DRUG INTERACTIONS SECTION.

7 DRUG INTERACTIONS. Interacting Drug Interaction Multivalent cation-containing products including antacids, metal cations or didanosineAbsorption of levofloxacin is decreased when the tablet formulation is taken within hours of these products. (2.4, 7.1)WarfarinEffect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (7.2) Antidiabetic agentsCarefully monitor blood glucose (5.11, 7.3). 7.1 Chelation Agents: Antacids, Sucralfate, Metal Cations, Multivitamins. While the chelation by divalent cations is less marked than with other fluoroquinolones, concurrent administration of levofloxacin tablets with antacids containing magnesium, or aluminum, as well as sucralfate, metal cations such as iron, and multivitamin preparations with zinc may interfere with the gastrointestinal absorption of levofloxacin, resulting in systemic levels considerably lower than desired. Tablets with antacids containing magnesium, aluminum, as well as sucralfate, metal cations such as iron, and multivitamins preparations with zinc or didanosine may substantially interfere with the gastrointestinal absorption of levofloxacin, resulting in systemic levels considerably lower than desired. These agents should be taken at least two hours before or two hours after oral levofloxacin administration. 7.2 Warfarin. No significant effect of levofloxacin on the peak plasma concentrations, AUC, and other disposition parameters for R- and S- warfarin was detected in clinical study involving healthy volunteers. Similarly, no apparent effect of warfarin on levofloxacin absorption and disposition was observed. However, there have been reports during the postmarketing experience in patients that levofloxacin enhances the effects of warfarin. Elevations of the prothrombin time in the setting of concurrent warfarin and levofloxacin use have been associated with episodes of bleeding. Prothrombin time, International Normalized Ratio (INR), or other suitable anticoagulation tests should be closely monitored if levofloxacin is administered concomitantly with warfarin. Patients should also be monitored for evidence of bleeding [see Adverse Reactions (6.3 ); Patient Counseling Information (17.4)]. 7.3 Antidiabetic Agents. Disturbances of blood glucose, including hyperglycemia and hypoglycemia, have been reported in patients treated concomitantly with fluoroquinolones and an antidiabetic agent. Therefore, careful monitoring of blood glucose is recommended when these agents are co-administered [see Warnings and Precautions (5.11); Adverse Reactions (6.2), Patient Counseling Information (17.4)]. 7.4 Non-Steroidal Anti-Inflammatory Drugs. The concomitant administration of non-steroidal anti-inflammatory drug with fluoroquinolone, including levofloxacin, may increase the risk of CNS stimulation and convulsive seizures [see Warnings and Precautions (5.6)].. 7.5 Theophylline. No significant effect of levofloxacin on the plasma concentrations, AUC, and other disposition parameters for theophylline was detected in clinical study involving healthy volunteers. Similarly, no apparent effect of theophylline on levofloxacin absorption and disposition was observed. However, concomitant administration of other fluoroquinolones with theophylline has resulted in prolonged elimination half-life, elevated serum theophylline levels, and subsequent increase in the risk of theophylline-related adverse reactions in the patient population. Therefore, theophylline levels should be closely monitored and appropriate dosage adjustments made when levofloxacin is coadministered. Adverse reactions, including seizures, may occur with or without an elevation in serum theophylline levels [see Warnings and Precautions (5.6)].. 7.6 Cyclosporine. No significant effect of levofloxacin on the peak plasma concentrations, AUC, and other disposition parameters for cyclosporine was detected in clinical study involving healthy volunteers. However, elevated serum levels of cyclosporine have been reported in the patient population when co-administered with some other fluoroquinolones. Levofloxacin Cmax and ke were slightly lower while Tmax and 1/2 were slightly longer in the presence of cyclosporine than those observed in other studies without concomitant medication. The differences, however, are not considered to be clinically significant. Therefore, no dosage adjustment is required for levofloxacin or cyclosporine when administered concomitantly.. 7.7 Digoxin. No significant effect of levofloxacin on the peak plasma concentrations, AUC, and other disposition parameters for digoxin was detected in clinical study involving healthy volunteers. Levofloxacin absorption and disposition kinetics were similar in the presence or absence of digoxin. Therefore, no dosage adjustment for levofloxacin or digoxin is required when administered concomitantly. 7.8 Probenecid and Cimetidine. No significant effect of probenecid or cimetidine on the Cmax of levofloxacin was observed in clinical study involving healthy volunteers. The AUC and 1/2 of levofloxacin were higher while CL/F and CLR were lower during concomitant treatment of levofloxacin with probenecid or cimetidine compared to levofloxacin alone. However, these changes do not warrant dosage adjustment for levofloxacinwhen probenecid or cimetidine is co-administered. 7.9 Interactions with Laboratory or Diagnostic Testing. Some fluoroquinolones, including levofloxacin, may produce false-positive urine screening results for opiates using commercially available immunoassay kits. Confirmation of positive opiate screens by more specific methods may be necessary.

ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS. The most common reactions (>=3%) were nausea, headache, diarrhea, insomnia, constipation and dizziness (6.2). To report SUSPECTED ADVERSE REACTIONS, contact Dr. Reddys Laboratories Inc. at 1-888-375-3784 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.. 6.1 Serious and Otherwise Important Adverse Reactions. oThe following serious and otherwise important adverse drug reactions are discussed in greater detail in other sections of labeling:oTendon Effects [seeWarnings and Precautions (5.1) ]oExacerbation of Myasthenia Gravis [see Warnings and Precautions (5.2)]oHypersensitivity Reactions [see Warnings and Precautions (5.3) ]oOther Serious and Sometimes Fatal Reactions [seeWarnings and Precautions (5.4) ]oHepatotoxicity [seeWarnings and Precautions (5.5) ]oCentral Nervous System Effects [seeWarnings and Precautions (5.6) ]oClostridium difficile-Associated Diarrhea [seeWarnings and Precautions (5.7) ]oPeripheral Neuropathy that mat be irreversible [seeWarnings and Precautions (5.8) ]oProlongation of the QT Interval [seeWarnings and Precautions (5.9) ]oMusculoskeletal Disorders in Pediatric Patients [seeWarnings and Precautions (5.10) ]oBlood Glucose Disturbances [seeWarnings and Precautions (5.11) ]oPhotosensitivity/Phototoxicity [seeWarnings and Precautions (5.12)]oDevelopment of Drug Resistant Bacteria [seeWarnings and Precautions (5.13) ]Crystalluria and cylindruria have been reported with quinolones, including levofloxacin. Therefore, adequate hydration of patients receiving levofloxacin should be maintained to prevent the formation of highly concentrated urine [see Dosageand Administration (2.5)]. oThe following serious and otherwise important adverse drug reactions are discussed in greater detail in other sections of labeling:. oTendon Effects [seeWarnings and Precautions (5.1) ]. oExacerbation of Myasthenia Gravis [see Warnings and Precautions (5.2)]. oHypersensitivity Reactions [see Warnings and Precautions (5.3) ]. oOther Serious and Sometimes Fatal Reactions [seeWarnings and Precautions (5.4) ]. oHepatotoxicity [seeWarnings and Precautions (5.5) ]. oCentral Nervous System Effects [seeWarnings and Precautions (5.6) ]. oClostridium difficile-Associated Diarrhea [seeWarnings and Precautions (5.7) ]. oPeripheral Neuropathy that mat be irreversible [seeWarnings and Precautions (5.8) ]. oProlongation of the QT Interval [seeWarnings and Precautions (5.9) ]. oMusculoskeletal Disorders in Pediatric Patients [seeWarnings and Precautions (5.10) ]. oBlood Glucose Disturbances [seeWarnings and Precautions (5.11) ]. oPhotosensitivity/Phototoxicity [seeWarnings and Precautions (5.12)]. oDevelopment of Drug Resistant Bacteria [seeWarnings and Precautions (5.13) ]. 6.2 Clinical Trial Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The data described below reflect exposure to levofloxacin in 7537 patients in 29 pooled Phase clinical trials. The population studied had mean age of 50 years (approximately 74% of the population was 65 years of age), 50% were male, 71% were Caucasian, 19% were Black. Patients were treated with levofloxacin for wide variety of infectious diseases [see Indications and Usage (1)]. Patients received levofloxacin doses of 750 mg once daily, 250 mg once daily, or 500 mg once or twice daily. Treatment duration was usually to 14 days, and the mean number of days on therapy was 10 days. The overall incidence, type and distribution of adverse reactions was similar in patients receiving levofloxacin doses of 750 mg once daily, 250 mg once daily, and 500 mg once or twice daily. Discontinuation of levofloxacin due to adverse drug reactions occurred in 4.3% of patients overall, 3.8% of patients treated with the 250 mg and 500 mg doses and 5.4% of patients treated with the 750 mg dose. The most common adverse drug reactions leading to discontinuation with the 250 and 500 mg doses were gastrointestinal (1.4%), primarily nausea (0.6%); vomiting (0.4%); dizziness (0.3%); and headache (0.2%). The most common adverse drug reactions leading to discontinuation with the 750 mg dose were gastrointestinal (1.2%), primarily nausea (0.6%), vomiting (0.5%); dizziness (0.3%); and headache (0.3%). Adverse reactions occurring in >=1% of levofloxacin-treated patients and less common adverse reactions, occurring in 0.1 to <1% of levofloxacin-treated patients, are shown in Table and Table 7, respectively. The most common adverse drug reactions (>=3%) are nausea, headache, diarrhea, insomnia, constipation, and dizziness.Table 6: Common (>=1%) Adverse Reactions Reported in Clinical Trials with levofloxacinSystem/Organ ClassAdverse Reaction% (N=7537)Infections and Infestationsmoniliasis1Psychiatric Disordersinsomnia [see Warnings and Precautions (5.6)] 4Nervous System Disordersheadachedizziness [see Warnings and Precautions (5.6) ]63Respiratory, Thoracic andMediastinal Disordersdyspnea [see Warnings and Precautions (5.3)] 1Gastrointestinal Disordersnauseadiarrhea constipation abdominal pain vomiting dyspepsia753222Skin and SubcutaneousTissue Disordersrash [see Warnings and Precautions (5.3) ]pruritus21Reproductive System andBreast Disordersvaginitis1+ General Disorders andAdministration SiteConditionsedemainjection site reaction chest pain111 = 7274+ N=3758 (women) Table Less Common (0.1 to 1%) Adverse Reactions Reported in Clinical Trials with levofloxacin (N=7537)System/Organ ClassAdverse ReactionInfections and Infestationsgenital moniliasisBlood and Lymphatic SystemDisordersanemiathrombocytopenia granulocytopenia[see Warnings and Precautions (5.4)] Immune System Disordersallergic reaction [See Warnings and Precautions (5.3, 5.4 )]Metabolism and NutritionDisordershyperglycemiahypoglycemia[see Warnings and Precautions (5.11)] hyperkalemiaPsychiatric Disordersanxietyagitation confusion depression hallucination nightmare [see Warnings and Precautions (5.6)] sleep disorder anorexiaabnormal dreaming Nervous System Disorderstremorconvulsions[see Warnings and Precautions (5.6) ]paresthesia [see Warnings and Precautions (5.8)] vertigo hypertonia hyperkinesiasabnormal gait somnolence syncopeRespiratory, Thoracic andMediastinal DisordersepistaxisCardiac Disorderscardiac arrestpalpitationventricular tachycardia ventricular arrhythmiaVascular DisordersphlebitisGastrointestinal Disordersgastritisstomatitis pancreatitis esophagitisgastroenteritisglossitispseudomembraneous/ C. difficile colitis [see Warnings andPrecautions (5.7)] Hepatobiliary Disordersabnormal hepatic functionincreased hepatic enzymes increased alkaline phosphataseSkin and Subcutaneous TissueDisordersurticaria [see Warnings and Precautions (5.3) ]Musculoskeletal and ConnectiveTissue Disordersarthralgiatendinitis[see Warnings and Precautions (5.1)] myalgia skeletal painRenal and Urinary Disordersabnormal renal functionacute renal failure [see Warnings and Precautions (5.4) N=7274In clinical trials using multiple-dose therapy, ophthalmologic abnormalities, including cataracts and multiple punctate lenticular opacities, have been noted in patients undergoing treatment with quinolones, including levofloxacin. The relationship of the drugs to these events is not presently established. 6.3 Postmarketing Experience. Table lists adverse reactions that have been identified during post-approval use of levofloxacin. Because these reactions are reported voluntarily from population of uncertain size, reliably estimating their frequency or establishing causal relationship to drug exposure is not always possible.Table 8: Postmarketing Reports Of Adverse Drug ReactionsSystem/Organ Class Adverse Reaction Blood and Lymphatic System Disorders pancytopenia aplastic anemia leukopenia hemolytic anemia [see Warnings and Precautions (5.4) eosinophiliaImmune System Disorders hypersensitivity reactions, sometimes fatal including: anaphylactic/anaphylactoid reactions anaphylactic shock angioneurotic edema serum sickness [see Warnings and Precautions (5.3, 5.4)] Psychiatric Disorders psychosis paranoia isolated reports of suicide attempt and suicidal ideation [see Warnings and Precautions (5.6)] Nervous System Disordersexacerbation of myasthenia gravis [see Warnings and Precautions (5.2)] anosmiaageusia parosmia dysgeusiaperipheral neuropathy (may be irreverisble) [see Warnings and Precautions (5.8)] isolated reports of encephalopathy abnormal electroencephalogram (EEG) dysphonia pseudotumor cerebri [see Warnings and Precautions (5.6) ]Eye Disordersvision disturbance, including diplopiavisual acuity reduced vision blurred scotomaEar and Labyrinth DisordershypoacusistinnitusCardiac Disordersisolated reports of torsade de pointeselectrocardiogram QT prolonged [see Warnings and Precautions (5.9)] tachycardiaVascular DisordersvasodilatationRespiratory, Thoracic andMediastinal Disordersisolated reports of allergic pneumonitis [see Warnings andPrecautions (5.4)] Hepatobiliary Disordershepatic failure (including fatal cases)hepatitis jaundice[see Warnings and Precautions (5.4), (5.5) ]Skin and Subcutaneous TissueDisordersbullous eruptions to include:Stevens-Johnson Syndrome toxic epidermal necrolysis erythema multiforme[see Warnings and Precautions (5.4) ]photosensitivity/phototoxicity reaction [see Warnings and Precautions (5.12)] leukocytoclastic vasculitisMusculoskeletal and ConnectiveTissue Disorderstendon rupture [see Warnings and Precautions (5.1)] muscle injury, including rupture rhabdomyolysisRenal and Urinary Disordersinterstitial nephritis [see Warnings and Precautions (5.4) ]General Disorders andAdministration Site Conditionsmulti-organ failurepyrexiaInvestigationsprothrombin time prolongedinternational normalized ratio prolonged muscle enzymes increased.

