillin (MIC ≥2 mcg/mL), 2nd generation cephalosporins (e.g., cefuroxime, macrolides, tetracyclines and trimethoprim/sulfamethoxazole). Of 40 microbiologically evaluable patients with MDRSP isolates, 38 patients (95.0%) achieved clinical and bacteriologic success at post-therapy. The clinical and bacterial success rates are shown in Table 15.
Table 15: Clinical and Bacterial Success Rates for LEVAQUIN®-Treated MDRSP in Community Acquired Pneumonia Patients (Population Valid for Efficacy)
|Screening Susceptibility||Clinical Success||Bacteriological SuccessOne patient had a respiratory isolate that was resistant to tetracycline, cefuroxime, macrolides and TMP/SMX and intermediate to penicillin and a blood isolate that was intermediate to penicillin and cefuroxime and resistant to the other classes. The patient is included in the database based on respiratory isolate.|
| ||n/Nn=the number of microbiologically evaluable patients who were clinical successes; N=number of microbiologically evaluable patients in the designated resistance group.||%||n/Nn=the number of MDRSP isolates eradicated or presumed eradicated in microbiologically evaluable patients; N=number of MDRSP isolates in a designated resistance group.||%|
| Penicillin-resistant ||16/17||94.1||16/17||94.1|
| 2nd generation Cephalosporin resistant ||31/32||96.9||31/32||96.9|
| Macrolide-resistant ||28/29||96.6||28/29||96.6|
| Trimethoprim/ Sulfamethoxazole resistant ||17/19||89.5||17/19||89.5|
| Tetracycline-resistant ||12/12||100||12/12||100|
Not all isolates were resistant to all antimicrobial classes tested. Success and eradication rates are summarized in Table 16.
Table 16: Clinical Success and Bacteriologic Eradication Rates for Resistant Streptococcus pneumoniae (Community Acquired Pneumonia)
|Type of Resistance||Clinical Success||Bacteriologic Eradication|
|Resistant to 2 antibacterials||17/18 (94.4%) ||17/18 (94.4%) |
|Resistant to 3 antibacterials||14/15 (93.3%)||14/15 (93.3%)|
|Resistant to 4 antibacterials||7/7 (100%) ||7/7 (100%) |
|Resistant to 5 antibacterials||0||0|
|Bacteremia with MDRSP ||8/9 (89%)||8/9 (89%)|
Community-Acquired Pneumonia: 5-Day Treatment Regimen
To evaluate the safety and efficacy of higher dose and shorter course of LEVAQUIN®, 528 outpatient and hospitalized adults with clinically and radiologically determined mild to severe community-acquired pneumonia were evaluated in a double-blind, randomized, prospective, multicenter study comparing LEVAQUIN® 750 mg, IV or orally, every day for five days or LEVAQUIN® 500 mg IV or orally, every day for 10 days.
Clinical success rates (cure plus improvement) in the clinically evaluable population were 90.9% in the LEVAQUIN® 750 mg group and 91.1% in the LEVAQUIN® 500 mg group. The 95% CI for the difference of response rates (LEVAQUIN® 750 minus LEVAQUIN® 500) was [-5.9, 5.4]. In the clinically evaluable population (31–38 days after enrollment) pneumonia was observed in 7 out of 151 patients in the LEVAQUIN® 750 mg group and 2 out of 147 patients in the LEVAQUIN® 500 mg group. Given the small numbers observed, the significance of this finding cannot be determined statistically. The microbiological efficacy of the 5-day regimen was documented for infections listed in Table 17.
Table 17: Microbiological Eradication Rates (Community-Acquired Pneumonia)
|Penicillin susceptible S. pneumoniae ||19/20|
| Haemophilus influenzae ||12/12|
| Haemophilus parainfluenzae ||10/10|
| Mycoplasma pneumoniae ||26/27|
| Chlamydophila pneumoniae ||13/15|
Acute Bacterial Sinusitis: 5-day and 10–14 day Treatment Regimens
LEVAQUIN® is approved for the treatment of acute bacterial sinusitis (ABS) using either 750 mg by mouth × 5 days or 500 mg by mouth once daily × 10–14 days. To evaluate the safety and efficacy of a high dose short course of LEVAQUIN®, 780 outpatient adults with clinically and radiologically determined acute bacterialsinusitis were evaluated in a double-blind, randomized, prospective, multicenter study comparing LEVAQUIN® 750 mg by mouth once daily for five days to LEVAQUIN® 500 mg by mouth once daily for 10 days.
