LEVOFLOXACIN 750 MG TABLET | WHITE CAPSULE I 18 NUCARE PHARMACEUTICALS,INC. 6807132181

WARNING: SERIOUS ADVERSE REACTIONS INCLUDING TENDINITIS, TENDON RUPTURE, PERIPHERAL NEUROPATHY, CENTRAL NERVOUS SYSTEM EFFECTS AND EXACERBATION OF MYASTHENIA GRAVIS Fluoroquinolones, including levofloxacin, have been associated with disabling and potentially irreversible serious adverse reactions that have occurred together [ see Warnings and Precautions ( 5.1) ], including: o Tendinitis and tendon rupture [ see Warnings and Precautions ( 5.2) ] o Peripheral neuropathy [ see Warnings and Precautions ( 5.3) ] o Central nervous system effects [ see Warnings and Precautions ( 5.4) ] Discontinue levofloxacin immediately and avoid the use of fluoroquinolones, including levofloxacin, in patients who experience any of these serious adverse reactions [ see Warnings and Precautions ( 5.1) ] Fluoroquinolones, including levofloxacin, may exacerbate muscle weakness in patients with myasthenia gravis. Avoid levofloxacin in patients with a known history of myasthenia gravis [ see Warnings and Precautions ( 5.5) ]. Because fluoroquinolones, including levofloxacin, have been associated with serious adverse reactions [ see Warnings and Precautions ( 5.1 to 5.14) ], reserve levofloxacin for use in patients who have no alternative treatment options for the following indications: o Uncomplicated urinary tract infection [ see Indications and Usage ( 1.12) ] o Acute bacterial exacerbation of chronic bronchitis [ see Indications and Usage ( 1.13) ] o Acute bacterial sinusitis [ see Indications and Usage ( 1.14) ]. WARNING: SERIOUS ADVERSE REACTIONS INCLUDING TENDINITIS, TENDON RUPTURE, PERIPHERAL NEUROPATHY, CENTRAL NERVOUS SYSTEM EFFECTS AND EXACERBATION OF MYASTHENIA GRAVIS See full prescribing information for complete boxed warning. Fluoroquinolones, including levofloxacin, have been associated with disabling and potentially irreversible serious adverse reactions that have occurred together ( 5.1), including: o Tendinitis and tendon rupture ( 5.2) o Peripheral neuropathy ( 5.3) o Central nervous system effects ( 5.4) Discontinue levofloxacin immediately and avoid the use of fluoroquinolones, including levofloxacin, in patients who experience any of these serious adverse reactions ( 5.1) Fluoroquinolones, including levofloxacin, may exacerbate muscle weakness in patients with myasthenia gravis. Avoid levofloxacin in patients with a known history of myasthenia gravis [ see Warnings and Precautions ( 5.5) ]. Because fluoroquinolones, including levofloxacin, have been associated with serious adverse reactions ( 5.1 to 5.14), reserve levofloxacin for use in patients who have no alternative treatment options for the following indications: o Uncomplicated urinary tract infection ( 1.12) o Acute bacterial exacerbation of chronic bronchitis ( 1.13) o Acute bacterial sinusitis ( 1.14)

The usual dose of levofloxacin tablets is 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 . The usual dose of levofloxacin tablets is 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 Infection* Dosed Every 24 hours Duration (days) Nosocomial Pneumonia 750 mg 7-14 Community Acquired Pneumonia 500 mg 7-14 Community Acquired Pneumonia 750 mg 5 Complicated Skin and Skin Structure Infections (SSSI) 750 mg 7-14 Uncomplicated SSSI 500 mg 7-10 Chronic Bacterial Prostatitis 500 mg 28 Inhalation Anthrax (Post-Exposure), adult and pediatric patients > 50 kg , Pediatric patients < 50 kg and 6 months of age , 500 mg see Table 2 below (2.2) 60 60 Plague, adult and pediatric patients > 50 kg Pediatric patients < 50 kg and 6 months of age 500 mg see Table 2 below (2.2) 10 to 14 10 to 14 Complicated Urinary Tract Infection (cUTI) or Acute Pyelonephritis (AP) 750 mg 5 Complicated Urinary Tract Infection (cUTI) or Acute Pyelonephritis (AP) # 250 mg 10 Uncomplicated Urinary Tract Infection 250 mg 3 Acute Bacterial Exacerbation of Chronic Bronchitis (ABECB) 500 mg 7 Acute Bacterial Sinusitis (ABS) 750 mg 5 500 mg 10-14 Due to the designated pathogens . Sequential therapy (intravenous to oral) may be instituted at the discretion of the physician. Due to methicillin-susceptible (including multi-drug-resistant isolates [MDRSP]), or . Due to (excluding multi-drug-resistant isolates [MDRSP]), . This regimen is indicated for cUTI due to and AP due to , including cases with concurrent bacteremia. This regimen is indicated for cUTI due to and for AP due to . Drug administration should begin as soon as possible after suspected or confirmed exposure to aerosolized . This indication is based on a surrogate