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. Levofloxacin is member of the fluoroquinolone class of antibacterial agents [see Microbiology (12.4)]. 12.3 Pharmacokinetics. The mean +-SD pharmacokinetic parameters of levofloxacin determined under single and steady-state conditions following oral tablet doses of levofloxacin are summarized in Table 10.Table 10: Mean +-SD Levofloxacin PK Parameters RegimenCmax (mcg/mL)Tmax (h)AUC (mcgoh/mL) CL/Fclearance /bioavailability(mL/min)Vd/Fvolume of distribution/bioavailability (L)t1/2 (h)CLR (mL/min)Single dose60 min infusion for 250 mg and 500 mg doses, 90 min infusion for 750 mg dose250 mg oral tablethealthy males 18 to 53 years of age 2.8 +- 0.41.6 +- 127.2 +- 3.9156 +- 20ND7.3 +- 0.9142 +- 21500 mg oral tablethealthy males 18 to 53 years of age 5.1 +- 0.81.3 +- 0.647.9 +- 6.8178 +- 28ND6.3 +- 0.6103 +- 30750 mg oral tablethealthy male and female subjects 18 to 54 years of age 9.3 +- 1.61.6 +- 0.8101 +- 20129 +- 2483 +- 177.5 +- 0.9NDMultiple dose500 mg every 24h oral tablet 500 mg every 48h for patients with moderate renal impairment (CLCR 20 to 50 mL/min) and infections of the respiratory tract or skin 5.7 +- 1.41.1 +- 0.447.5 +- 6.7175 +- 25102 +- 227.6 +- 1.6116 +- 31750 mg every 24h oral tablet 8.6 +- 1.91.4 +- 0.590.7 +- 17.6143 +- 29100 +- 168.8 +- 1.5116 +- 28500 mg oral tablet single dose, effects of gender and age:Malehealthy males 22 to 75 years of age 5.5 +- 1.11.2 +- 0.454.4 +- 18.9166 +- 4489 +- 137.5 +- 2.1126 +- 38Femalehealthy females 18 to 80 years of age 7.0 +- 1.61.7 +- 0.567.7 +- 24.2136 +- 4462 +- 166.1 +- 0.8106 +- 40Youngyoung healthy male and female subjects 18 to 36 years of age 5.5 +- 11.5 +- 0.647.5 +- 9.8182 +- 3583 +- 186.0 +- 0.9140 +- 33Elderlyhealthy males and females 19 to 55 years of age. 7.0 +- 1.61.4 +- 0.574.7 +- 23.3121 +- 3367 +- 197.6 +- 291 +- 29500 mg oral single dose tablet, patients with renal insufficiency:CLCR 50 to 80 mL/min 7.5 +- 1.81.5 +- 0.595.6 +- 11.888 +- 10ND9.1 +- 0.957 +- 8CLCR 20 to 49 mL/min 7.1 +- 3.12.1 +- 1.3182.1 +- 62.651 +- 19ND27 +- 1026 +- 13CLCR <20 mL/min 8.2 +- 2.61.1 +- 1263.5 +- 72.533 +- 8ND35 +- 513 +- 3Hemodialysis 5.7 +- 12.8 +- 2.2NDNDND76 +- 42NDCAPD 6.9 +- 2.31.4 +- 1.1NDNDND51 +- 24NDAbsolute bioavailability; F=0.99 +- 0.08 from 500 mg tablet and F=0.99 +- 0.06 from 750 mg tablet;ND= not determined. Absorption. 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 500 mg tablet and 750 mg tablet of levofloxacin are both approximately 99%, demonstrating complete oral absorption of levofloxacin. Following single intravenous dose of levofloxacin to healthy volunteers, the mean +-SD peak plasma concentration attained was 6.2 +-1 mcg/mL after 500 mg dose infused over 60 minutes and 11.5 +-4 mcg/mL after 750 mg dose infused over 90 minutes. Levofloxacin 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 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 500 mg dose of levofloxacin with food prolongs the time to peak concentration by approximately hour and decreases the peak concentration by approximately 14% following tablet and approximately 25% following oral solution administration. Therefore, levofloxacin tablets can be administered without regard to food.The plasma concentration profile of levofloxacin after IV administration is similar and comparable in extent of exposure (AUC) to that observed for levofloxacin tablets when equal doses (mg/mg) are administered. Therefore, the oral and IV routes of administration can be considered interchangeable (see Figure and Figure 3).Figure 2: Mean Levofloxacin Plasma Concentration vs. Time Profile: 750 mgFigure 3: Mean Levofloxacin Plasma Concentration vs. Time Profile: 500 mg. Figure 2. Figure 3. Distribution The mean volume of distribution of levofloxacin generally ranges from 74 to 112 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 hours after dosing. The skin tissue biopsy to plasma AUC ratio is approximately and the blister fluid to plasma AUC ratio is approximately 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 24-hour period after single 500 mg oral dose. In vitro, over 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 to 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 500 mg oral dose of levofloxacin to healthy elderly subjects (66 to 80 years of age), the mean terminal plasma elimination half-life of levofloxacin was about 7.6 hours, as compared to approximately 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 single mg/kg intravenous dose were investigated in pediatric patients ranging in age from months to 16 years. Pediatric patients cleared levofloxacin faster than adult patients, resulting in lower plasma exposures than adults for given mg/kg dose. Subsequent pharmacokinetic analyses predicted that dosage regimen of mg/kg every 12 hours (not to exceed 250 mg per dose) for pediatric patients 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.. 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 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 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. Quantitative methods that require measurement of zone diameters also provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. One such standardized procedure2,3 requires the use of standardized inoculum concentrations. This procedure uses paper disks impregnated with mcg levofloxacin to test the susceptibility of bacteria to levofloxacin. Mechanism of ActionLevofloxacin is the L-isomer of the racemate, ofloxacin, 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 ResistanceFluoroquinolone 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 -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 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 BacteriaEnterococcus faecalisStaphylococcus aureus (methicillin-susceptible isolates)Staphylococcus epidermidis (methicillin-susceptible isolates)Staphylococcus saprophyticus Streptococcus pneumoniae (including multi-drug resistant isolates [MDRSP])1 Streptococcus pyogenes1MDRSP (Multi-drug resistant Streptococcus pneumoniae) isolates are isolates resistant to two or more of the following antibiotics: penicillin (MIC >=2 mcg/mL), 2nd generation cephalosporins, e.g., cefuroxime; macrolides, tetracyclines and trimethoprim/sulfamethoxazole.Gram-Negative BacteriaEnterobacter cloacae Escherichia coli Haemophilus influenzae Haemophilus parainfluenzae Klebsiella pneumoniae Legionella pneumophila Moraxella catarrhalis Proteus mirabilis Pseudomonas aeruginosaSerratia marcescensOther BacteriaChlamydophila 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 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 BacteriaStaphylococcus haemolyticus -hemolytic Streptococcus (Group C/F)-hemolytic Streptococcus (Group G)Streptococcus agalactiae Streptococcus milleri Viridans group streptococci Bacillus anthracis Gram-Negative BacteriaAcinetobacter 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 BacteriaClostridium 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 standardized procedure. Standardized procedures are based on dilution method(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 procedure2,3 requires the use of standardized inoculum concentrations. This procedure uses paper disks impregnated with mcg levofloxacin to test the susceptibility of bacteria to levofloxacin.Reports from the laboratory providing results of the standard single-disk susceptibility test with 5 mcg levofloxacin disk should be interpreted according the criteria outlined in Table 11.Table 11: Susceptibility Test Interpretive Criteria for LevofloxacinMinimum Inhibitory Concentrations (mcg/mL)S Susceptible, = Intermediate, = Resistant Disk Diffusion (zone diameter in mm)Pathogen SIRSIREnterobacteriaceae<=24>=8>=1714 to 16<=13Enterococcus faecalis<=24>=8>=1714 to 16<=13Staphylococcus species<=24>=8>=1714 to 16<=13Pseudomonas aeruginosa<=24>=8>=1714 to 16<=13Haemophilus influenzae<=2- The current absence of data on resistant isolates precludes defining any categories other than Susceptible. Isolates yielding MIC /zone diameter results suggestive of nonsusceptible category should be submitted to reference laboratory for further testing. ->=17--Haemophilus parainfluenzae<=2-->=17--Streptococcus pneumoniae<=24>=8>=1714 to 16<=13Streptococcus pyogenes<=24>=8>=1714 to 16<=13Yersinia pestisThe current absence of data on resistant isolates precludes defining any categories other than Susceptible. Isolates yielding MIC /zone diameter results suggestive of nonsusceptible category should be submitted to reference laboratory for further testing.<=0.25----------Bacillus anthracis<=0.25----------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. report of Intermediate indicates that the result should be considered equivocal, and, if the microorganism is not fully susceptible to alternative, clinically feasible drugs, the test should be repeated. This category implies possible clinical applicability in body sites where the drug is physiologically concentrated or in situations where high dosage of drug can be used. This category also provides buffer zone which prevents small uncontrolled technical factors from causing major discrepancies in interpretation. 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 12. For the diffusion technique using the mcg disk, the criteria in Table 12 should be achieved.Table 12: Quality Control Ranges for Susceptibility TestingMicroorganism Microorganism QC Number MIC (mcg/mL) Disk Diffusion (zone diameter in mm) Enterococcus faecalisATCC 292120.25 to 2--Escherichia coli ATCC 259220.008 to 0.0629 to 37Escherichia coli ATCC 352180.015 to 0.06--Haemophilus influenzaeATCC 492470.008 to 0.0332 to 40Pseudomonas aeruginosa ATCC 278530.5 to 419 to 26Staphylococcus aureusATCC 292130.06 to 0.5--Staphylococcus aureusATCC 25923--25 to 30Streptococcus pneumoniae ATCC 496190.5 to 220 to 25.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. 14.1 Nosocomial Pneumonia. Adult patients with clinically and radiologically documented nosocomial pneumonia were enrolled in multicenter, randomized, open-label study comparing intravenous levofloxacin (750 mg once daily) followed by oral levofloxacin (750 mg once daily) for total of to 15 days to intravenous imipenem/cilastatin (500 to 1000 mg every to hours daily) followed by oral ciprofloxacin (750 mg every 12 hours daily) for total of to 15 days. Levofloxacin-treated patients received an average of days of intravenous therapy (range: to 16 days); comparator-treated patients received an average of days of intravenous therapy (range: to 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 days in the levofloxacin arm and 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 to 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]. 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 13.Table 13: Clinical Success Rates and Bacteriological Eradication Rates (Nosocomial Pneumonia)Pathogen Levofloxacin No. (%) of Patients Microbiologic/ Clinical Outcomes Imipenem/Cilastatin No. (%) of Patients Microbiologic/ Clinical Outcomes MSSAMethicillin-susceptible S. aureus2114 (66.7)/13 (61.9)1913 (68.4)/15 (78.9)P. aeruginosaSee above text for use of combination therapy 1710 (58.8)/11 (64.7)175 (29.4)/7 (41.2)S. marcescens 119 (81.8)/7 (63.6)72 (28.6)/3 (42.9)E. coli 1210 (83.3)/7 (58.3)117 (63.6)/8 (72.7)K. pneumoniaeThe observed differences in rates for the clinical and microbiological outcomes may reflect other factors that were not accounted for in the study119 (81.8)/5 (45.5)76 (85.7)/3 (42.9)H. influenzae1613 (81.3)/10 (62.5)1514 (93.3)/11 (73.3)S. pneumoniae43 (75.0)/3 (75.0)75 (71.4)/4 (57.1). 14.2 Community-Acquired Pneumonia: to 14 day Treatment Regimen. Adult inpatients and outpatients with diagnosis of community-acquired bacterial pneumonia were evaluated in pivotal clinical studies. In the first study, 590 patients were enrolled in prospective, multi-center, unblinded randomized trial comparing levofloxacin 500 mg once daily orally or intravenously for to 14 days to ceftriaxone to grams intravenously once or in equally divided doses twice daily followed by cefuroxime axetil 500 mg orally twice daily for total of 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, to days posttherapy, and to weeks posttherapy. Clinical success (cure plus improvement) with levofloxacin at to 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 prospective, multi-center, non-comparative trial of 500 mg levofloxacin administered orally or intravenously once daily for 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: Bacteriological Eradication Rates Across Community Acquired Pneumonia Clinical Studies Pathogen No. Pathogens Bacteriological Eradication Rate (%) H. influenzae 5598S. pneumoniae 8395S. aureus 1788M. catarrhalis 1894H. parainfluenzae1995K. pneumoniae 10100Community-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), 2nd generation cephalosporins (e.g., cefuroxime, macrolides, tetracyclines and trimethoprim/sulfamethoxazole). Of 40 microbiologically evaluable patients with MDRSP isolates, 38 patients (95%) 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 levofloxacin-Treated MDRSP in Community Acquired Pneumonia Patients (Population Valid for Efficacy)Screening SusceptibilityClinical SuccessBacteriological Successn=the number of MDRSP isolates eradicated or presumed eradicated in microbiologically evaluable patients;Not all isolates were resistant to all antimicrobial classes tested. Success and eradication rates are summarized in Table 16.n/NOne patient had respiratory isolate that was resistant to tetracycline, cefuroxime, macrolides and TMP/SMX and intermediate to penicillin and 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=number of MDRSP isolates in designated resistance group%n/Nn=the number of microbiologically evaluable patients who were clinical successes; N=number of microbiologically evaluable patients in the designated resistance group.