Levofloxacin

Distribution

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 levofloxacin, 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.

Metabolism

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.

Excretion

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 levofloxacin.

Geriatric

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 levofloxacin 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. Levofloxacin dose adjustment based on age alone is not necessary [see Use in Specific Populations (8.5)].

Pediatrics

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 (AUC_0-24 and C_max) to those observed in adult patients administered 500 mg of levofloxacin once every 24 hours.

Gender

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 levofloxacin 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.

Race

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.

Renal Impairment

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 levofloxacin are not required following hemodialysis or CAPD [see Dosage and Administration (2.3), Use in Specific Populations (8.6)].

Hepatic Impairment

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 (8.7)].

Bacterial Infection

The pharmacokinetics of levofloxacin 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 levofloxacin and antacids, warfarin, theophylline, cyclosporine, digoxin, probenecid, and cimetidine has been evaluated [see Drug Interactions (7)].

12.4 Microbiology

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.

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 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). 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 Gram-negative and Gram-positive bacteria.

Levofloxacin has been shown to be active against most isolates of the following bacteria both in vitro and in clinical infections as described in Indications and Usage (1):

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] 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.)

Streptococcus pyogenes

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:

Levofloxacin 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 levofloxacin in treating clinical infections due to these bacteria have not been established in adequate and well-controlled clinical trials.

Gram-Positive Bacteria

Staphylococcus haemolyticus

β-hemolytic Streptococcus (Group C/F)

β-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 method^{1 ,2,4} (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 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 procedure^{2 ,3} requires the use of standardized inoculum concentrations. This procedure uses paper disks impregnated with 5 mcg levofloxacin to test the susceptibility of bacteria 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 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 levofloxacin 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.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

In a lifetime bioassay in rats, levofloxacin exhibited no carcinogenic potential following daily dietary administration for 2 years; the highest dose (100 mg/kg/day) was 1.4 times the highest recommended human dose (750 mg) based upon relative body surface area. Levofloxacin did not shorten the time to tumor development of UV-induced skin tumors in hairless albino (Skh-1) mice at any levofloxacin dose level and was therefore not photo-carcinogenic under conditions of this study. Dermal levofloxacin concentrations in the hairless mice ranged from 25 to 42 mcg/g at the highest levofloxacin dose level (300 mg/kg/day) used in the photo-carcinogenicity study. By comparison, dermal levofloxacin concentrations in human subjects receiving 750 mg of levofloxacin averaged approximately 11.8 mcg/g at C_max.

Levofloxacin was not mutagenic in the following assays: Ames bacterial mutation assay (S. typhimurium and E. coli), CHO/HGPRT forward mutation assay, mouse micronucleus test, mouse dominant lethal test, rat unscheduled DNA synthesis assay, and the mouse sister chromatid exchange assay. It was positive in the in vitro chromosomal aberration (CHL cell line) and sister chromatid exchange (CHL/IU cell line) assays.

Levofloxacin caused no impairment of fertility or reproductive performance in rats at oral doses as high as 360 mg/kg/day, corresponding to 4.2 times the highest recommended human dose based upon relative body surface area and intravenous doses as high as 100 mg/kg/day, corresponding to 1.2 times the highest recommended human dose based upon relative body surface area.

13.2 Animal Toxicology and/or Pharmacology

Levofloxacin and other quinolones have been shown to cause arthropathy in immature animals of most species tested [see Warnings and Precautions (5.10)]. In immature dogs (4-5 months old), oral doses of 10 mg/kg/day for 7 days and intravenous doses of 4 mg/kg/day for 14 days of levofloxacin resulted in arthropathic lesions. Administration at oral doses of 300 mg/kg/day for 7 days and intravenous doses of 60 mg/kg/day for 4 weeks produced arthropathy in juvenile rats. Three-month old beagle dogs dosed orally with levofloxacin at 40 mg/kg/day exhibited clinically severe arthrotoxicity resulting in the termination of dosing at Day 8 of a 14-day dosing routine. Slight musculoskeletal clinical effects, in the absence of gross pathological or histopathological effects, resulted from the lowest dose level of 2.5 mg/kg/day (approximately 0.2-fold the pediatric dose based upon AUC comparisons). Synovitis and articular cartilage lesions were observed at the 10 and 40 mg/kg dose levels (approximately 0.7-fold and 2.4-fold the pediatric dose, respectively, based on AUC comparisons). Articular cartilage gross pathology and histopathology persisted to the end of the 18-week recovery period for those dogs from the 10 and 40 mg/kg/day dose levels.