endpoint. Levofloxacin plasma concentrations achieved in humans are reasonably likely to predict clinical benefit The safety of levofloxacin in adults for duration 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 . Prolonged levofloxacin therapy should only be used when the benefit outweighs the risk. Drug administration should begin as soon as possible after suspected or confirmed exposure to . Higher doses of levofloxacin typically used for treatment of pneumonia can be used for treatment of plague, if clinically indicated. *Due to the designated pathogens [see Indications and Usage ( 1)] . Sequential therapy (intravenous to oral) may be instituted at the discretion of the physician. 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 Usage ( 1.2)] . Due to Streptococcus pneumoniae (excluding multi-drug-resistant isolates [MDRSP]), Haemophilusinfluenzae, Haemophilus parainfluenzae, Mycoplasma pneumoniae, or Chlamydophila pneumoniae [see Indications and Usage ( 1.3)] . 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. #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. Drug administration should begin as soon as possible after suspected or confirmed exposure to aerosolized B.anthracis. This indication is based on a surrogate endpoint. Levofloxacin plasma concentrations achieved in humans are reasonably likely to predict clinical benefit [see Clinical Studies ( 14.9)]. The safety of levofloxacin in adults for duration 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 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. Drug 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.

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a 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 3 clinical trials. The population studied had a 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 a 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 3 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 4 and Table 5, respectively. The most common adverse drug reactions ( 3%) are nausea, headache, diarrhea, insomnia, constipation, and dizziness. Table 4:Common ( 1%) Adverse Reactions Reported in Clinical Trials with Levofloxacin System/Organ Class Adverse Reaction % (N=7537) Infections and Infestations moniliasis 1 Psychiatric Disorders insomnia * [see Warnings and Precautions ( 5.4)] 4 Nervous System Disorders headache dizziness [see Warnings and Precautions ( 5.4)] 6 3 Respiratory, Thoracic and Mediastinal Disorders dyspnea [see Warnings and Precautions ( 5.7)] 1 Gastrointestinal Disorders nausea diarrhea constipation abdominal pain vomiting dyspepsia 7 5 3 2 2 2 Skin and Subcutaneous Tissue Disorders rash [see Warnings and Precautions ( 5.7)] pruritus 2 1 Reproductive System and Breast Disorders vaginitis 1 General Disorders and Administration Site Conditions edema injection site reaction chest pain 1 1 1 *N = 7274 N=3758 (women) Table 5: Less Common (0.1 to 1%) Adverse Reactions Reported in Clinical Trials with Levofloxacin (N=7537) System/Organ Class Adverse Reaction Infections and Infestations genital moniliasis Blood and Lymphatic System Disorders anemiathrombocytopenia granulocytopenia [see Warnings and Precautions ( 5.6)] Immune System Disorders allergic reaction [see Warnings and Precautions ( 5.6, 5.7)] Metabolism and Nutrition Disorders hyperglycemia hypoglycemia [see Warnings and Precautions ( 5.12)] hyperkalemia Psychiatric Disorders anxiety agitation confusion depression hallucination nightmare * [see Warnings and Precautions ( 5.4)] sleep disorder * anorexia abnormal dreaming * Nervous System Disorders tremorconvulsions [see Warnings and Precautions ( 5.4)] paresthesia [see Warnings and Precautions ( 5.3)] vertigo hypertonia hyperkinesias abnormal gait somnolence * syncope Respiratory, Thoraic and Mediastinal Disorders epistaxis Cardiac Disorders cardiac arrestpalpitation ventricular tachycardia ventricular arrhythmia Vascular Disorders phlebitis Gastrointestinal Disorders gastritisstomatitis pancreatitis esophagitis gastroenteritis glossitis pseudomembranous/ C. difficile colitis [see Warnings and Precautions ( 5.9)] Hepatobiliary Disorders abnormal hepatic functionincreased hepatic enzymes increased alkaline phosphatase Skin and Subcutaneous Tissue Disorders urticaria [see Warnings and Precautions ( 5.7)] Musculoskeletal and Connective Tissue Disorders arthralgiatendinitis [see Warnings and Precautions ( 5.2)] myalgia skeletal pain Renal and Urinary Disorders abnormal renal functionacute renal failure [see Warnings and Precautions ( 5.6)] *N = 7274 In 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.