%Penicillin-resistant16/1794.116/1794.12nd generation Cephalosporin resistant31/3296.931/3296.9Macrolide-resistant28/2996.628/2996.6Trimethoprim/ Sulfamethoxazole resistant17/1989.517/1989.5Tetracycline-resistant12/1210012/12100Table 16: Clinical Success and Bacteriologic Eradication Rates for Resistant Streptococcus pneumoniae (Community Acquired Pneumonia)Type of Resistance Clinical Success Bacteriologic Eradication Resistant to antibacterials17/18 (94.4%)17/18 (94.4%)Resistant to antibacterials14/15 (93.3%)14/15 (93.3%)Resistant to antibacterials7/7 (100%)7/7 (100%)Resistant to antibacterials00Bacteremia with MDRSP8/9 (89%)8/9 (89%). 14.3 Community-Acquired Pneumonia: 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 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 to 38 days after enrollment) pneumonia was observed in out of 151 patients in the levofloxacin 750 mg group and 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 17.Table 17: Bacteriological Eradication Rates (Community-Acquired Pneumonia) S. pneumoniae19/20 (95%)Haemophilus influenzae 12/12 (100%)Haemophilus parainfluenzae10/10 (100%)Mycoplasma pneumoniae 26/27 (96%)Chlamydophila pneumoniae 13/15 (87%). 14.4 Acute Bacterial Sinusitis: day and 10 to 14 day Treatment Regimens. Levofloxacin 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 to 14 days. To evaluate the safety and efficacy of high dose short course of levofloxacin, 780 outpatient adults with clinically and radiologically determined acute bacterial sinusitis were evaluated in 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] 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.Table 18: Clinical Success Rate by Pathogen at the TOC in Microbiologically Evaluable Subjects Who Underwent Antral Puncture (Acute Bacterial Sinusitis)Pathogen Levofloxacin 750 mg 5 days Levofloxacin 500 mg 10 days Streptococcus pneumoniae25/27 (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%) Note: Forty percent of the subjects in this trial had specimens obtained by sinus endoscopy. The efficacy data for subjects whose specimen was obtained endoscopically were comparable to those presented in the above table.. 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 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 to 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 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 multicenter, randomized, double-blind study comparing oral levofloxacin 500 mg, once daily for total of 28 days to oral ciprofloxacin 500 mg, twice daily for total of 28 days. The primary efficacy endpoint was microbiologic efficacy in microbiologically evaluable patients. 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 to 18 days after completion of therapy was 75% 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 19.Table 19: Bacteriological Eradication Rates (Chronic Bacterial Prostatitis)Levofloxacin(N=136)Ciprofloxacin (N=125)PathogenNEradicationNEradicationE. coli1514 (93.3%)119 (81.8%)E. faecalis5439 (72.2%)4433 (75%)S. epidermidis119 (81.8%)1411 (78.6%) Eradication rates shown are for patients who had sole pathogen only; mixed cultures were excluded.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 to 18 days after completion of therapy were 75% 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 to 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: 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 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 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 pathogen identified at baseline. The post-therapy (test-of-cure) visit occurred 10 to 14 days after the last active dose of levofloxacin and to 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 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 at Test-of-CureLevofloxacin750 mg orally orIV once daily for daysCiprofloxacin 400mg IV/500 mg orally twice daily for 10 daysOverall Difference [95% CI]n/N%n/N%Levofloxacin-CiprofloxacinmITT PopulationThe mITT population included patients who received study medication and who had positive (>=105 CFU/mL) urine culture with no more than uropathogens at baseline. Patients with missing response were counted as failures in this analysis.Overall (cUTI or AP)252/33375.7239/31875.20.5 (-6.1, 7.1)cUTI168/23073.0157/21373.7AP84/10381.682/10578.1Microbiologically Evaluable PopulationThe Microbiologically Evaluable population included patients with confirmed diagnosis of cUTI or AP, causative organism(s) at baseline present at >= 105 CFU/mL, 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).Microbiologic eradication rates in theOverall (cUTI or AP)228/26586.0215/24189.2-3.2 [-8.9, 2.5]cUTI154/18583.2144/16587.3AP74/8092.571/7693.4Microbiologically Evaluable population at TOC for individual pathogens recovered from patients randomized to levofloxacin treatment are presented in Table 21.Table 21: Bacteriological Eradication Rates for Individual Pathogens Recovered From Patients Randomized to levofloxacin 750 mg QD for Days TreatmentPathogen Bacteriological Eradication Rate (n/N) %Escherichia coli 155/17290Klebsiella pneumoniae20/2387Proteus mirabilis 12/12100 The predominant organism isolated from patients with AP was E. coli: 91% (63/69) eradication in AP and 89% (92/103) in patients with cUTI.. 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 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 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 to 12 days post-therapy in patients with 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 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. Bacteriological Eradication Overall (cUTI or AP) at Test-Of-CureLevofloxacin250 mg once daily for 10 daysCiprofloxacin1 to days posttherapy for 30% of subjects enrolled prior to protocol amendment; to 12 days posttherapy for 70% of subjects.500 mg twice daily for 10 daysn/N%n/N%mITT PopulationThe mITT population included patients who had pathogen isolated at baseline. Patients with missingresponse were counted as failures in this analysis.174/20983.3184/21984Microbiologically Evaluable PopulationThe Microbiologically Evaluable population included mITT patients who met protocol-specified evaluability criteria.164/17792.7159/17193. 14.9 Inhalational Anthrax (Post-Exposure). The effectiveness of levofloxacin for this indication is based on plasma concentrations achieved in humans, 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 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 (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 months to 17 years receiving 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 (~2.7 106) 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 mcg.h/mL). Mortality due to anthrax for animals that received 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 Fishers 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 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 (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 months to 17 years receiving 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 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 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) AUC0-24 was 11.9 (3.1) mcg.h/mL (range 9.50 to 16.86 mcg.h/mL). Animals were randomized to receive either 10-day regimen of i.v. levefloxacin or placebo beginning within hrs of the onset of telemetered fever (>= 39C for more than hour). Mortality in the levofloxacin group was significantly lower (1/17) compared to the placebo group (7/7) [p<0.001, Fishers Exact Test; exact 95% confidence interval (-99.9%, -55.5%) for the difference in mortality]. One levofloxacin-treated animal was euthanized on Day post-exposure to Y. pestis due to gastric complication; it had blood culture positive for Y. pestis on Day and all subsequent daily blood cultures from Day through Day were negative.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. 1.Dosage in patients with normal renal function (2.1) Type of Infection Dose Every 24 hoursDuration (days)Nosocomial Pneumonia (1.1) 750 mg7 to 14Community Acquired Pneumonia (1.2) 500 mg7 to 14Community Acquired Pneumonia (1.3) 750 mg5Acute Bacterial Sinusitis (1.4) 750 mg5500 mg10 to 14Acute Bacterial Exacerbation of Chronic Bronchitis (1.5) 500 mg7Complicated Skin and Skin Structure Infections (SSSI) (1.6) 750 mg7 to 14Uncomplicated SSSI (1.7) 500 mg7 to 10Chronic Bacterial Prostatitis (1.8) 500 mg28Complicated Urinary Tract Infection (1.9) or Acute Pyelonephritis (1.11) 750 mg5Complicated Urinary Tract Infection (1.10) or 250 mg10Acute Pyelonephritis (1.11) Uncomplicated Urinary Tract Infection (1.12) 250 mg3Inhalational Anthrax (Post-Exposure) (1.13) Adults and Pediatric Patients 50 kg500 mg60Pediatric Patients 50 kg and >= months of age8 mg/kg BID (not to exceed 250 mg/dose)60Plague (1.14) Adults and Pediatric Patients 50 kgPediatric Patients 50 kg and >= months of age500 mg8 mg/kg BID (not to exceed 250 mg/dose)10 to 1410 to 141.Adjust dose for creatinine clearance <50 ml/min (2.3, 8.6, 12.3). 1.Dosage in patients with normal renal function (2.1) 1.Adjust dose for creatinine clearance <50 ml/min (2.3, 8.6, 12.3). 2.1 Dosage in Adult Patients with Normal Renal Function. The usual dose of levofloxacin tablets are 250 mg, 500 mg, or 750 mg administered orally every 24 hours, as indicated by infection and described in Table 1.These recommendations apply to patients with creatinine clearance >= 50 mL/min. For patients with creatinine clearance <50 mL/min, adjustments to the dosing regimen are required [see Dosage and Administration (2.3)].Table 1: Dosage in Adult Patients with Normal Renal Function (creatinine clearance >= 50 mL/min) Type of InfectionDue to the designated pathogens [see Indications and UsageHYPERLINK \l RefINDICATIONSANDUSAGE (1)].Dosed Every 24 hoursDuration (days)Sequential therapy (intravenous to oral) may be instituted at the discretion of the physician.Nosocomial Pneumonia750 mg7 to 14Community Acquired Pneumonia Due to methicillin-susceptible Staphylococcus aureus, Streptococcus pneumoniae (including multi-drug-resistant isolates [MDRSP]), Haemophilus influenzae, Haemophilus parainfluenzae, Klebsiella pneumoniae, Moraxella catarrhalis, Chlamydophila pneumoniae, Legionella pneumophila, or Mycoplasma pneumoniae [see Indications and UsageHYPERLINK \l Refcd55f535-bc4f-26eb-5f98-c25935287e6 (1.2)]. 500 mg7 to 14Community Acquired PneumoniaDue to Streptococcus pneumoniae (excluding multi-drug-resistant isolates [MDRSP]), Haemophilus influenzae, Haemophilus parainfluenzae, Mycoplasma pneumoniae, or Chlamydophila pneumoniae [see Indications and UsageHYPERLINK \l Ref10fa1391-4861-375e-e722-fda832a596a (1.3)]. 750 mg5Acute Bacterial Sinusitis750 mg5500 mg10 to 14Acute Bacterial Exacerbation of Chronic Bronchitis500 mg7Complicated Skin and Skin Structure Infections (SSSI)750 mg7 to 14Uncomplicated SSSI500 mg7 to 10Chronic Bacterial Prostatitis500 mg28Complicated Urinary Tract Infection (cUTI) or Acute Pyelonephritis (AP)This regimen is indicated for cUTI due to Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis and AP due to E. coli, including cases with concurrent bacteremia. 750 mg5Complicated Urinary Tract Infection (cUTI) or Acute Pyelonephritis (AP)This regimen is indicated for cUTI due to Enterococcus faecalis, Enterococcus cloacae, Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Pseudomonas aeruginosa; and for AP due to E. coli. 250 mg10Uncomplicated Urinary Tract Infection250 mg3Inhalational Anthrax (Post-Exposure), adult and pediatric patients 50 kg Drug administration should begin as soon as possible after suspected or confirmed exposure to aerosolized B. anthracis. This indication is based on surrogate endpoint. Levofloxacin plasma concentrations achieved in humans are reasonably likely to predict clinical benefit [see Clinical StudiesHYPERLINK \l Ref8b0fe90b-f154-e516-63e6-69d9217a8f0 (14.9)].,The safety of levofloxacin in adults for durations of therapy beyond 28 days or in pediatric patients for durations beyond 14 days has not been studied. An increased incidence of musculoskeletal adverse events compared to controls has been observed in pediatric patients [see Warnings and PrecautionsHYPERLINK \l Ref9697f448-d255-5ba4-05a0-d00b0688a83 (5.10), Use in Specific PopulationsHYPERLINK \l RefPEDIATRICUSE (8.4), and Clinical StudiesHYPERLINK \l Ref8b0fe90b-f154-e516-63e6-69d9217a8f0 (14.9)]. Prolonged levofloxacin therapy should only be used when the benefit outweighs the risk. Pediatric patients 50 kg and >= months of age 500 mg see Table below (2.2)60 60 Plague, adult and pediatric patients 50 kgDrug administration should begin as soon as possible after suspected or confirmed exposure to Yersinia pestis. Higher doses of levofloxacin typically used for treatment of pneumonia can be used for treatment of plague, if clinically indicated. Pediatric patients 50 kg and >= months of age500 mgsee Table below (2.2)10 to 1410 to 14. 