When tested in a mouse ear swelling bioassay, levofloxacin exhibited phototoxicity similar in magnitude to ofloxacin, but less phototoxicity than other quinolones.

While crystalluria has been observed in some intravenous rat studies, urinary crystals are not formed in the bladder, being present only after micturition and are not associated with nephrotoxicity.

In mice, the CNS stimulatory effect of quinolones is enhanced by concomitant administration of non-steroidal anti-inflammatory drugs.

In dogs, levofloxacin administered at 6 mg/kg or higher by rapid intravenous injection produced hypotensive effects. These effects were considered to be related to histamine release.

In vitro and in vivo studies in animals indicate that levofloxacin is neither an enzyme inducer nor inhibitor in the human therapeutic plasma concentration range; therefore, no drug metabolizing enzyme-related interactions with other drugs or agents are anticipated.

14 CLINICAL STUDIES

14.1 Nosocomial Pneumonia

Adult patients with clinically and radiologically documented nosocomial pneumonia were enrolled in a multicenter, randomized, open-label study comparing intravenous levofloxacin (750 mg once daily) followed by oral levofloxacin (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. Levofloxacin-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 levofloxacin arm and 53 of 94 (56.4%) patients in the comparator arm. The average duration of adjunctive therapy was 7 days in the levofloxacin 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 levofloxacin 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 levofloxacin 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 levofloxacin and 60.6% for comparator. The 95% CI for the difference of response rates (levofloxacin minus comparator) was [-17.2, 12.0]. The microbiological eradication rates at the posttherapy visit were 66.7% for levofloxacin and 60.6% for comparator. The 95% CI for the difference of eradication rates (levofloxacin minus comparator) was [-8.3, 20.3]. Clinical success and microbiological eradication rates by pathogen are detailed in Table 11.

14.2 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 levofloxacin 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 levofloxacin 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 (levofloxacin minus comparator) was [-6, 19]. In the second study, 264 patients were enrolled in a prospective, multi-center, non-comparative trial of 500 mg levofloxacin 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 12.

Community-Acquired Pneumonia Due to Multi-Drug Resistant Streptococcus pneumoniae

Levofloxacin was effective for the treatment of community-acquired pneumonia caused by multi-drug resistant Streptococcus pneumoniae (MDRSP). MDRSP isolates are isolates resistant to two or more of the following antibacterials: penicillin (MIC ≥ 2 mcg/mL), 2^nd 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 13.

Table 13: Clinical and Bacterial Success Rates for Levofloxacin-Treated MDRSP in Community Acquired Pneumonia Patients (Population Valid for Efficacy)

	Clinical Success		Bacteriological Success One 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.
Screening Susceptibility	n/N n=the number of microbiologically evaluable patients who were clinical successes; N=number of microbiologically evaluable patients in the designated resistance group.	%	n/N n=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
2 nd 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 14.

14.3 Community-Acquired Pneumonia: 5-Day Treatment Regimen

To evaluate the safety and efficacy of the higher dose and shorter course of levofloxacin, 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 levofloxacin 750 mg, IV or orally, every day for five days or levofloxacin 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 levofloxacin 750 mg group and 91.1% in the levofloxacin 500 mg group. The 95% CI for the difference of response rates (levofloxacin 750 minus levofloxacin 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 levofloxacin 750 mg group and 2 out of 147 patients in the levofloxacin 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 15.

14.4 Acute Bacterial Sinusitis: 5-day and 10-14 day Treatment Regimens

Levofloxacin is approved for the treatment of acute bacterial sinusitis (ABS) using either 750 mg by mouth x 5 days or 500 mg by mouth once daily x 10-14 days. To evaluate the safety and efficacy of a high dose short course of levofloxacin, 780 outpatient adults with clinically and radiologically determined acute bacterial sinusitis were evaluated in a double-blind, randomized, prospective, multicenter study comparing levofloxacin 750 mg by mouth once daily for five days to levofloxacin 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 levofloxacin 750 mg group and 88.6% (132/149) in the levofloxacin 500 mg group at the test-of-cure (TOC) visit (95% CI [-4.2, 10.0] for levofloxacin 750 mg minus levofloxacin 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.

14.5 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 levofloxacin 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 levofloxacin and comparator groups. Surgery (incision and drainage or debridement) was performed on 45% of the levofloxacin-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 levofloxacin 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.