Table 6 lists adverse reactions that have been identified during post-approval use of levofloxacin. Because these reactions are reported voluntarily from a population of uncertain size, reliably estimating their frequency or establishing a causal relationship to drug exposure is not always possible. Table 6: Postmarketing Reports Of Adverse Drug Reactions System/Organ Class Adverse Reaction Blood and Lymphatic System Disorders pancytopenia aplastic anemia leukopenia hemolytic anemia [see Warnings and Precautions ( 5.6)] eosinophilia Immune System Disorders hypersensitivity reactions, sometimes fatal including: anaphylactic/anaphylactoid reactions anaphylactic shock angioneurotic edema serum sickness [see Warnings and Precautions ( 5.6, 5.7)] Psychiatric Disorders psychosis paranoia isolated reports of suicide attempt and suicidal ideation [see Warnings and Precautions ( 5.4)] Nervous System Disorders exacerbation of myasthenia gravis [see Warnings and Precautions ( 5.2)] anosmia ageusia parosmia dysgeusia peripheral neuropathy (may be irreversible) [see Warnings and Precautions ( 5.3)] isolated reports of encephalopathy abnormal electroencephalogram (EEG) dysphonia pseudotumor cerebri [see Warning and Precautions ( 5.4)] Eye Disorders uveitis vision disturbance, including diplopia visual acuity reduced vision blurred scotoma Ear and Labyrinth Disorders hypoacusis tinnitus Cardiac Disorders isolated reports of torsade de pointes electrocardiogram QT prolonged [see Warnings and Precautions ( 5.10)] tachycardia Vascular Disorders vasodilatation Respiratory, Thoracic and Mediastinal Disorders isolated reports of allergic pneumonitis [see Warnings and Precautions ( 5.6)] Hepatobiliary Disorders hepatic failure (including fatal cases) hepatitis jaundice [see Warnings and Precautions ( 5.6), ( 5.8)] Skin and Subcutaneous Tissue Disorders bullous eruptions to include: Stevens-Johnson Syndrome toxic epidermal necrolysis erythema multiforme [see Warnings and Precautions ( 5.6)] photosensitivity/phototoxicity reaction [see Warnings and Precautions ( 5.13)] leukocytoclastic vasculitis Musculoskeletal and Connective Tissue Disorders tendon rupture [see Warnings and Precautions ( 5.2)] muscle injury, including rupture rhabdomyolysis Renal and Urinary Disorders interstitial nephritis [see Warnings and Precautions ( 5.6)] General Disorders and Administration Site Conditions multi-organ failure pyrexia Investigations prothrombin time prolonged international normalized ratio prolonged muscle enzymes increased

Quinolones, including levofloxacin, cause arthropathy and osteochondrosis in juvenile animals of several species. [see Warnings and Precautions ( 5.11) and Animal Toxicologyand/or Pharmacology ( 13.2)] . Inhalational Anthrax (Post-Exposure) Levofloxacin is indicated in pediatric patients 6 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 ( 1.7), Dosage and Administration ( 2.2) and Clinical Studies ( 14.9)] . Plague Levofloxacin is indicated in pediatric patients, 6 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 ( 1.8), 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 Events In clinical trials, 1534 children (6 months to 16 years of age) were treated with oral and intravenous levofloxacin. Children 6 months to 5 years of age received levofloxacin 10 mg/kg twice a day and children greater than 5 years of age received 10 mg/kg once a 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 a prospective, long-term surveillance study to assess the incidence of protocol-defined musculoskeletal disorders (arthralgia, arthritis, tendinopathy, gait abnormality) during 60 days and 1 year following the first dose of the study drug. Children treated with levofloxacin had a significantly higher incidence of musculoskeletal disorders when compared to the non-fluoroquinolone-treated children as illustrated in Table 7. Table 7: Incidence of Musculoskeletal Disorders in Pediatric Clinical Trial Follow-up Period Levofloxacin N = 1340 Non-Fluoroquinolone * N = 893 p-value 60 days 28 (2.1%) 8 (0.9%) p = 0.038 1 year 46 (3.4%) 16 (1.8%) p = 0.025 *Non-Fluoroquinolone: ceftriaxone, amoxicillin/clavulanate, clarithromycin 2-sided Fisher's Exact Test There were 1199 levofloxacin-treated and 804 non-fluoroquinolone-treated children who had a 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 completed the 1-year evaluation visit. Arthralgia 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 7 days for levofloxacin-treated children and 9 for non-fluoroquinolone-treated children (approximately 80% resolved within 2 months in both groups). No child had a 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.