2.2 Dosage in Pediatric Patients. The dosage in pediatric patients >= months of age is described below in Table 2.Table 2: Dosage in Pediatric Patients >= months of age Type of InfectionDue to Bacillus anthracis [see Indications and UsageHYPERLINK \l Ref44e8b8b4-7787-1604-7e7b-4abf6e612f3 (1.13)] and Yersinia pestis [see Indications and UsageHYPERLINK \l Ref37b72727-96be-cb93-91f4-bc446d623da (1.14)].DoseFreq. Once everyDurationSequential therapy (intravenous to oral) may be instituted at the discretion of the physician.Inhalational Anthrax (post-exposure) Drug administration should begin as soon as possible after suspected or confirmed exposure toaerosolizedB. anthracis. This indication is based on surrogate endpoint. Levofloxacin plasma concentrationsachieved in humans are reasonably likely to predict clinical benefit [see Clinical StudiesHYPERLINK \l Ref8b0fe90b-f154-e516-63e6-69d9217a8f0 (14.9)] The safety of levofloxacin in pediatric patients for durations of therapy beyond 14 days has not beenstudied. An increased incidence of musculoskeletal adverse events compared to controls has been observed in pediatric patients [see Warnings and Precautions (5.10), Use in Specific Populations (8.4), and Clinical Studies (14.9)]. Prolonged levofloxacin therapy should only be used when the benefit outweighs the risk. Pediatric patients 50 kg500 mg 24 hr 60 daysThe safety of levofloxacin in pediatric patients for durations of therapy beyond 14 days has not beenstudied. An increased incidence of musculoskeletal adverse events compared to controls has been observed in pediatric patients [see Warnings and Precautions (5.10), Use in Specific Populations (8.4), and Clinical Studies (14.9)]. Prolonged levofloxacin therapy should only be used when the benefit outweighs the risk. Pediatric patients 50 kg and >= months of age8 mg/kg (not to exceed 250 mg per dose)12 hr60 days PlagueDrug administration should begin as soon as possible after suspected or confirmed exposure to Yersinia pestis. Pediatric patients 50 kg500 mg24 hr10 to 14 daysPediatric patients 50 kg and >= months of age8 mg/kg (not to exceed 250 mg per dose)12 hr10 to 14 days. 2.3 Dosage Adjustment in Adults with Renal Impairment. Administer levofloxacin with caution in the presence of renal insufficiency. Careful clinical observation and appropriate laboratory studies should be performed prior to and during therapy since elimination of levofloxacin may be reduced. No adjustment is necessary for patients with creatinine clearance >= 50 mL/min. In patients with impaired renal function (creatinine clearance <50 mL/min), adjustment of the dosage regimen is necessary to avoid the accumulation of levofloxacin due to decreased clearance [see Use in Specific Populations (8.6)]. Table shows how to adjust dose based on creatinine clearance.Table 3: Dosage Adjustment in Adult Patients with Renal Impairment (creatinine clearance <50 mL/min)Dosage in Normal Renal Function Every 24 hours Creatinine Clearance 20 to 49 mL/min Creatinine Clearance 10 to 19 mL/min Hemodialysis or Chronic Ambulatory Peritoneal Dialysis (CAPD) 750 mg750 mg every 48 hours750 mg initial dose, then 500 mg every 48 hours750 mg initial dose, then 500 mg every 48 hours500 mg500 mg initial dose, then250 mg every 24 hours500 mg initial dose, then250 mg every 48 hours500 mg initial dose, then250 mg every 48 hours250 mgNo dosage adjustment required250 mg every 48 hours. If treating uncomplicated UTI, then no dosage adjustment is requiredNo information on dosing adjustment is available. 2.4 Drug Interaction with Chelation Agents:. Antacids, Sucralfate, Metal Cations, MultivitaminsLevofloxacin tablets should be administered at least two hours before or two hours after antacids containing magnesium, aluminum, as well as sucralfate, metal cations such as iron, and multivitamin preparations with zinc or didanosine chewable/buffered tablets or the pediatric powder for oral solution [see DrugInteractions (7.1) and Patient Counseling Information (17.2)] 2.5 Administration Instructions. Food and Levofloxacin Tablets Levofloxacin tablets can be administered without regard to food. Hydration for Patients Receiving Levofloxacin Tablets Adequate hydration of patients receiving oral levofloxacin should be maintained to prevent the formation of highly concentrated urine. Crystalluria and cylindruria have been reported with quinolones [see Adverse Reactions (6.1) and Patient Counseling Information (17.2)].

INDICATIONS & USAGE SECTION.

1 INDICATIONS AND USAGE. To reduce the development of drug-resistant bacteria and maintain the effectiveness of levofloxacin and other antibacterial drugs, levofloxacin should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy. Levofloxacin tablets are indicated for the treatment of adults (>=18 years of age) with mild, moderate, and severe infections caused by susceptible isolates of the designated microorganisms in the conditions listed in this section. Culture and susceptibility testing Appropriate culture and susceptibility tests should be performed before treatment in order to isolate and identify organisms causing the infection and to determine their susceptibility to levofloxacin [see Microbiology (12.4)]. Therapy with levofloxacin may be initiated before results of these tests are known; once results become available, appropriate therapy should be selected. As with other drugs in this class, some isolates of Pseudomonas aeruginosa may develop resistance fairly rapidly during treatment with levofloxacin. Culture and susceptibility testing performed periodically during therapy will provide information about the continued susceptibility of the pathogens to the antimicrobial agent and also the possible emergence of bacterial resistance. Levofloxacin is fluoroquinolone antibacterial indicated in adults (>=18 years of age) with infections caused by designated, susceptible bacteria (1, 12.4).oPneumonia: nosocomial (1.1) and community acquired (1.2, 1.3)oAcute bacterial sinusitis (1.4)oAcute bacterial exacerbation of chronic bronchitis (1.5)oSkin and skin structure infections: complicated (1.6) and uncomplicated (1.7)oChronic bacterial prostatitis (1.8)oUrinary tract infections: complicated (1.9, 1.10) and uncomplicated (1.12)oAcute pyelonephritis (1.11)oInhalational anthrax, post-exposure (1.13).oPlague (1.14). oPneumonia: nosocomial (1.1) and community acquired (1.2, 1.3). oAcute bacterial sinusitis (1.4). oAcute bacterial exacerbation of chronic bronchitis (1.5). oSkin and skin structure infections: complicated (1.6) and uncomplicated (1.7). oChronic bacterial prostatitis (1.8). oUrinary tract infections: complicated (1.9, 1.10) and uncomplicated (1.12). oAcute pyelonephritis (1.11). oInhalational anthrax, post-exposure (1.13).. oPlague (1.14). 1.1 Nosocomial Pneumonia. Levofloxacin tablets are indicated for the treatment of nosocomial pneumonia due to methicillin-susceptible Staphylococcus aureus, Pseudomonas aeruginosa, Serratia marcescens, Escherichia coli, Klebsiella pneumoniae, Haemophilus influenzae, or Streptococcus pneumoniae. Adjunctive therapy should be used as clinically indicated. Where Pseudomonas aeruginosa is documented or presumptive pathogen, combination therapy with an anti-pseudomonal -lactam is recommended [see ClinicalStudies (14.1 )]. 1.2 Community-Acquired Pneumonia: to 14 day Treatment Regimen. Levofloxacin tablets are indicated for the treatment of community-acquired pneumonia due to methicillin-susceptible Staphylococcus aureus, Streptococcus pneumoniae (including multi-drug-resistant Streptococcus pneumoniae [MDRSP]), Haemophilus influenzae, Haemophilus parainfluenzae, Klebsiella pneumoniae, Moraxella catarrhalis, Chlamydophila pneumoniae, Legionella pneumophila, or Mycoplasma pneumoniae [see Dosageand Administration (2.1) and Clinical Studies (14.2) ].MDRSP isolates are isolates 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.. 1.3 Community-Acquired Pneumonia: day Treatment Regimen. Levofloxacin tablets are indicated for the treatment of community-acquired pneumonia due to Streptococcus pneumoniae (excluding multi-drug-resistant isolates [MDRSP]), Haemophilus influenzae, Haemophilus parainfluenzae, Mycoplasma pneumoniae, or Chlamydophila pneumoniae [see Dosageand Administration (2.1) and Clinical Studies (14.3) ]. 1.4 Acute Bacterial Sinusitis: day and 10 to 14 day Treatment Regimens. Levofloxacin tablets are indicated for the treatment of acute bacterial sinusitis due to Streptococcus pneumoniae, Haemophilus influenzae, or Moraxella catarrhalis [see Clinical Studies (14.4)]. 1.5 Acute Bacterial Exacerbation of Chronic Bronchitis. Levofloxacin tablets are indicated for the treatment of acute bacterial exacerbation of chronic bronchitis due to methicillin-susceptible Staphylococcus aureus, Streptococcus pneumoniae, Haemophilus influenzae, Haemophilus parainfluenzae, or Moraxella catarrhalis. 1.6 Complicated Skin and Skin Structure Infections. Levofloxacin tablets are indicated for the treatment of complicated skin and skin structure infections due to methicillin-susceptible Staphylococcus aureus, Enterococcus faecalis, Streptococcus pyogenes, or Proteus mirabilis [see ClinicalStudies(14.5)].. 1.7 Uncomplicated Skin and Skin Structure Infections. Levofloxacin tablets are indicated for the treatment of uncomplicated skin and skin structure infections (mild to moderate) including abscesses, cellulitis, furuncles, impetigo, pyoderma, wound infections, due to methicillin-susceptible Staphylococcus aureus, or Streptococcus pyogenes. 1.8 Chronic Bacterial Prostatitis. Levofloxacin tablets are indicated for the treatment of chronic bacterial prostatitis due to Escherichia coli, Enterococcus faecalis, or methicillin-susceptible Staphylococcus epidermidis [see ClinicalStudies(14.6)].. 1.9 Complicated Urinary Tract Infections: day Treatment Regimen. Levofloxacin tablets are indicated for the treatment of complicated urinary tract infections due to Escherichia coli, Klebsiella pneumoniae, or Proteus mirabilis [see ClinicalStudies (14.7) ]. 1.10 Complicated Urinary Tract Infections: 10 day Treatment Regimen. Levofloxacin tablets are indicated for the treatment of complicated urinary tract infections (mild to moderate) due to Enterococcus faecalis, Enterobacter cloacae, Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, or Pseudomonas aeruginosa [see ClinicalStudies (14.8) ]. 1.11 Acute Pyelonephritis: or 10 day Treatment Regimen. Levofloxacin tablets are indicated for the treatment of acute pyelonephritis caused by Escherichia coli, including cases with concurrent bacteremia [see Clinical Studies (14.7, 14.8)]. 1.12 Uncomplicated Urinary Tract Infections. Levofloxacin tablets are indicated for the treatment of uncomplicated urinary tract infections (mild to moderate) due to Escherichia coli, Klebsiella pneumoniae, or Staphylococcus saprophyticus. 1.13 Inhalational Anthrax (Post-Exposure). Levofloxacin tablets are indicated for inhalational anthrax (post-exposure) to reduce the incidence or progression of disease following exposure to aerosolized Bacillus anthracis. The effectiveness of levofloxacin is based on plasma concentrations achieved in humans, surrogate endpoint reasonably likely to predict clinical benefit. Levofloxacin has not been tested in humans for the post-exposure prevention of inhalation anthrax. The safety of levofloxacin in adults for durations of therapy beyond 28 days or in pediatric patients for durations of therapy beyond 14 days has not been studied. Prolonged levofloxacin therapy should only be used when the benefit outweighs the risk [see Dosage and Administration (2.1, 2.2) and ClinicalStudies(14.9)].. 1.14 Plague. Levofloxacin tablets are indicated for treatment of plague, including pneumonic and septicemic plague, due to Yersinia pestis (Y. pestis) and prophylaxis for plague in adults and pediatric patients, months of age and older. Efficacy studies of levofloxacin tablets could not be conducted in humans with plague for ethical and feasibility reasons. Therefore, approval of this indication was based on an efficacy study conducted in animals [see Dosage and Administration (2.1, 2.2) and Clinical Studies (14.10)].