14.6 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 levofloxacin 500 mg, once daily for 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 levofloxacin and ciprofloxacin groups, respectively. The microbiologic eradication rate by patient infection at 5-18 days after completion of therapy was 75.0% in the levofloxacin group and 76.8% in the ciprofloxacin group (95% CI [-12.58, 8.98] for levofloxacin minus ciprofloxacin). The overall eradication rates for pathogens of interest are presented in Table 17.

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 levofloxacin-treated patients and 72.8% for ciprofloxacin-treated patients (95% CI [-8.87, 13.27] for levofloxacin minus ciprofloxacin). Clinical long-term success (24-45 days after completion of therapy) rates were 66.7% for the levofloxacin-treated patients and 76.9% for the ciprofloxacin-treated patients (95% CI [-23.40, 2.89] for levofloxacin minus ciprofloxacin).

14.7 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 levofloxacin, 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 levofloxacin 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 levofloxacin and 5 to 9 days after the last dose of active ciprofloxacin.

The bacteriologic cure rates overall for levofloxacin 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 18.

Microbiologic eradication rates in the Microbiologically Evaluable population at TOC for individual pathogens recovered from patients randomized to levofloxacin treatment are presented in Table 19.

14.8 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 levofloxacin, 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 levofloxacin 250 mg 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 levofloxacin 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: Bacteriological 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.

	Levofloxacin 250 mg once daily for 10 days		Ciprofloxacin 500 mg twice daily for 10 days
	n/N	%	n/N	%
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

14.9 Inhalational Anthrax (Post-Exposure)

The effectiveness of levofloxacin for this indication is based on plasma concentrations achieved in humans, a surrogate endpoint reasonably likely to predict clinical benefit. Levofloxacin has not been tested in humans for the post-exposure prevention of inhalation anthrax. The mean plasma concentrations of levofloxacin 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 (1.13); 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 (AUC_0-24) 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 (12.3)].

In adults, the safety of levofloxacin 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 levofloxacin 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, tendinopathy, 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 (5.10), Use in Specific Populations (8.4)].

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 T_max (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 AUC_0-24 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 levofloxacin 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.

14.10 Plague

Efficacy studies of levofloxacin could not be conducted in humans with pneumonic plague for ethical and feasibility reasons. Therefore, approval of this indication was based on an efficacy study conducted in animals.

The mean plasma concentrations of levofloxacin associated with a statistically significant improvement in survival over placebo in an African green monkey model of pneumonic plague are reached or exceeded in adult and pediatric patients receiving the recommended oral and intravenous dosage regimens [see Indications and Usage (1.14), 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 (AUC_0-24) 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 (12.3)].

A placebo-controlled animal study in African green monkeys exposed to an inhaled mean dose of 65 LD₅₀ (range 3 to 145 LD₅₀) of Yersinia pestis (CO92 strain) was conducted. The minimal inhibitory concentration (MIC) of levofloxacin for the Y. pestis strain used in this study was 0.03 mcg/mL. Mean plasma concentrations of levofloxacin achieved at the end of a single 30-min infusion ranged from 2.84 to 3.50 mcg/mL in African green monkeys. Trough concentrations at 24 hours post-dose ranged from <0.03 to 0.06 mcg/mL. Mean (SD) AUC_0-24 was 11.9 (3.1) mcg.h/mL (range 9.50 to 16.86 mcg.h/mL). Animals were randomized to receive either a 10-day regimen of i.v. levofloxacin or placebo beginning within 6 hrs of the onset of telemetered fever (≥ 39°C for more than 1 hour). Mortality in the levofloxacin group was significantly lower (1/17) compared to the placebo group (7/7) [p<0.001, Fisher’s Exact Test; exact 95% confidence interval (-99.9%, -55.5%) for the difference in mortality]. One levofloxacin-treated animal was euthanized on Day 9 post-exposure to Y. pestis due to a gastric complication; it had a blood culture positive for Y. pestis on Day 3 and all subsequent daily blood cultures from Day 4 through Day 7 were negative.

15 REFERENCES

• 1.Clinical and Laboratory Standards Institute (CLSI). Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria That Grow Aerobically Approved Standard – 9^th ed. CLSI Document, M7-A9, CLSI, 950 West Valley Rd., Suite 2500, Wayne, PA, 2012.
• 2.CLSI. Performance Standards for Antimicrobial Susceptibility Testing; 22^nd Informational Supplement. CLSI Document M100 - S22, 2012.
• 3.CLSI Performance Standards for Antimicrobial Disk Susceptibility Tests. Approved Standard – 11th ed. CLSI M2-A11, 2012.
• 4.CLSI. Methods for Antimicrobial Dilution and Disk Susceptibility Testing of Infrequently Isolated or Fastidious Bacteria; Approved Guideline – 2nd ed. CLSI Document M45-A2, 2010.