Clinical success rates (defined as complete or partial resolution of the pre-treatment signs and symptoms of ABS to such an extent that no further antibiotic treatment was deemed necessary) in the microbiologically evaluable population were 91.4% (139/152) in the LEVAQUIN® 750 mg group and 88.6% (132/149) in the LEVAQUIN® 500 mg group at the test-of-cure (TOC) visit (95% CI [-4.2, 10.0] for LEVAQUIN® 750 mg minus LEVAQUIN® 500 mg).
Rates of clinical success by pathogen in the microbiologically evaluable population who had specimens obtained by antral tap at study entry showed comparable results for the five- and ten-day regimens at the test-of-cure visit 22 days post treatment.
Table 18: Clinical Success Rate by Pathogen at the TOC in Microbiologically Evaluable Subjects Who Underwent Antral Puncture (Acute Bacterial Sinusitis)
|Pathogen||LEVAQUIN® 750 mg × 5 days||LEVAQUIN® 500 mg × 10 days|
| Streptococcus pneumoniae
||25/27 (92.6%)||26/27 (96.3%)|
| Haemophilus influenzae ||19/21 (90.5%)||25/27 (92.6%)|
| Moraxella catarrhalis ||10/11 (90.9%)||13/13 (100%)|
Complicated Skin and Skin Structure Infections
Three hundred ninety-nine patients were enrolled in an open-label, randomized, comparative study for complicated skin and skin structure infections. The patients were randomized to receive either LEVAQUIN® 750 mg once daily (IV followed by oral), or an approved comparator for a median of 10 ± 4.7 days. As is expected in complicated skin and skin structure infections, surgical procedures were performed in the LEVAQUIN® and comparator groups. Surgery (incision and drainage or debridement) was performed on 45% of the LEVAQUIN®-treated patients and 44% of the comparator treated patients, either shortly before or during antibiotic treatment and formed an integral part of therapy for this indication.
Among those who could be evaluated clinically 2–5 days after completion of study drug, overall success rates (improved or cured) were 116/138 (84.1%) for patients treated with LEVAQUIN® and 106/132 (80.3%) for patients treated with the comparator.
Success rates varied with the type of diagnosis ranging from 68% in patients with infected ulcers to 90% in patients with infected wounds and abscesses. These rates were equivalent to those seen with comparator drugs.
Chronic Bacterial Prostatitis
Adult patients with a clinical diagnosis of prostatitis and microbiological culture results from urine sample collected after prostatic massage (VB3) or expressed prostatic secretion (EPS) specimens obtained via the Meares-Stamey procedure were enrolled in a multicenter, randomized, double-blind study comparing oral LEVAQUIN® 500 mg, once dailyfor a total of 28 days to oral ciprofloxacin 500 mg, twice daily for a total of 28 days. The primary efficacy endpoint was microbiologic efficacy in microbiologically evaluable patients. A total of 136 and 125 microbiologically evaluable patients were enrolled in the LEVAQUIN® and ciprofloxacin groups, respectively. The microbiologic eradication rate by patient infection at 5–18 days after completion of therapy was 75.0% in the LEVAQUIN® group and 76.8% in the ciprofloxacin group (95% CI [-12.58, 8.98] for LEVAQUIN® minus ciprofloxacin). The overall eradication rates for pathogens of interest are presented in Table 19.
Table 19: Microbiological Eradication Rates (Chronic Bacterial Prostatitis)
|LEVAQUIN® (N=136)||Ciprofloxacin (N=125)|
| E. coli ||15||14 (93.3%)||11||9 (81.8%)|
| E. faecalis ||54||39 (72.2%)||44||33 (75.0%)|
| S. epidermidis Eradication rates shown are for patients who had a sole pathogen only; mixed cultures were excluded.||11||9 (81.8%)||14||11 (78.6%)|
Eradication rates for S. epidermidis when found with other co-pathogens are consistent with rates seen in pure isolates.