INFORMATION FOR PATIENTS SECTION.

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 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 be informed that levofloxacin tablets may be taken with or without food. The tablet should be taken at the same time each day. Patients should drink fluids liberally while taking levofloxacin to avoid formation of highly concentrated urine and crystal formation in the urine. Antacids containing magnesium, or aluminum, as well as sucralfate, metal cations such as iron, and multivitamin preparations with zinc or didanosine should be taken at least two hours before or two hours after oral levofloxacin administration. 17.3 Serious and Potentially Serious Adverse Reactions. Patients should be informed of the following serious adverse reactions that have been associated with levofloxacin or other fluoroquinolone use:oTendon Disorders: Patients should contact their healthcare provider if they experience pain, swelling, or inflammation of 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.oExacerbation 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.oHypersensitivity 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 skin rash, hives or other skin reactions, 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.oHepatotoxicity: 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 levofloxacintreatment 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.oConvulsions: Convulsions have been reported in patients taking fluoroquinolones, including levofloxacin. Patients should notify their physician before taking this drug if they have history of convulsions.oNeurologic Adverse Effects (e.g., dizziness, lightheadedness increased intracranial pressure): Patients should know how they react to levofloxacinbefore 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.oDiarrhea: Diarrhea is 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.oPeripheral Neuropathies: Patients should be informed that peripheral neuropathy has been associated with levofloxacin use. Symptoms may occur soon after initiation of therapy and may be irreversible. If symptoms of peripheral neuropathy including pain, burning, tingling, numbness, and/or weakness develop, patients should immediately discontinue treatment and contact their physician.oProlongation 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 loss of consciousness.oMusculoskeletal Disorders in Pediatric Patients: Parents should inform their childs physician if their child has history of joint-related problems before taking this drug. Parents of pediatric patients should also notify their childs 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)]. oPhotosensitivity/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 sunburn like reaction or skin eruption occurs, patients should contact their physician.. oTendon Disorders: Patients should contact their healthcare provider if they experience pain, swelling, or inflammation of 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.. oExacerbation 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.. oHypersensitivity 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 skin rash, hives or other skin reactions, 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.. oHepatotoxicity: 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 levofloxacintreatment 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.. oConvulsions: Convulsions have been reported in patients taking fluoroquinolones, including levofloxacin. Patients should notify their physician before taking this drug if they have history of convulsions.. oNeurologic Adverse Effects (e.g., dizziness, lightheadedness increased intracranial pressure): Patients should know how they react to levofloxacinbefore 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.. oDiarrhea: Diarrhea is 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.. oPeripheral Neuropathies: Patients should be informed that peripheral neuropathy has been associated with levofloxacin use. Symptoms may occur soon after initiation of therapy and may be irreversible. If symptoms of peripheral neuropathy including pain, burning, tingling, numbness, and/or weakness develop, patients should immediately discontinue treatment and contact their physician.. oProlongation 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 loss of consciousness.. oMusculoskeletal Disorders in Pediatric Patients: Parents should inform their childs physician if their child has history of joint-related problems before taking this drug. Parents of pediatric patients should also notify their childs 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)]. oPhotosensitivity/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 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 hypoglycemic reaction occurs, they should discontinue levofloxacin and consult 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.. 17.6 FDA-Approved Medication Guide.

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. The mean +-SD pharmacokinetic parameters of levofloxacin determined under single and steady-state conditions following oral tablet doses of levofloxacin are summarized in Table 10.Table 10: Mean +-SD Levofloxacin PK Parameters RegimenCmax (mcg/mL)Tmax (h)AUC (mcgoh/mL) CL/Fclearance /bioavailability(mL/min)Vd/Fvolume of distribution/bioavailability (L)t1/2 (h)CLR (mL/min)Single dose60 min infusion for 250 mg and 500 mg doses, 90 min infusion for 750 mg dose250 mg oral tablethealthy males 18 to 53 years of age 2.8 +- 0.41.6 +- 127.2 +- 3.9156 +- 20ND7.3 +- 0.9142 +- 21500 mg oral tablethealthy males 18 to 53 years of age 5.1 +- 0.81.3 +- 0.647.9 +- 6.8178 +- 28ND6.3 +- 0.6103 +- 30750 mg oral tablethealthy male and female subjects 18 to 54 years of age 9.3 +- 1.61.6 +- 0.8101 +- 20129 +- 2483 +- 177.5 +- 0.9NDMultiple dose500 mg every 24h oral tablet 500 mg every 48h for patients with moderate renal impairment (CLCR 20 to 50 mL/min) and infections of the respiratory tract or skin 5.7 +- 1.41.1 +- 0.447.5 +- 6.7175 +- 25102 +- 227.6 +- 1.6116 +- 31750 mg every 24h oral tablet 8.6 +- 1.91.4 +- 0.590.7 +- 17.6143 +- 29100 +- 168.8 +- 1.5116 +- 28500 mg oral tablet single dose, effects of gender and age:Malehealthy males 22 to 75 years of age 5.5 +- 1.11.2 +- 0.454.4 +- 18.9166 +- 4489 +- 137.5 +- 2.1126 +- 38Femalehealthy females 18 to 80 years of age 7.0 +- 1.61.7 +- 0.567.7 +- 24.2136 +- 4462 +- 166.1 +- 0.8106 +- 40Youngyoung healthy male and female subjects 18 to 36 years of age 5.5 +- 11.5 +- 0.647.5 +- 9.8182 +- 3583 +- 186.0 +- 0.9140 +- 33Elderlyhealthy males and females 19 to 55 years of age. 7.0 +- 1.61.4 +- 0.574.7 +- 23.3121 +- 3367 +- 197.6 +- 291 +- 29500 mg oral single dose tablet, patients with renal insufficiency:CLCR 50 to 80 mL/min 7.5 +- 1.81.5 +- 0.595.6 +- 11.888 +- 10ND9.1 +- 0.957 +- 8CLCR 20 to 49 mL/min 7.1 +- 3.12.1 +- 1.3182.1 +- 62.651 +- 19ND27 +- 1026 +- 13CLCR <20 mL/min 8.2 +- 2.61.1 +- 1263.5 +- 72.533 +- 8ND35 +- 513 +- 3Hemodialysis 5.7 +- 12.8 +- 2.2NDNDND76 +- 42NDCAPD 6.9 +- 2.31.4 +- 1.1NDNDND51 +- 24NDAbsolute bioavailability; F=0.99 +- 0.08 from 500 mg tablet and F=0.99 +- 0.06 from 750 mg tablet;ND= not determined. Absorption. 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 500 mg tablet and 750 mg tablet of levofloxacin are both approximately 99%, demonstrating complete oral absorption of levofloxacin. Following single intravenous dose of levofloxacin to healthy volunteers, the mean +-SD peak plasma concentration attained was 6.2 +-1 mcg/mL after 500 mg dose infused over 60 minutes and 11.5 +-4 mcg/mL after 750 mg dose infused over 90 minutes. Levofloxacin 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 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 500 mg dose of levofloxacin with food prolongs the time to peak concentration by approximately hour and decreases the peak concentration by approximately 14% following tablet and approximately 25% following oral solution administration. Therefore, levofloxacin tablets can be administered without regard to food.The plasma concentration profile of levofloxacin after IV administration is similar and comparable in extent of exposure (AUC) to that observed for levofloxacin tablets when equal doses (mg/mg) are administered. Therefore, the oral and IV routes of administration can be considered interchangeable (see Figure and Figure 3).Figure 2: Mean Levofloxacin Plasma Concentration vs. Time Profile: 750 mgFigure 3: Mean Levofloxacin Plasma Concentration vs. Time Profile: 500 mg. Figure 2. Figure 3. Distribution The mean volume of distribution of levofloxacin generally ranges from 74 to 112 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 hours after dosing. The skin tissue biopsy to plasma AUC ratio is approximately and the blister fluid to plasma AUC ratio is approximately 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 24-hour period after single 500 mg oral dose. In vitro, over 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 to 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 500 mg oral dose of levofloxacin to healthy elderly subjects (66 to 80 years of age), the mean terminal plasma elimination half-life of levofloxacin was about 7.6 hours, as compared to approximately 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 single mg/kg intravenous dose were investigated in pediatric patients ranging in age from months to 16 years. Pediatric patients cleared levofloxacin faster than adult patients, resulting in lower plasma exposures than adults for given mg/kg dose. Subsequent pharmacokinetic analyses predicted that dosage regimen of mg/kg every 12 hours (not to exceed 250 mg per dose) for pediatric patients 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.. 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 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 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)].

SPL MEDGUIDE SECTION.