16 HOW SUPPLIED/STORAGE AND HANDLING

16.1 LEVOFLOXACIN INJECTION Pre-Mixed Solution, Single-Use in Flexible Container

Levofloxacin Injection in 5% dextrose is supplied as a single-use, premixed solution in flexible containers. Each bag contains a dilute solution with the equivalent of 250, 500, or 750 mg of levofloxacin, respectively, in 5% Dextrose (D₅W).

Storage Conditions

Store at or below 25°C (77°F); however, brief exposure up to 40°C (104°F) does not adversely affect the product.

Avoid excessive heat. Protect from freezing.

Protect from light.

Sterile, Nonpyrogenic , Preservative-free, PVC-free, DEHP-free.

The container closure is not made with natural rubber latex.

17 PATIENT COUNSELING INFORMATION

See FDA-Approved Medication Guide (17.6)

17.1 Antibacterial Resistance

Antibacterial drugs including levofloxacin should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When levofloxacin is prescribed to treat a bacterial infection, patients should be told that although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed. Skipping doses or not completing the full course of therapy may (1) decrease the effectiveness of the immediate treatment and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by levofloxacin or other antibacterial drugs in the future.

17.2 Administration with Food, Fluids, and Concomitant Medications

Patients should drink fluids liberally while taking levofloxacin to avoid formation of a highly concentrated urine and crystal formation in the urine.

17.3 Serious and Potentially Serious Side Effects

Patients should be informed of the following serious adverse reactions that have been associated with levofloxacin or other fluoroquinolone use:

• • Tendon Disorders: Patients should contact their healthcare provider if they experience pain, swelling, or inflammation of a tendon, or weakness or inability to use one of their joints; rest and refrain from exercise; and discontinue levofloxacin treatment. The risk of severe tendon disorders with fluoroquinolones is higher in older patients usually over 60 years of age, in patients taking corticosteroid drugs, and in patients with kidney, heart or lung transplants.
• • Exacerbation of Myasthenia Gravis: Patients should inform their physician of any history of myasthenia gravis. Patients should notify their physician if they experience any symptoms of muscle weakness, including respiratory difficulties.
• • Hypersensitivity Reactions: Patients should be informed that levofloxacin can cause hypersensitivity reactions, even following the first dose. Patients should discontinue the drug at the first sign of a skin rash, hives or other skin reactions, a rapid heartbeat, difficulty in swallowing or breathing, any swelling suggesting angioedema (e.g., swelling of the lips, tongue, face, tightness of the throat, hoarseness), or other symptoms of an allergic reaction.
• • Hepatotoxicity: Severe hepatotoxicity (including acute hepatitis and fatal events) has been reported in patients taking levofloxacin. Patients should inform their physician and be instructed to discontinue levofloxacin treatment immediately if they experience any signs or symptoms of liver injury including: loss of appetite, nausea, vomiting, fever, weakness, tiredness, right upper quadrant tenderness, itching, yellowing of the skin and eyes, light colored bowel movements or dark colored urine.
• • Convulsions: Convulsions have been reported in patients taking fluoroquinolones, including levofloxacin. Patients should notify their physician before taking this drug if they have a history of convulsions.
• • Neurologic Adverse Effects (e.g., dizziness, lightheadedness, increased intracranial pressure): Patients should know how they react to levofloxacin before they operate an automobile or machinery or engage in other activities requiring mental alertness and coordination. Patients should notify their physician if persistent headache with or without blurred vision occurs.
• • Diarrhea: Diarrhea is a common problem caused by antibiotics which usually ends when the antibiotic is discontinued. Sometimes after starting treatment with antibiotics, patients can develop watery and bloody stools (with or without stomach cramps and fever) even as late as two or more months after having taken the last dose of the antibiotic. If this occurs, patients should contact their physician as soon as possible.
• • Peripheral Neuropathies: If symptoms of peripheral neuropathy including pain, burning, tingling, numbness, and/or weakness develop, patients should discontinue treatment and contact their physician.
• • Prolongation of the QT Interval: Patients should inform their physician of any personal or family history of QT prolongation or proarrhythmic conditions such as hypokalemia, bradycardia, or recent myocardial ischemia; if they are taking any Class IA (quinidine, procainamide), or Class III (amiodarone, sotalol) antiarrhythmic agents. Patients should notify their physicians if they have any symptoms of prolongation of the QT interval, including prolonged heart palpitations or a loss of consciousness.
• • Musculoskeletal Disorders in Pediatric Patients: Parents should inform their child's physician if their child has a history of joint-related problems before taking this drug. Parents of pediatric patients should also notify their child's physician of any tendon or joint-related problems that occur during or following levofloxacin therapy [see Warnings and Precautions (5.10) and Use in Specific Populations (8.4)].
• • Photosensitivity/ Phototoxicity : Patients should be advised that photosensitivity/phototoxicity has been reported in patients receiving fluoroquinolone antibiotics. Patients should minimize or avoid exposure to natural or artificial sunlight (tanning beds or UVA/B treatment) while taking fluoroquinolones. If patients need to be outdoors when taking fluoroquinolones, they should wear loose-fitting clothes that protect skin from sun exposure and discuss other sun protection measures with their physician. If a sunburn like reaction or skin eruption occurs, patients should contact their physician.