Geriatric patients are at increased risk for developing severe tendon disorders including tendon rupture when being treated with a 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 ( 5.2); and Adverse Reactions ( 6.3)] . In phase 3 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 ( 5.8)] . 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 ( 5.10)] . 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)] .

Levofloxacin, USP is a synthetic broad-spectrum antibacterial agent for oral administration. Chemically, levofloxacin, a chiral fluorinated carboxyquinolone, is the pure (-)-(S)-enantiomer of the racemic drug substance ofloxacin. The chemical name is (-)-(S)-9-fluoro-2,3-dihydro-3-methyl-10-(4-methyl-1-piperazinyl)-7-oxo-7H-pyrido [1,2,3-de]-1,4 benzoxazine-6-carboxylic acid hemihydrate. Figure 1: The Chemical Structure of Levofloxacin, USP The molecular formula is C 18H 20FN 3O 4 1/2 H 2O and the molecular weight is 370.38. Levofloxacin, USP is a light yellowish-white to yellow-white crystals or crystalline powder. The molecule exists as a zwitterion at the pH conditions in the small intestine. The data demonstrate that from pH 0.6 to 5.8, the solubility of levofloxacin, USP is essentially constant (approximately 100 mg/mL). Levofloxacin, USP is considered soluble to freely soluble in this pH range, as defined by USP nomenclature. Above pH 5.8, the solubility increases rapidly to its maximum at pH 6.7 (272 mg/mL) and is considered freely soluble in this range. Above pH 6.7, the solubility decreases and reaches a minimum value (about 50 mg/mL) at a pH of approximately 6.9. Levofloxacin, USP has the potential to form stable coordination compounds with many metal ions. This in vitro chelation potential has the following formation order: Al +3>Cu +2>Zn +2>Mg +2>Ca +2. Excipients and Description of Dosage Form Levofloxacin Tablets, USP are available as film-coated tablets and contain the following inactive ingredients: 250 mg: croscarmellose sodium, hypromellose, iron oxide red, magnesium stearate, microcrystalline cellulose, polyethylene glycol, polysorbate 80, povidone and titanium dioxide. 500 mg: croscarmellose sodium, hypromellose, iron oxide red, iron oxide yellow magnesium stearate, microcrystalline cellulose, polyethylene glycol, polysorbate 80, povidone and titanium dioxide. 750 mg: croscarmellose sodium, hypromellose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, polysorbate 80, povidone and titanium dioxide. Levofloxacin tablets, USP meets USP Dissolution Test 2.