MEDICATION GUIDE. Levofloxacin Tablets, 500 mg and 750 mg TabletsRead this Medication Guide before you start taking levofloxacin tablets and each time you get 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 should know about levofloxacin tablets Levofloxacin tablets, 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 tablets, get medical help right away. Talk with your healthcare provider about whether you should continue to take levofloxacin tablets.1. Tendon rupture or swelling of the tendon (tendinitis). oTendon problems can happen in people of all ages who takelevofloxacin tablets. 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.oThe risk of getting tendon problems while you take levofloxacin if you:oare over 60 years of ageoare taking steroids (corticosteroids)ohave had kidney, heart, or lung transplant.oTendon problems can happen in people who do not have the above risk factors when they take levofloxacin tablets.oOther reasons that can increase your risk of tendon problems can include:ophysical activity or exerciseokidney failureotendon problems in the past, such as in people with rheumatoid arthritis (RA).oCall your healthcare provider right away at the first sign of tendon pain, swelling or inflammation. Stop taking levofloxacin tablets 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 tablets. You may need different antibiotic that is not fluoroquinolone to treat your infection.oTendon rupture can happen while you are taking or after you have finished taking levofloxacin tablets. Tendon ruptures have happened up to several months after people have finished taking their fluoroquinolone.oGet medical help right away if you get any of the following signs or symptoms of tendon rupture:ohear or feel snap or pop in tendon areaobruising right after an injury in tendon areaounable to move the affected area or bear weight2. Worsening of myasthenia gravis (a problem that causes muscle weakness). Fluoroquinolones like levofloxacin tabletsmay 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. oSee What are the possible side effects of levofloxacin tabletsWhat are levofloxacin tablets Levofloxacin tablet is 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: onosocomial pneumoniaocommunity-acquired pneumoniaoacute sinus infectionoacute worsening of chronic bronchitisoskin infections, complicated and uncomplicatedochronic prostate infectionourinary tract infections, complicated and uncomplicatedoacute kidney infection (pyelonephritis)oinhalational anthraxoplague Studies of levofloxacin tablets 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 tablets are also used to treat children who are 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 tablets are safe and effective in children under months of age. The safety and effectiveness in children treated with levofloxacin tablets for more than 14 days is not known. Who should not take levofloxacin tablets Do not take levofloxacin tablets if you have ever had severe allergic reaction to an antibiotic known as fluoroquinolone, or if you are allergic to levofloxacin or any of the ingredients in levofloxacin tablets. See the end of this leaflet for complete list of ingredients in levofloxacin tablets.What should tell my healthcare provider before taking levofloxacin tablets Before you take levofloxacin tablets, tell your healthcare provider if you:ohave tendon problemsohave problem that causes muscle weakness (myasthenia gravis)ohave central nervous system problems such as seizures (epilepsy)ohave nerve problems have or anyone in your family has an irregular heartbeat, especially condition called QT prolongation.ohave low blood potassium (hypokalemia)ohave bone problemsohave joint problems including rheumatoid arthritis (RA)ohave kidney problems. You may need lower dose of levofloxacin tablets if your kidneys do not work well.ohave liver problemsohave diabetes or problems with low blood sugar (hypoglycemia)oare pregnant or plan to become pregnant. It is not known if levofloxacin tablets will harm your unborn child.oare 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 tablets 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 tablets and other medicines can affect each other causing side effects. Especially tell your healthcare provider if you take:oa steroid medicine.oan anti-psychotic medicineoa tricyclic antidepressantoa water pill (diuretic)ocertain medicines may keep levofloxacin tablets from working correctly. Take levofloxacin Tablets either hours before or hours after taking these medicines or supplements:oan antacid, multivitamin, or other medicines or supplements that have magnesium, aluminum, iron, or zincosucralfate (Carafate(R))odidanosine (Videx(R),Videx(R) EC)oa blood thinner (warfarin, Coumadin, Jantoven)oan oral anti-diabetes medicine or insulinoan NSAID (Non-Steroidal Anti-Inflammatory Drug). Many common medicines for pain relief are NSAIDs. Taking an NSAID while you take levofloxacin tablets or other fluoroquinolones may increase your risk of central nervous system effects and seizures.otheophylline (Theo-24(R), Elixophyllin(R), Theochron(R), Uniphyl(R), Theolair(R))oa 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 list of your medicines and show it to your healthcare provider and pharmacist when you get new medicine.How should take levofloxacin tablets oTake levofloxacin tablets exactly as your healthcare provider tells you to take it.oTake levofloxacin tablets at about the same time each day.oDrink plenty of fluids while you take levofloxacin tablets.oLevofloxacin tablets can be taken with or without food.oIf you miss dose of levofloxacin tablets, take it as soon as you remember.oDo not take more than dose in day. Do not skip any doses of levofloxacin tablets, or stop taking it even if you begin to feel better, until you finish your prescribed treatment unless:oyou have tendon problems. See What is the most important information should know about levofloxacin tablets.oyou have serious allergic reaction. See What are the possible side effects oflevofloxacin tablets. oyour healthcare provider tells you to stop taking levofloxacin tablets.Taking all of your levofloxacin tablets doses will help make sure that all of the bacteria are killed. Taking all of your levofloxacin tablets doses will help you lower the chance that the bacteria will become resistant to levofloxacin tablets. If your infection does not get better while you take levofloxacin tablets, it may mean that the bacteria causing your infection may be resistant to levofloxacin tablets. If your infection does not get better, call your healthcare provider. If your infection does not get better, levofloxacin tablets and other similar antibiotic medicines may not work for you in the future. oIf you take too much levofloxacin tablets, call your healthcare provider or get medical help right away.What should avoid while taking levofloxacin tablets oLevofloxacin tablets 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 tablets affects you.oAvoid sunlamps, tanning beds, and try to limit your time in the sun. Levofloxacin tablets 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 tablets, call your healthcare provider right away. You should use sunscreen and wear hat and clothes that cover your skin if you have to be in sunlight.What are the possible side effects of levofloxacin tablets Levofloxacin tablets can cause serious side effects, including:oSee What is the most important information should know about levofloxacin tablets oSerious allergic reactions. Allergic reactions can happen in people taking fluoroquinolones, including levofloxacin tablets, even after only dose. Stop taking levofloxacin tablets and get emergency medical help right away if you have any of the following symptoms of severe allergic reaction:ohivesotrouble breathing or swallowingoswelling of the lips, tongue, facethroat tightness, hoarsenessorapid heartbeatofaintoskin rash Skin rash may happen in people taking levofloxacin tablets, even after only dose. Stop taking levofloxacin tablets at the first sign of skin rash and call your healthcare provider. Skin rash may be sign of more serious reaction to levofloxacin tablets. oLiver damage (hepatotoxicity): Hepatotoxicity can happen in people who take levofloxacin tablets. Call your healthcare provider right away if you have unexplained symptoms such as: onausea or vomitingostomach painofeveroweaknessoabdominal pain or tendernessoitchingounusual tirednessloss of appetiteolight colored bowel movementsodark colored urineoyellowing of your skin or the whites of your eyes Stop taking levofloxacin tablets 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 serious reaction to levofloxacin tablets (a liver problem).oCentral Nervous System Effects. Seizures have been reported in people who take fluoroquinolone antibiotics including levofloxacin tablets. Tell your healthcare provider if you have history of seizures. Ask your healthcare provider whether taking levofloxacin tablets will change your risk of having seizure. oCentral Nervous System (CNS) side effects may happen as soon as after taking the first dose of levofloxacin tablets. Talk to your healthcare provider right away if you get any of these side effects, or other changes in mood or behavior: oseizuresohear voices, see things, or sense things that are not there (hallucinations)ofeel restlessotremorsofeel anxious or nervousoconfusionodepressionotrouble sleepingonightmaresofeel lightheadedofeel more suspicious (paranoia)osuicidal thoughts or actsoa headache that will not go away, with or without blurred vision. oIntestine infection (Pseudomembranous colitis)Pseudomembranous colitis can happen with many antibiotics, including levofloxacin tablets. 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 fever. Pseudomembranous colitis can happen or more months after you have finished your antibiotic. oChanges in sensation and nerve damage (Peripheral Neuropathy) Damage to the nerves in arms, hands, legs, or feet can happen in people taking fluoroquinolones, including levofloxacin tablets. Stop levofloxacin tablets and 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:opainoburningotinglingonumbnessoweakness The nerve damage may be permanent.oSerious heart rhythm changes (QT prolongation and torsades de pointes)Tell your healthcare provider right away if you have change in your heart beat (a fast or irregular heartbeat), or if you faint. Levofloxacin tablets may cause 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:owho are elderlyowith family history of prolonged QT intervalowith low blood potassium (hypokalemia)owho take certain medicines to control heart rhythm (antiarrhythmics)oJoint Problems Increased chance of problems with joints and tissues around joints in children can happen. Tell your childs healthcare provider if your child has any joint problems during or after treatment with levofloxacin tablets.oChanges in blood sugarPeople who take levofloxacin tablets 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 providers instructions for how often to check your blood sugar. If you have diabetes and you get low blood sugar while taking levofloxacin tablets, stop taking levofloxacin tablets and call your healthcare provider right away. Your antibiotic medicine may need to be changed. oSensitivity to sunlight (photosensitivity)See What should avoid while taking levofloxacin tablets The most common side effects of levofloxacin tablets include:onauseaoheadacheodiarrheaoinsomniaoconstipationodizzinessIn children months and older who take levofloxacin tablets to treat anthrax disease or plague, vomiting is also common.Levofloxacin tablets may cause false-positive urine screening results for opiates when testing is done with some commercially available kits. positive result should be confirmed using more specific test. These are not all the possible side effects of levofloxacin tablets. 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 store levofloxacin tablets Levofloxacin tablets should be stored at 20 to 25C (68 to 77F) [See Controlled Room Temperature] in well-closed containers. Keep levofloxacin tablets and all medicines out of the reach of children. General Information about the safe and effective use of levofloxacin tabletsMedicines are sometimes prescribed for purposes other than those listed in Medication Guide. Do not use levofloxacin tablets for condition for which it is not prescribed. Do not give levofloxacin tablets 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 tablets. If you would like more information about levofloxacin tablets, talk with your healthcare provider. You can ask your healthcare provider or pharmacist for information about levofloxacin tablets that is written for healthcare professionals. For more information go to call 1-888-375-3784.What are the ingredients in levofloxacin tablets Levofloxacin Film-Coated Tablets:Active ingredient: Levofloxacin USP Inactive ingredients:500 mg (as expressed in the anhydrous form): colloidal silicon dioxide, corn starch, crospovidone, FD&C yellow no. aluminum lake, FD&C yellow no. aluminum lake, hypromellose, magnesium stearate, microcrystalline cellulose, polyethylene glycol and titanium dioxide.750 mg (as expressed in the anhydrous form): colloidal silicon dioxide, corn starch, crospovidone, hypromellose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, synthetic yellow iron oxide and titanium dioxide.This Medication Guide has been approved by the U.S. Food and Drug Administration. To reorder additional Medication Guides, contact Dr. Reddys Customer Service at 1-866-733-3952.Rx Only Manufactured by:Dr. Reddys Laboratories LimitedBachupally 500 090 INDIAPackaged/ Marketed by:Blenheim Pharmacal, Inc.North Blenheim, New York (NY) 12131, (USA)Revised: 0913. oTendon problems can happen in people of all ages who takelevofloxacin tablets. Tendons are tough cords of tissue that connect muscles to bones. oThe risk of getting tendon problems while you take levofloxacin if you:oare over 60 years of ageoare taking steroids (corticosteroids)ohave had kidney, heart, or lung transplant.. oare over 60 years of age. oare taking steroids (corticosteroids). ohave had kidney, heart, or lung transplant.. oTendon problems can happen in people who do not have the above risk factors when they take levofloxacin tablets.. oOther reasons that can increase your risk of tendon problems can include:ophysical activity or exerciseokidney failureotendon problems in the past, such as in people with rheumatoid arthritis (RA).. ophysical activity or exercise. okidney failure. otendon problems in the past, such as in people with rheumatoid arthritis (RA).. oCall your healthcare provider right away at the first sign of tendon pain, swelling or inflammation. Stop taking levofloxacin tablets until tendinitis or tendon rupture has been ruled out by your healthcare provider. Avoid exercise and using the affected area.. oTendon rupture can happen while you are taking or after you have finished taking levofloxacin tablets. Tendon ruptures have happened up to several months after people have finished taking their fluoroquinolone.. oGet medical help right away if you get any of the following signs or symptoms of tendon rupture:ohear or feel snap or pop in tendon areaobruising right after an injury in tendon areaounable to move the affected area or bear weight. ohear or feel snap or pop in tendon area. obruising right after an injury in tendon area. ounable to move the affected area or bear weight. oSee What are the possible side effects of levofloxacin tablets. onosocomial pneumonia. ocommunity-acquired pneumonia. oacute sinus infection. oacute worsening of chronic bronchitis. oskin infections, complicated and uncomplicated. ochronic prostate infection. ourinary tract infections, complicated and uncomplicated. oacute kidney infection (pyelonephritis). oinhalational anthrax. oplague ohave tendon problems. ohave problem that causes muscle weakness (myasthenia gravis). ohave central nervous system problems such as seizures (epilepsy). ohave nerve problems have or anyone in your family has an irregular heartbeat, especially condition called QT prolongation.. ohave low blood potassium (hypokalemia). ohave