17.4 Drug Interactions with Insulin, Oral Hypoglycemic Agents, and Warfarin

Patients should be informed that if they are diabetic and are being treated with insulin or an oral hypoglycemic agent and a hypoglycemic reaction occurs, they should discontinue levofloxacin and consult a physician.

Patients should be informed that concurrent administration of warfarin and levofloxacin has been associated with increases of the International Normalized Ratio (INR) or prothrombin time and clinical episodes of bleeding. Patients should notify their physician if they are taking warfarin, be monitored for evidence of bleeding, and also have their anticoagulation tests closely monitored while taking warfarin concomitantly.

17.5 Plague and Anthrax Studies

Patients given levofloxacin for these conditions should be informed that efficacy studies could not be conducted in humans for ethical and feasibility reasons. Therefore, approval for these conditions was based on efficacy studies conducted in animals.

Manufactured by

ACS Dobfar Info S.A.

Casai, 7748 - Campascio, Switzerland for

Sandoz Inc.,

Princeton, NJ 08540

Revised: May 2012

17.6 FDA-Approved Medication Guide

MEDICATION GUIDE

LEVOFLOXACIN (lee voe FLOX a sin) INJECTION

in 5% Dextrose

For Intravenous Use

Read this Medication Guide before you start taking LEVOFLOXACIN and each time you get a refill. There may be new information. This Medication Guide does not take the place of talking to your healthcare provider about your medical condition or your treatment.

What is the most important information I should know about LEVOFLOXACIN?

LEVOFLOXACIN , a fluoroquinolone antibiotic, can cause serious side effects. Some of these serious side effects could result in death.

If you have any of the following serious side effects while you take LEVOFLOXACIN, get medical help right away. Talk with your healthcare provider about whether you should continue to take LEVOFLOXACIN.

• 1. Tendon rupture or swelling of the tendon (tendinitis).

• • Tendon problems can happen in people of all ages who take LEVOFLOXACIN.
  Tendons are tough cords of tissue that connect muscles to bones.
  Some tendon problems include pain, swelling, tears, and inflammation of tendons including the back of the ankle (Achilles), shoulder, hand, or other tendon sites.
• •The risk of getting tendon problems while you take LEVOFLOXACIN is higher if you:
  • oare over 60 years of age
  • oare taking steroids (corticosteroids)
  • ohave had a kidney, heart or lung transplant.
• •Tendon problems can happen in people who do not have the above risk factors when they take LEVOFLOXACIN.
• •Other reasons that can increase your risk of tendon problems can include:
  • ophysical activity or exercise
  • okidney failure
  • otendon problems in the past, such as in people with rheumatoid arthritis (RA).
• •Call your healthcare provider right away at the first sign of tendon pain, swelling or inflammation. Stop taking LEVOFLOXACIN until tendinitis or tendon rupture has been ruled out by your healthcare provider. Avoid exercise and using the affected area.
  The most common area of pain and swelling is the Achilles tendon at the back of your ankle. This can also happen with other tendons. Talk to your healthcare provider about the risk of tendon rupture with continued use of LEVOFLOXACIN. You may need a different antibiotic that is not a fluoroquinolone to treat your infection.
• •Tendon rupture can happen while you are taking or after you have finished taking LEVOFLOXACIN. Tendon ruptures have happened up to several months after people have finished taking their fluoroquinolone.
• •Get medical help right away if you get any of the following signs or symptoms of a tendon rupture:
  • ohear or feel a snap or pop in a tendon area
  • obruising right after an injury in a tendon area
  • ounable to move the affected area or bear weight
• 2. Worsening of myasthenia gravis (a problem that causes muscle weakness). Fluoroquinolones like LEVOFLOXACIN may cause worsening of myasthenia gravis symptoms, including muscle weakness and breathing problems. Call your healthcare provider right away if you have any worsening muscle weakness or breathing problems.