Clinical success (cure + improvement with no need for further antibiotic therapy) rates in microbiologically evaluable population 5–18 days after completion of therapy were 75.0% for LEVAQUIN®-treated patients and 72.8% for ciprofloxacin-treated patients (95% CI [-8.87, 13.27] for LEVAQUIN® minus ciprofloxacin). Clinical long-term success (24–45 days after completion of therapy) rates were 66.7% for the LEVAQUIN®-treated patients and 76.9% for the ciprofloxacin-treated patients (95% CI [-23.40, 2.89] for LEVAQUIN® minus ciprofloxacin).
Complicated Urinary Tract Infections and Acute Pyelonephritis: 5-day Treatment Regimen
To evaluate the safety and efficacy of the higher dose and shorter course of LEVAQUIN®, 1109 patients with cUTI and AP were enrolled in a randomized, double-blind, multicenter clinical trial conducted in the US from November 2004 to April 2006 comparing LEVAQUIN® 750 mg IV or orally once daily for 5 days (546 patients) with ciprofloxacin 400 mg IV or 500 mg orally twice daily for 10 days (563 patients). Patients with AP complicated by underlying renal diseases or conditions such as complete obstruction, surgery, transplantation, concurrent infection or congenital malformation were excluded. Efficacy was measured by bacteriologic eradication of the baseline organism(s) at the post-therapy visit in patients with a pathogen identified at baseline. The post-therapy (test-of-cure) visit occurred 10 to 14 days after the last active dose of LEVAQUIN® and 5 to 9 days after the last dose of active ciprofloxacin.
The bacteriologic cure rates overall for LEVAQUIN® and control at the test-of-cure (TOC) visit for the group of all patients with a documented pathogen at baseline (modified intent to treat or mITT) and the group of patients in the mITT population who closely followed the protocol (Microbiologically Evaluable) are summarized in Table 20.
Table 20: Bacteriologic Eradication at Test-of-Cure
| ||LEVAQUIN® 750 mg orally or IV once daily for 5 days||Ciprofloxacin 400 mg IV/500 mg orally twice daily for 10 days||Overall Difference [95% CI]|
| mITT Population The mITT population included patients who received study medication and who had a positive (≥105 CFU/mL) urine culture with no more than 2 uropathogens at baseline. Patients with missing response were counted as failures in this analysis.|
|Overall (cUTI or AP)||252/333||75.7||239/318||75.2||0.5 (-6.1, 7.1)|
| Microbiologically Evaluable Population The Microbiologically Evaluable population included patients with a confirmed diagnosis of cUTI or AP, a causative organism(s) at baseline present at ≥ 105 CFU/mL, a valid test-of-cure urine culture, no pathogen isolated from blood resistant to study drug, no premature discontinuation or loss to follow-up, and compliance with treatment (among other criteria).|
|Overall (cUTI or AP)||228/265||86.0||215/241||89.2||-3.2 [-8.9, 2.5]|
Microbiologic eradication rates in the Microbiologically Evaluable population at TOC for individual pathogens recovered from patients randomized to LEVAQUIN® treatment are presented in Table 21.
Table 21: Microbiological Eradication Rates for Individual Pathogens Recovered From Patients Randomized to LEVAQUIN® 750 mg QD for 5 Days Treatment
|Pathogen||Microbiologic Eradication Rate|
| Escherichia coliThe predominant organism isolated from patients with AP was E. coli: 91% (63/69) eradication in AP and 89% (92/103) in patients with cUTI. ||155/172||90|
| Klebsiella pneumoniae ||20/23||87|
| Proteus mirabilis ||12/12||100|
Complicated Urinary Tract Infections and Acute Pyelonephritis: 10-day Treatment Regimen
To evaluate the safety and efficacy of the 250 mg dose, 10 day regimen of LEVAQUIN®, 567 patients with uncomplicated UTI, mild-to-moderate cUTI, and mild-to-moderate AP were enrolled in a randomized, double-blind, multicenter clinical trial conducted in the US from June 1993 to January 1995 comparing LEVAQUIN® 250 orally once daily for 10 days (285 patients) with ciprofloxacin 500 mg orally twice daily for 10 days (282 patients). Patients with a resistant pathogen, recurrent UTI, women over age 55 years, and with an indwelling catheter were initially excluded, prior to protocol amendment which took place after 30% of enrollment. Microbiological efficacy was measured by bacteriologic eradication of the baseline organism(s) at 1–12 days post-therapy in patients with a pathogen identified at baseline.