bone problems. ohave joint problems including rheumatoid arthritis (RA). ohave kidney problems. You may need lower dose of levofloxacin tablets if your kidneys do not work well.. ohave liver problems. ohave diabetes or problems with low blood sugar (hypoglycemia). oare pregnant or plan to become pregnant. It is not known if levofloxacin tablets will harm your unborn child.. oare 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 tablets or breastfeed. You should not do both.. oa steroid medicine.. oan anti-psychotic medicine. oa tricyclic antidepressant. oa water pill (diuretic). ocertain medicines may keep levofloxacin tablets from working correctly. Take levofloxacin Tablets either hours before or hours after taking these medicines or supplements:oan antacid, multivitamin, or other medicines or supplements that have magnesium, aluminum, iron, or zincosucralfate (Carafate(R))odidanosine (Videx(R),Videx(R) EC). oan antacid, multivitamin, or other medicines or supplements that have magnesium, aluminum, iron, or zinc. osucralfate (Carafate(R)). odidanosine (Videx(R),Videx(R) EC). oa blood thinner (warfarin, Coumadin, Jantoven). oan oral anti-diabetes medicine or insulin. oan NSAID (Non-Steroidal Anti-Inflammatory Drug). Many common medicines for pain relief are NSAIDs. Taking an NSAID while you take levofloxacin tablets or other fluoroquinolones may increase your risk of central nervous system effects and seizures.. otheophylline (Theo-24(R), Elixophyllin(R), Theochron(R), Uniphyl(R), Theolair(R)). oa medicine to control your heart rate or rhythm (antiarrhythmics). oTake levofloxacin tablets exactly as your healthcare provider tells you to take it.. oTake levofloxacin tablets at about the same time each day.. oDrink plenty of fluids while you take levofloxacin tablets.. oLevofloxacin tablets can be taken with or without food.. oIf you miss dose of levofloxacin tablets, take it as soon as you remember.. oDo not take more than dose in day. Do not skip any doses of levofloxacin tablets, or stop taking it even if you begin to feel better, until you finish your prescribed treatment unless:oyou have tendon problems. See What is the most important information should know about levofloxacin tablets.oyou have serious allergic reaction. See What are the possible side effects oflevofloxacin tablets. oyour healthcare provider tells you to stop taking levofloxacin tablets.. oyou have tendon problems. See What is the most important information should know about levofloxacin tablets.. oyou have serious allergic reaction. See What are the possible side effects oflevofloxacin tablets. oyour healthcare provider tells you to stop taking levofloxacin tablets.. oIf you take too much levofloxacin tablets, call your healthcare provider or get medical help right away.. oLevofloxacin tablets 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 tablets affects you.. oAvoid sunlamps, tanning beds, and try to limit your time in the sun. Levofloxacin tablets 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 tablets, call your healthcare provider right away. You should use sunscreen and wear hat and clothes that cover your skin if you have to be in sunlight.. oSee What is the most important information should know about levofloxacin tablets oSerious allergic reactions. Allergic reactions can happen in people taking fluoroquinolones, including levofloxacin tablets, even after only dose. Stop taking levofloxacin tablets and get emergency medical help right away if you have any of the following symptoms of severe allergic reaction:ohivesotrouble breathing or swallowingoswelling of the lips, tongue, facethroat tightness, hoarsenessorapid heartbeatofaintoskin rash ohives. otrouble breathing or swallowing. oswelling of the lips, tongue, facethroat tightness, hoarseness. orapid heartbeat. ofaint. oskin rash oLiver damage (hepatotoxicity): Hepatotoxicity can happen in people who take levofloxacin tablets. Call your healthcare provider right away if you have unexplained symptoms such as: onausea or vomitingostomach painofeveroweaknessoabdominal pain or tendernessoitchingounusual tirednessloss of appetiteolight colored bowel movementsodark colored urineoyellowing of your skin or the whites of your eyes onausea or vomiting. ostomach pain. ofever. oweakness. oabdominal pain or tenderness. oitching. ounusual tirednessloss of appetite. olight colored bowel movements. odark colored urine. oyellowing of your skin or the whites of your eyes oCentral Nervous System Effects. Seizures have been reported in people who take fluoroquinolone antibiotics including levofloxacin tablets. Tell your healthcare provider if you have history of seizures. Ask your healthcare provider whether taking levofloxacin tablets will change your risk of having seizure. oCentral Nervous System (CNS) side effects may happen as soon as after taking the first dose of levofloxacin tablets. Talk to your healthcare provider right away if you get any of these side effects, or other changes in mood or behavior: oseizuresohear voices, see things, or sense things that are not there (hallucinations)ofeel restlessotremorsofeel anxious or nervousoconfusionodepressionotrouble sleepingonightmaresofeel lightheadedofeel more suspicious (paranoia)osuicidal thoughts or actsoa headache that will not go away, with or without blurred vision. oseizures. ohear voices, see things, or sense things that are not there (hallucinations). ofeel restless. otremors. ofeel anxious or nervous. oconfusion. odepression. otrouble sleeping. onightmares. ofeel lightheaded. ofeel more suspicious (paranoia). osuicidal thoughts or acts. oa headache that will not go away, with or without blurred vision. oIntestine infection (Pseudomembranous colitis). oChanges in sensation and nerve damage (Peripheral Neuropathy) Damage to the nerves in arms, hands, legs, or feet can happen in people taking fluoroquinolones, including levofloxacin tablets. Stop levofloxacin tablets and 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:opainoburningotinglingonumbnessoweakness opain. oburning. otingling. onumbness. oweakness oSerious heart rhythm changes (QT prolongation and torsades de pointes)Tell your healthcare provider right away if you have change in your heart beat (a fast or irregular heartbeat), or if you faint. Levofloxacin tablets may cause 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:owho are elderlyowith family history of prolonged QT intervalowith low blood potassium (hypokalemia)owho take certain medicines to control heart rhythm (antiarrhythmics). owho are elderly. owith family history of prolonged QT interval. owith low blood potassium (hypokalemia). owho take certain medicines to control heart rhythm (antiarrhythmics). oJoint Problems oChanges in blood sugar. oSensitivity to sunlight (photosensitivity). onausea. oheadache. odiarrhea. oinsomnia. oconstipation. odizziness.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. oGeriatrics: Severe hepatotoxicity has been reported. The majority of reports describe patients 65 years of age or older (5.5, 8.5, 17). May have increased risk of tendinopathy (including rupture), especially with concomitant corticosteroid use (5.1, 8.5, 17). May be more susceptible to prolongation of the QT interval. (5.9, 8.5, 17).oPediatrics: Musculoskeletal disorders (arthralgia, arthritis, tendonopathy, and gait abnormality) seen in more levofloxacin-treated patients than in comparator. Shown to cause arthropathy and osteochondrosis in juvenile animals (5.10, 8.4, 13.2). Safety in pediatric patients treated for more than 14 days has not been studied. Risk-benefit appropriate only for the treatment of inhalational anthrax (post-exposure) (1.13, 2.2, 8.4, 14.9) and plague (1.14, 2.2, 8.4, 14.10).. oGeriatrics: Severe hepatotoxicity has been reported. The majority of reports describe patients 65 years of age or older (5.5, 8.5, 17). May have increased risk of tendinopathy (including rupture), especially with concomitant corticosteroid use (5.1, 8.5, 17). May be more susceptible to prolongation of the QT interval. (5.9, 8.5, 17).. oPediatrics: Musculoskeletal disorders (arthralgia, arthritis, tendonopathy, and gait abnormality) seen in more levofloxacin-treated patients than in comparator. Shown to cause arthropathy and osteochondrosis in juvenile animals (5.10, 8.4, 13.2). Safety in pediatric patients treated for more than 14 days has not been studied. Risk-benefit appropriate only for the treatment of inhalational anthrax (post-exposure) (1.13, 2.2, 8.4, 14.9) and plague (1.14, 2.2, 8.4, 14.10).. 8.1 Pregnancy. Pregnancy Category C. Levofloxacin was not teratogenic in rats at oral doses as high as 810 mg/kg/day which corresponds to 9.4 times the highest recommended human dose based upon relative body surface area, or at intravenous doses as high as 160 mg/kg/day corresponding to 1.9 times the highest recommended human dose based upon relative body surface area. The oral dose of 810 mg/kg/day to rats caused decreased fetal body weight and increased fetal mortality. No teratogenicity was observed when rabbits were dosed orally as high as 50 mg/kg/day which corresponds to 1.1 times the highest recommended human dose based upon relative body surface area, or when dosed intravenously as high as 25 mg/kg/day, corresponding to 0.5 times the highest recommended human dose based upon relative body surface area.There are, however, no adequate and well-controlled studies in pregnant women. Levofloxacin should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. 8.3 Nursing Mothers. Based on data on other fluoroquinolones and very limited data on levofloxacin, it can be presumed that levofloxacin will be excreted in human milk. Because of the potential for serious adverse reactions from levofloxacin in nursing infants, decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.. 8.4 Pediatric Use. Quinolones, including levofloxacin, cause arthropathy and osteochondrosis in juvenile animals of several species. [see Warnings and Precautions (5.10) and Animal Toxicology and/or Pharmacology (13.2)]. Inhalational Anthrax (Post-Exposure)Levofloxacin is indicated in pediatric patients months of age and older, for inhalational anthrax (post-exposure). The risk-benefit assessment indicates that administration of levofloxacin to pediatric patients is appropriate. The safety of levofloxacin in pediatric patients treated for more than 14 days has not been studied [see Indications and Usage(1.13), Dosage and Administration(2.2) and Clinical Studies (14.9) ].Plague Levofloxacin is indicated in pediatric patients, months of age and older, for treatment of plague, including pneumonic and septicemic plague due to Yersinia pestis (Y. pestis) and prophylaxis for 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 risk-benefit assessment indicates that administration of levofloxacin to pediatric patients is appropriate [see Indications and Usage(1.14), Dosage and Administration(2.2) and Clinical Studies (14.10)]. Safety and effectiveness in pediatric patients below the age of six months have not been established.Adverse EventsIn clinical trials, 1534 children (6 months to 16 years of age) were treated with oral and intravenous levofloxacin. Children months to years of age received levofloxacin10 mg/kg twice day and children greater than years of age received 10 mg/kg once day (maximum 500 mg per day) for approximately 10 days.A subset of children in the clinical trials (1340 levofloxacin-treated and 893 non-fluoroquinolone-treated) enrolled in prospective, long-term surveillance study to assess the incidence of protocol-defined musculoskeletal disorders (arthralgia, arthritis, tendinopathy, gait abnormality) during 60 days and year following the first dose of the study drug. Children treated with levofloxacin had significantly higher incidence of musculoskeletal disorders when compared to the non-fluoroquinolone-treated children as illustrated in Table 9.Table 9: Incidence of Musculoskeletal Disorders in Pediatric Clinical TrialFollow-up PeriodLevofloxacinN 1340Non-FluoroquinoloneNon-Fluoroquinolone: ceftriaxone, amoxicillin/ clavulanate, clarithromycinN 893p-value2-sided Fishers Exact Test 60 days28 (2.1%)8 (0.9%)p 0.0381 yearThere were 1199 levofloxacin-treated and 804 non-fluoroquinolone-treated children who had one-year evaluation visit. However, the incidence of musculoskeletal disorders was calculated using all reported events during the specified period for all children enrolled regardless of whether they completedthe 1-year evaluation visit.46 (3.4%)16 (1.8%)p 0.025Arthralgia was the most frequently occurring musculoskeletal disorder in both treatment groups. Most of the musculoskeletal disorders in both groups involved multiple weight-bearing joints. Disorders were moderate in 8/46 (17%) children and mild in 35/46 (76%) levofloxacin-treated children and most were treated with analgesics. The median time to resolution was days for levofloxacin-treated children and for non-fluoroquinolone-treated children (approximately 80% resolved within months in both groups). No child had severe or serious disorder and all musculoskeletal disorders resolved without sequelae.Vomiting and diarrhea were the most frequently reported adverse events, occurring in similar frequency in the levofloxacin-treated and non-fluoroquinolone-treated children.In addition to the events reported in pediatric patients in clinical trials, events reported in adults during clinical trials or post-marketing experience [see Adverse Reactions (6)] may also be expected to occur in pediatric patients.. 8.5 Geriatric Use. Geriatric patients are at increased risk for developing severe tendon disorders including tendon rupture when being treated with fluoroquinolone such as levofloxacin. This risk is further increased in patients receiving concomitant corticosteroid therapy. Tendinitis or tendon rupture can involve the Achilles, hand, shoulder, or other tendon sites and can occur during or after completion of therapy; cases occurring up to several months after fluoroquinolone treatment have been reported. Caution should be used when prescribing levofloxacin to elderly patients especially those on corticosteroids. Patients should be informed of this potential side effect and advised to discontinue levofloxacin and contact their healthcare provider if any symptoms of tendinitis or tendon rupture occur [see Boxed Warning;Warnings and Precautions (5.1); and Adverse Reactions (6.3)]. In phase clinical trials, 1,945 levofloxacin-treated patients (26%) were >= 65 years of age. Of these, 1,081 patients (14%) were between the ages of 65 and 74 and 864 patients (12%) were 75 years or older. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, but greater sensitivity of some older individuals cannot be ruled out.Severe, and sometimes fatal, cases of hepatotoxicity have been reported post-marketing in association with levofloxacin. The majority of fatal hepatotoxicity reports occurred in patients 65 years of age or older and most were not associated with hypersensitivity. Levofloxacin should be discontinued immediately if the patient develops signs and symptoms of hepatitis [see Warnings and Precautions (5.5)]. Elderly patients may be more susceptible to drug-associated effects on the QT interval. Therefore, precaution should be taken when using levofloxacin with concomitant drugs that can result in prolongation of the QT interval (e.g., Class IA or Class III antiarrhythmics) or in patients with risk factors for torsade de pointes (e.g., known QT prolongation, uncorrected hypokalemia) [see Warnings and Precautions (5.9)]. The pharmacokinetic properties of levofloxacin in younger adults and elderly adults do not differ significantly when creatinine clearance is taken into consideration. However, since the drug is known to be substantially excreted by the kidney, the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function [see Clinical Pharmacology (12.3)]. 8.6 Renal Impairment. Clearance of levofloxacin is substantially reduced and plasma elimination half-life is substantially prolonged in 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)].. 8.7 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.