• •See “What are the possible side effects of LEVOFLOXACIN?”

What is LEVOFLOXACIN?

LEVOFLOXACIN is a fluoroquinolone antibiotic medicine used in adults age 18 years or older to treat certain infections caused by certain germs called bacteria. These bacterial infections include:

• •nosocomial pneumonia
• •community-acquired pneumonia
• •acute sinus infection
• •acute worsening of chronic bronchitis
• •skin infections, complicated and uncomplicated
• •chronic prostate infection
• •urinary tract infections, complicated and uncomplicated
• •acute kidney infection (pyelonephritis)
• •inhalational anthrax
• •plague

Studies of LEVOFLOXACIN for use in the treatment of plague and anthrax were done in animals only, because plague and anthrax could not be studied in people.

LEVOFLOXACIN is also used to treat children who are 6 months of age or older and may have breathed in anthrax germs, have plague, or been exposed to plague germs.

It is not known if LEVOFLOXACIN is safe and effective in children under 6 months of age.

The safety and effectiveness in children treated with LEVOFLOXACIN for more than 14 days is not known.

Who should not take LEVOFLOXACIN?

Do not take LEVOFLOXACIN if you have ever had a severe allergic reaction to an antibiotic known as a fluoroquinolone, or if you are allergic to LEVOFLOXACIN or any of the ingredients in LEVOFLOXACIN. See the end of this leaflet for a complete list of ingredients in LEVOFLOXACIN.

What should I tell my healthcare provider before taking LEVOFLOXACIN?

Before you take LEVOFLOXACIN, tell your healthcare provider if you:

• •have tendon problems
• •have a problem that causes muscle weakness (myasthenia gravis)
• •have central nervous system problems such as seizures (epilepsy)
• •have nerve problems
• •have or anyone in your family has an irregular heartbeat, especially a condition called “QT prolongation.”
• •have low blood potassium (hypokalemia)
• •have bone problems
• •have joint problems including rheumatoid arthritis (RA)
• •have kidney problems. You may need a lower dose of LEVOFLOXACIN if your kidneys do not work well.
• •have liver problems
• •have diabetes or problems with low blood sugar (hypoglycemia)
• •are pregnant or plan to become pregnant. It is not known if LEVOFLOXACIN will harm your unborn child.
• •are breastfeeding or plan to breastfeed. It is not known if LEVOFLOXACIN passes into your breast milk. You and your healthcare provider should decide if you will take LEVOFLOXACIN or breastfeed. You should not do both.

Tell your healthcare provider about all the medicines you take, including prescription and non-prescription medicines, vitamins, and herbal supplements.

LEVOFLOXACIN and other medicines can affect each other causing side effects.

Especially tell your healthcare provider if you take:

• •a steroid medicine
• •an anti-psychotic medicine
• •a tricyclic antidepressant
• •a water pill (diuretic)
• •a blood thinner (warfarin, Coumadin, Jantoven)
• •an oral anti-diabetes medicine or insulin
• •an NSAID (Non-Steroidal Anti-Inflammatory Drug). Many common medicines for pain relief are NSAIDs. Taking an NSAID while you take LEVOFLOXACIN or other fluoroquinolones may increase your risk of central nervous system effects and seizures.
• •theophylline (Theo-24®, Elixophyllin®, Theochron®, Uniphyl®, Theolair®)
• •a medicine to control your heart rate or rhythm (antiarrhythmics).

Ask your healthcare provider if you are not sure if any of your medicines are listed above.

Know the medicines you take. Keep a list of your medicines and show it to your healthcare provider and pharmacist when you get a new medicine.

How should I take LEVOFLOXACIN?