The bacteriologic cure rates overall for LEVAQUIN® and control at the test-of-cure (TOC) visit for the group of all patients with a documented pathogen at baseline (modified intent to treat or mITT) and the group of patients in the mITT population who closely followed the protocol (Microbiologically Evaluable) are summarized in Table 22.
Table 22. Bacteriologic Eradication Overall (cUTI or AP) at Test-Of-Cure1–9 days posttherapy for 30% of subjects enrolled prior to a protocol amendment; 5–12 days posttherapy for 70% of subjects.
250 mg once daily for 10 days
500 mg twice daily for 10 days
| mITT Population The mITT population included patients who had a pathogen isolated at baseline. Patients with missing response were counted as failures in this analysis.||174/209||83.3||184/219||84.0|
| Microbiologically Evaluable Population The Microbiologically Evaluable population included mITT patients who met protocol-specified evaluability criteria.||164/177||92.7||159/171||93.0|
Inhalational Anthrax (Post-Exposure)
The effectiveness of LEVAQUIN® for this indication is based on plasma concentrations achieved in humans, a surrogate endpoint reasonably likely to predict clinical benefit. LEVAQUIN® has not been tested in humans for the post-exposure prevention of inhalation anthrax. The mean plasma concentrations of LEVAQUIN® associated with a statistically significant improvement in survival over placebo in the rhesus monkey model of inhalational anthrax are reached or exceeded in adult and pediatric patients receiving the recommended oral and intravenous dosage regimens [see Indications and Usage; Dosage and Administration (2.1, 2.2) ].
Levofloxacin pharmacokinetics have been evaluated in adult and pediatric patients. The mean (± SD) steady state peak plasma concentration in human adults receiving 500 mg orally or intravenously once daily is 5.7 ± 1.4 and 6.4 ± 0.8 mcg/mL, respectively; and the corresponding total plasma exposure (AUC0-24) is 47.5 ± 6.7 and 54.6 ± 11.1 mcg.h/mL, respectively. The predicted steady-state pharmacokinetic parameters in pediatric patients ranging in age from 6 months to 17 years receiving 8 mg/kg orally every 12 hours (not to exceed 250 mg per dose) were calculated to be comparable to those observed in adults receiving 500 mg orally once daily [see Clinical Pharmacology].
In adults, the safety of LEVAQUIN® for treatment durations of up to 28 days is well characterized. However, information pertaining to extended use at 500 mg daily up to 60 days is limited. Prolonged LEVAQUIN® therapy in adults should only be used when the benefit outweighs the risk.
In pediatric patients, the safety of levofloxacin for treatment durations of more than 14 days has not been studied. An increased incidence of musculoskeletal adverse events (arthralgia, arthritis, tendonopathy, gait abnormality) compared to controls has been observed in clinical studies with treatment duration of up to 14 days. Long-term safety data, including effects on cartilage, following the administration of levofloxacin to pediatric patients is limited [ see Warnings and Precautions, Use in Specific Populations ].
A placebo-controlled animal study in rhesus monkeys exposed to an inhaled mean dose of 49 LD50 (~2.7 X 106) spores (range 17 - 118 LD50) of B. anthracis (Ames strain) was conducted. The minimal inhibitory concentration (MIC) of levofloxacin for the anthrax strain used in this study was 0.125 mcg/mL. In the animals studied, mean plasma concentrations of levofloxacin achieved at expected Tmax (1 hour post dose) following oral dosing to steady state ranged from 2.79 to 4.87 mcg/mL. Steady state trough concentrations at 24 hours post-dose ranged from 0.107 to 0.164 mcg/mL. Mean (SD) steady state AUC0-24 was 33.4 ± 3.2 mcg.h/mL (range 30.4 to 36.0 mcg.h/mL). Mortality due to anthrax for animals that received a 30 day regimen of oral LEVAQUIN® beginning 24 hrs post exposure was significantly lower (1/10), compared to the placebo group (9/10) [P=0.0011, 2-sided Fisher’s Exact Test]. The one levofloxacin treated animal that died of anthrax did so following the 30-day drug administration period.
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