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. 1.Risk of tendinitis and tendon rupture is increased. This risk is further increased in older patients usually over 60 years of age, in patients taking corticosteroids, and in patients with kidney, heart or lung transplants. Discontinue if pain or inflammation in tendon occurs (5.1, 8.5)2.May exacerbate muscle weakness in persons with myasthenia gravis. Avoid use in patients with known history of myasthenia gravis (5.2). 3.Anaphylactic reactions and allergic skin reactions, serious, occasionally fatal, may occur after first dose (4, 5.3) 4.Hematologic (including agranulocytosis, thrombocytopenia), and renal toxicities may occur after multiple doses (5.4)5.Hepatotoxicity: Severe, and sometimes fatal, hepatoxicity has been reported. Discontinue immediately if signs and symptoms of hepatitis occur (5.5) 6.Central nervous system effects, including convulsions, anxiety, confusion, depression, and insomnia may occur after the first dose. Use with caution in patients with known or suspected disorders that may predispose them to seizures or lower the seizure threshold. Increased intracranial pressure (pseudotumorcerebri) has been reported (5.6)7.Clostridium difficile-associated colitis: evaluate if diarrhea occurs (5.7)8.Peripheral neuropathy: discontinue immediately if symptoms occur in order to prevent irreversibility (5.8)9.Prolongation of the QT interval and isolated cases of torsade de pointes have been reported. Avoid use in patients with known prolongation, those with hypokalemia, and with other drugs that prolong the QT interval (5.9, 8.5). 1.Risk of tendinitis and tendon rupture is increased. This risk is further increased in older patients usually over 60 years of age, in patients taking corticosteroids, and in patients with kidney, heart or lung transplants. Discontinue if pain or inflammation in tendon occurs (5.1, 8.5). 2.May exacerbate muscle weakness in persons with myasthenia gravis. Avoid use in patients with known history of myasthenia gravis (5.2). 3.Anaphylactic reactions and allergic skin reactions, serious, occasionally fatal, may occur after first dose (4, 5.3) 4.Hematologic (including agranulocytosis, thrombocytopenia), and renal toxicities may occur after multiple doses (5.4). 5.Hepatotoxicity: Severe, and sometimes fatal, hepatoxicity has been reported. Discontinue immediately if signs and symptoms of hepatitis occur (5.5) 6.Central nervous system effects, including convulsions, anxiety, confusion, depression, and insomnia may occur after the first dose. Use with caution in patients with known or suspected disorders that may predispose them to seizures or lower the seizure threshold. Increased intracranial pressure (pseudotumorcerebri) has been reported (5.6). 7.Clostridium difficile-associated colitis: evaluate if diarrhea occurs (5.7). 8.Peripheral neuropathy: discontinue immediately if symptoms occur in order to prevent irreversibility (5.8). 9.Prolongation of the QT interval and isolated cases of torsade de pointes have been reported. Avoid use in patients with known prolongation, those with hypokalemia, and with other drugs that prolong the QT interval (5.9, 8.5). 5.1 Tendinopathy and Tendon Rupture. Fluoroquinolones, including levofloxacin, are associated with an increased risk of tendinitis and tendon rupture in all ages. This adverse reaction most frequently involves the Achilles tendon, and rupture of the Achilles tendon may require surgical repair. Tendinitis and tendon rupture in the rotator cuff (the shoulder), the hand, the biceps, the thumb, and other tendon sites have also been reported. The risk of developing fluoroquinolone-associated tendinitis and tendon rupture is further increased in older patients usually over 60 years of age, in those taking corticosteroid drugs, and in patients with kidney, heart or lung transplants. Factors, in addition to age and corticosteroid use, that may independently increase the risk of tendon rupture include strenuous physical activity, renal failure, and previous tendon disorders such as rheumatoid arthritis. Tendinitis and tendon rupture have been reported in patients taking fluoroquinolones who do not have the above risk factors. Tendon rupture can occur during or after completion of therapy; cases occurring up to several months after completion of therapy have been reported. Levofloxacin should be discontinued if the patient experiences pain, swelling, inflammation or rupture of tendon. Patients should be advised to rest at the first sign of tendinitis or tendon rupture, and to contact their healthcare provider regarding changing to non-quinolone antimicrobial drug. [see Adverse Reactions(6.3); Patient Counseling Information (17.3)]. 5.2 Exacerbation of Myasthenia Gravis Fluoroquinolones, including levofloxacin, have neuromuscular blocking activity and may exacerbate muscle weakness in persons with myasthenia gravis. Postmarketing serious adverse events, including deaths and requirement for ventilatory support, have been associated with fluoroquinolone use in persons with myasthenia gravis. Avoid levofloxacinin patients with known history of myasthenia gravis [see Adverse Reactions (6.3); Patient Counseling Information(17.3)]. 5.3 Hypersensitivity Reactions. Serious and occasionally fatal hypersensitivity and/or anaphylactic reactions have been reported in patients receiving therapy with fluoroquinolones, including levofloxacin. These reactions often occur following the first dose. Some reactions have been accompanied by cardiovascular collapse, hypotension/shock, seizure, loss of consciousness, tingling, angioedema (including tongue, laryngeal, throat, or facial edema/swelling), airway obstruction (including bronchospasm, shortness of breath, and acute respiratory distress), dyspnea, urticaria, itching, and other serious skin reactions. Levofloxacin should be discontinued immediately at the first appearance of skin rash or any other sign of hypersensitivity. Serious acute hypersensitivity reactions may require treatment with epinephrine and other resuscitative measures, including oxygen, intravenous fluids, antihistamines, corticosteroids, pressor amines, and airway management, as clinically indicated [see Adverse Reactions (6); Patient Counseling Information (17.3)]. 5.4 Other Serious and Sometimes Fatal Reactions. Other serious and sometimes fatal events, some due to hypersensitivity, and some due to uncertain etiology, have been reported rarely in patients receiving therapy with fluoroquinolones, including levofloxacin. These events may be severe and generally occur following the administration of multiple doses. Clinical manifestations may include one or more of the following:ofever, rash, or severe dermatologic reactions (e.g., toxic epidermal necrolysis, Stevens-Johnson Syndrome);ovasculitis; arthralgia; myalgia; serum sickness;oallergic pneumonitis;ointerstitial nephritis; acute renal insufficiency or failure;ohepatitis; jaundice; acute hepatic necrosis or failure;oanemia, including hemolytic and aplastic; thrombocytopenia, including thrombotic thrombocytopenic purpura; leukopenia; agranulocytosis; pancytopenia; and/or other hematologic abnormalities.The drug should be discontinued immediately at the first appearance of skin rash, jaundice, or any other sign of hypersensitivity and supportive measures instituted [see AdverseReactions (6); Patient Counseling Information (17.3)]. ofever, rash, or severe dermatologic reactions (e.g., toxic epidermal necrolysis, Stevens-Johnson Syndrome);. ovasculitis; arthralgia; myalgia; serum sickness;. oallergic pneumonitis;. ointerstitial nephritis; acute renal insufficiency or failure;. ohepatitis; jaundice; acute hepatic necrosis or failure;. oanemia, including hemolytic and aplastic; thrombocytopenia, including thrombotic thrombocytopenic purpura; leukopenia; agranulocytosis; pancytopenia; and/or other hematologic abnormalities.. 5.5 Hepatotoxicity. Post-marketing reports of severe hepatotoxicity (including acute hepatitis and fatal events) have been received for patients treated with levofloxacin. No evidence of serious drug-associated hepatotoxicity was detected in clinical trials of over 7,000 patients. Severe hepatotoxicity generally occurred within 14 days of initiation of therapy and most cases occurred within days. Most cases of severe hepatotoxicity were not associated with hypersensitivity [see Warnings and Precautions (5.4)]. The majority of fatal hepatotoxicity reports occurred in patients 65 years of age or older and most were not associated with hypersensitivity. Levofloxacin should be discontinued immediately if the patient develops signs and symptoms of hepatitis [see AdverseReactions (6); Patient Counseling Information (17.3)]. 5.6 Central Nervous System Effects. Convulsions and toxic psychoses, increased intracranial pressure (including pseudotumor cerebri) have been reported in patients receiving fluoroquinolones, including levofloxacin. Fluoroquinolones may also cause central nervous system stimulation which may lead to tremors, restlessness, anxiety, lightheadedness, confusion, hallucinations, paranoia, depression, nightmares, insomnia, and, rarely, suicidal thoughts or acts. These reactions may occur following the first dose. If these reactions occur in patients receiving levofloxacin, the drug should be discontinued and appropriate measures instituted. As with other fluoroquinolones, levofloxacin should be used with caution in patients with known or suspected central nervous system (CNS) disorder that may predispose them to seizures or lower the seizure threshold (e.g., severe cerebral arteriosclerosis, epilepsy) or in the presence of other risk factors that may predispose them to seizures or lower the seizure threshold (e.g., certain drug therapy, renal dysfunction.). [see AdverseReactions (6); Drug Interactions (7.4, 7.5); Patient Counseling Information (17.3)]. 5.7 Clostridium difficile-Associated Diarrhea. Clostridium difficile-associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including levofloxacin, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile.C. difficile produces toxins and which contribute to the development of CDAD. Hypertoxin producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibiotic use. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents.If CDAD is suspected or confirmed, ongoing antibiotic use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibiotic treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated [see AdverseReactions (6); Patient Counseling Information (17.3)]. 5.8 Peripheral Neuropathy. Cases of sensory or sensorimotor axonal polyneuropathy affecting small and/or large axons resulting in paresthesias, hypoesthesias, dysesthesias and weakness have been reported in patients receiving fluoroquinolones, including levofloxacin. Symptoms may occur soon after initiation of levofloxacinand may be irreversible. Levofloxacinshould be discontinued immediately if the patient experiences symptoms of neuropathy including pain, burning, tingling, numbness, and/or weakness or other alterations of sensation including light touch, pain, temperature, position sense, and vibratory sensation [see AdverseReactions (6); Patient Counseling Information (17.3)]. 5.9 Prolongation of the QT Interval. Some fluoroquinolones, including levofloxacin, have been associated with prolongation of the QT interval on the electrocardiogram and infrequent cases of arrhythmia. Rare cases of torsade de pointes have been spontaneously reported during postmarketing surveillance in patients receiving fluoroquinolones, including levofloxacin. Levofloxacin should be avoided in patients with known prolongation of the QT interval, patients with uncorrected hypokalemia, and patients receiving Class IA (quinidine, procainamide), or Class III (amiodarone, sotalol) antiarrhythmic agents. Elderly patients may be more susceptible to drug-associated effects on the QT interval [see AdverseReactions (6.3), Use in Specific Populations (8.5), and Patient Counseling Information (17.3)]. 5.10 Musculoskeletal Disorders in Pediatric Patients and Arthropathic Effects in Animals Levofloxacin is indicated in pediatric patients (6 months of age and older) only for the prevention of inhalational anthrax (post-exposure) and for plague [see Indications and Usage (1.13, 1.14)]. An increased incidence of musculoskeletal disorders (arthralgia, arthritis, tendinopathy, and gait abnormality) compared to controls has been observed in pediatric patients receiving levofloxacin[see Use in Specific Populations (8.4)].In immature rats and dogs, the oral and intravenous administration of levofloxacin resulted in increased osteochondrosis. Histopathological examination of the weight-bearing joints of immature dogs dosed with levofloxacin revealed persistent lesions of the cartilage. Other fluoroquinolones also produce similar erosions in the weight-bearing joints and other signs of arthropathy in immature animals of various species [see Animal Toxicology and/or Pharmacology (13.2)].. 5.11 Blood Glucose Disturbances. As with other fluoroquinolones, disturbances of blood glucose, including symptomatic hyper- and hypoglycemia, have been reported with levofloxacin, usually in diabetic patients receiving concomitant treatment with an oral hypoglycemic agent (e.g., glyburide) or with insulin. In these patients, careful monitoring of blood glucose is recommended. If hypoglycemic reaction occurs in patient being treated with levofloxacin, levofloxacinshould be discontinued and appropriate therapy should be initiated immediately [see Adverse Reactions (6.2); Drug Interactions (7.3); Patient Counseling Information (17.4)]. 5.12 Photosensitivity/Phototoxicity. Moderate to severe photosensitivity/phototoxicity reactions, the latter of which may manifest as exaggerated sunburn reactions (e.g., burning, erythema, exudation, vesicles, blistering, edema) involving areas exposed to light (typically the face, V area of the neck, extensor surfaces of the forearms, dorsa of the hands), can be associated with the use of fluoroquinolones after sun or UV light exposure. Therefore, excessive exposure to these sources of light should be avoided. Drug therapy should be discontinued if photosensitivity/phototoxicity occurs [see Adverse Reactions (6.3); Patient Counseling Information (17.3)].. 5.13 Development of Drug Resistant Bacteria. Prescribing levofloxacin in the absence of proven or strongly suspected bacterial infection or prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria [see Patient Counseling Information (17.1)].