• •Take LEVOFLOXACIN at about the same time each day.
• •Drink plenty of fluids while you take LEVOFLOXACIN.
• •If you miss a dose of LEVOFLOXACIN, take it as soon as you remember. Do not take more than 1 dose in 1 day.
• •Take LEVOFLOXACIN exactly as your healthcare provider tells you to take it.
• •LEVOFLOXACIN for Injection is given by slow intravenous (I.V.) infusion into your vein over 60 or 90 minutes as prescribed by your healthcare provider.
• •Do not skip any doses of LEVOFLOXACIN or stop taking it, even if you begin to feel better, until you finish your prescribed treatment unless:
  • ∘you have tendon problems. See “What is the most important information I should know about LEVOFLOXACIN?”
  • ∘you have a serious allergic reaction. See “What are the possible side effects of LEVOFLOXACIN?”
  • ∘your healthcare provider tells you to stop taking LEVOFLOXACIN.

Taking all of your LEVOFLOXACIN doses will help make sure that all of the bacteria are killed. Taking all of your LEVOFLOXACIN doses will help you lower the chance that the bacteria will become resistant to LEVOFLOXACIN. If your infection does not get better while you take LEVOFLOXACIN, it may mean that the bacteria causing your infection may be resistant to LEVOFLOXACIN. If your infection does not get better, call your healthcare provider. If your infection does not get better, LEVOFLOXACIN and other similar antibiotic medicines may not work for you in the future.

• •If you take too much LEVOFLOXACIN, call your healthcare provider or get medical help right away.

What should I avoid while taking LEVOFLOXACIN?

• •LEVOFLOXACIN can make you feel dizzy and lightheaded. Do not drive, operate machinery, or do other activities that require mental alertness or coordination until you know how LEVOFLOXACIN affects you.
• •Avoid sunlamps, tanning beds, and try to limit your time in the sun. LEVOFLOXACIN can make your skin sensitive to the sun (photosensitivity) and the light from sunlamps and tanning beds. You could get severe sunburn, blisters or swelling of your skin. If you get any of these symptoms while you take LEVOFLOXACIN, call your healthcare provider right away. You should use a sunscreen and wear a hat and clothes that cover your skin if you have to be in sunlight.

What are the possible side effects of LEVOFLOXACIN?

LEVOFLOXACIN can cause serious side effects, including:

• •See “What is the most important information I should know about LEVOFLOXACIN?”
• • Serious allergic reactions.
  Allergic reactions can happen in people taking fluoroquinolones, including LEVOFLOXACIN, even after only 1 dose. Stop taking LEVOFLOXACIN and get emergency medical help right away if you have any of the following symptoms of a severe allergic reaction:
  • ∘hives
  • ∘trouble breathing or swallowing
  • ∘swelling of the lips, tongue, face
  • ∘throat tightness, hoarseness
  • ∘rapid heartbeat
  • ∘faint
  • ∘skin rash
    Skin rash may happen in people taking LEVOFLOXACIN, even after only 1 dose. Stop taking LEVOFLOXACIN at the first sign of a skin rash and call your healthcare provider. Skin rash may be a sign of a more serious reaction to LEVOFLOXACIN.
• • Liver damage (hepatotoxicity): Hepatotoxicity can happen in people who take LEVOFLOXACIN. Call your healthcare provider right away if you have unexplained symptoms such as:
  • ∘nausea or vomiting
  • ∘stomach pain
  • ∘fever
  • ∘weakness
  • ∘abdominal pain or tenderness
  • ∘itching
  • ∘unusual tiredness
  • ∘loss of appetite
  • ∘light colored bowel movements
  • ∘dark colored urine
  • ∘yellowing of your skin or the whites of your eyes
    Stop taking LEVOFLOXACIN and tell your healthcare provider right away if you have yellowing of your skin or white part of your eyes, or if you have dark urine. These can be signs of a serious reaction to LEVOFLOXACIN (a liver problem).
• • Central Nervous System Effects. Seizures have been reported in people who take fluoroquinolone antibiotics including LEVOFLOXACIN. Tell your healthcare provider if you have a history of seizures. Ask your healthcare provider whether taking LEVOFLOXACIN will change your risk of having a seizure.
  
  Central Nervous System (CNS) side effects may happen as soon as after taking the first dose of LEVOFLOXACIN. Talk to your healthcare provider right away if you get any of these side effects, or other changes in mood or behavior:
  • ∘seizures
  • ∘hear voices, see things, or sense things that are not there (hallucinations)
  • ∘feel restless
  • ∘tremors
  • ∘feel anxious or nervous
  • ∘confusion
  • ∘depression
  • ∘trouble sleeping
  • ∘nightmares
  • ∘feel lightheaded
  • ∘feel more suspicious (paranoia)
  • ∘suicidal thoughts or acts
  • ∘a headache that will not go away, with or without blurred vision
• • Intestine infection (Pseudomembranous colitis )
  Pseudomembranous colitis can happen with many antibiotics, including LEVOFLOXACIN. Call your healthcare provider right away if you get watery diarrhea, diarrhea that does not go away, or bloody stools. You may have stomach cramps and a fever. Pseudomembranous colitis can happen 2 or more months after you have finished your antibiotic.
• • Changes in sensation and possible nerve damage (Peripheral Neuropathy )
  Damage to the nerves in arms, hands, legs, or feet can happen in people taking fluoroquinolones, including LEVOFLOXACIN. Talk with your healthcare provider right away if you get any of the following symptoms of peripheral neuropathy in your arms, hands, legs, or feet:
  • ∘pain
  • ∘burning
  • ∘tingling
  • ∘numbness
  • ∘weakness

LEVOFLOXACIN may need to be stopped to prevent permanent nerve damage.

• • Serious heart rhythm changes (QT prolongation and torsades de pointes )
  Tell your healthcare provider right away if you have a change in your heart beat (a fast or irregular heartbeat), or if you faint. LEVOFLOXACIN may cause a rare heart problem known as prolongation of the QT interval. This condition can cause an abnormal heartbeat and can be very dangerous. The chances of this happening are higher in people:
  • ∘who are elderly
  • ∘with a family history of prolonged QT interval
  • ∘with low blood potassium (hypokalemia)
  • ∘who take certain medicines to control heart rhythm (antiarrhythmics)
• • Joint Problems
  Increased chance of problems with joints and tissues around joints in children can happen. Tell your child's healthcare provider if your child has any joint problems during or after treatment with LEVOFLOXACIN.
• • Changes in blood sugar
  People who take LEVOFLOXACIN and other fluoroquinolone medicines with oral anti-diabetes medicines or with insulin can get low blood sugar (hypoglycemia) and high blood sugar (hyperglycemia). Follow your healthcare provider's instructions for how often to check your blood sugar. If you have diabetes and you get low blood sugar while taking LEVOFLOXACIN, stop taking LEVOFLOXACIN and call your healthcare provider right away. Your antibiotic medicine may need to be changed.
• • Sensitivity to sunlight (photosensitivity )
  See “What should I avoid while taking LEVOFLOXACIN?”

The most common side effects of LEVOFLOXACIN include:

• • ∘nausea
  • ∘headache
  • ∘diarrhea
  • ∘insomnia
  • ∘constipation
  • ∘dizziness

In children 6 months and older who take LEVOFLOXACIN to treat anthrax disease or plague, vomiting is also common.

Low blood pressure can happen when LEVOFLOXACIN is given too fast by IV injection. Tell your healthcare provider if you feel dizzy or faint during a treatment with LEVOFLOXACIN Injection.

LEVOFLOXACIN may cause false-positive urine screening results for opiates when testing is done with some commercially available kits. A positive result should be confirmed using a more specific test.

These are not all the possible side effects of LEVOFLOXACIN. Tell your healthcare provider about any side effect that bothers you or that does not go away.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

How should I store levofloxacin?

Store at or below 25°C (77°F); however, brief exposure up to 40°C (104°F) does not adversely

affect the product.

Avoid excessive heat. Protect from freezing.

Protect from light

Keep LEVOFLOXACIN and all medicines out of the reach of children.

General Information about the safe and effective use of LEVOFLOXACIN

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use LEVOFLOXACIN for a condition for which it is not prescribed. Do not give LEVOFLOXACIN to other people, even if they have the same symptoms that you have. It may harm them.

This Medication Guide summarizes the most important information about LEVOFLOXACIN. If you would like more information about LEVOFLOXACIN, talk with your healthcare provider. You can ask your healthcare provider or pharmacist for information about LEVOFLOXACIN that is written for healthcare professionals.

What are the ingredients in LEVOFLOXACIN?

LEVOFLOXACIN Injection in 5% dextrose in Single-Use Flexible Containers:

• •Active ingredient: levofloxacin.
• •Inactive ingredients: Dextrose (D₅W). Solutions of hydrochloric acid and sodium hydroxide may have been added to adjust the pH.

Revised: May 2012

L20USLFX03

Manufactured by

ACS Dobfar Info S.A.

Casai, 7748 - Campascio, Switzerland for

Sandoz Inc.,

Princeton, NJ 08540

This Medication Guide has been approved by the U.S. Food and Drug Administration.

50 mL Carton