The mean SD pharmacokinetic parameters of levofloxacin determined under single and steady-state conditions following oral tablet, oral solution, or intravenous (IV) doses of levofloxacin are summarized in Table 8. Table 8: Mean SD Levofloxacin PK Parameters Regimen C max (mcg/mL) T max (h) AUC (mcg h/mL) CL/F 1 (mL/min) Vd/F 2 (L) t 1/2 (h) CL R (mL/min) Single dose 250 mg oral tablet 3 2.8 0.4 1.6 1 27.2 3.9 156 20 ND 7.3 0.9 142 21 500 mg oral tablet 3* 5.1 0.8 1.3 0.6 47.9 6.8 178 28 ND 6.3 0.6 103 30 500 mg oral solution 12 5.8 1.8 0.8 0.7 47.8 10.8 183 40 112 37.2 7 1.4 ND 500 mg IV 3 6.2 1 1 0.1 48.3 5.4 175 20 90 11 6.4 0.7 112 25 750 mg oral tablet 5* 9.3 1.6 1.6 0.8 101 20 129 24 83 17 7.5 0.9 ND 750 mg IV 5 11.5 4 4 ND 110 40 126 39 75 13 7.5 1.6 ND Multiple dose 500 mg every 24h oral tablet 3 5.7 1.4 1.1 0.4 47.5 6.7 175 25 102 22 7.6 1.6 116 31 500 mg every 24h IV 3 6.4 0.8 ND 54.6 11.1 158 29 91 12 7 0.8 99 28 500 mg or 250 mg every 24h IV, patients with bacterial infection 6 8.7 4 7 ND 72.5 51.2 7 154 72 111 58 ND ND 750 mg every 24h oral tablet 5 8.6 1.9 1.4 0.5 90.7 17.6 143 29 100 16 8.8 1.5 116 28 750 mg every 24h IV 5 12.1 4.1 4 ND 108 34 126 37 80 27 7.9 1.9 ND 500 mg oral tablet single dose, effects of gender and age: Male 8 5.5 1.1 1.2 0.4 54.4 18.9 166 44 89 13 7.5 2.1 126 38 Female 9 7 1.6 1.7 0.5 67.7 24.2 136 44 62 16 6.1 0.8 106 40 Young 10 5.5 1 1.5 0.6 47.5 9.8 182 35 83 18 6 0.9 140 33 Elderly 11 7 1.6 1.4 0.5 74.7 23.3 121 33 67 19 7.6 2 091 29 500 mg oral single dose tablet, patients with renal insufficiency: CLCR 50-80 mL/min 7.5 1.8 1.5 0.5 95.6 11.8 88 10 ND 9.1 0.9 57 8 CLCR 20-49 mL/min 7.1 3.1 2.1 1.3 182.1 62.6 51 19 ND 27 10 26 13 CLCR <20 mL/min 8.2 2.6 1.1 1 263.5 72.5 33 8 ND 35 5 13 3 Hemodialysis 5.7 1 2.8 2.2 ND ND ND 76 42 ND CAPD 6.9 2.3 1.4 1.1 ND ND ND 51 24 ND 1clearance/bioavailability 2volume of distribution/bioavailability 3healthy males 18 to 53 years of age 460 min infusion for 250 mg and 500 mg doses, 90 min infusion for 750 mg dose 5healthy male and female subjects 18 to 54 years of age 6500 mg every 48h for patients with moderate renal impairment (CLCR 20 to 50 mL/min) and infections of the respiratory tract or skin 7dose-normalized values (to 500 mg dose), estimated by population pharmacokinetic modeling 8 healthy males 22 to 75 years of age 9 healthy females 18 to 80 years of age 10 young healthy male and female subjects 18 to 36 years of age 11healthy elderly male and female subjects 66 to 80 years of age 12healthy males and females 19 to 55 years of age. *Absolute bioavailability; F=0.99 0.08 from a 500 mg tablet and F=0.99 0.06 from a 750 mg tablet; 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 a 500 mg tablet and a 750 mg tablet of levofloxacin are both approximately 99%, demonstrating complete oral absorption of levofloxacin. Following a single intravenous dose of levofloxacin to healthy volunteers, the mean SD peak plasma concentration attained was 6.2 1 mcg/mL after a 500 mg dose infused over 60 minutes and 11.5 4 mcg/mL after a 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 a 500 mg or 750 mg once-daily dosage regimen. The mean SD peak and trough plasma concentrations attained following multiple once-daily oral dosage regimens were approximately 5.7 1.4 and 0.5 0.2 mcg/mL after the 500 mg doses, and 8.6 1.9 and 1.1 0.4 mcg/mL after the 750 mg doses, respectively. The mean SD peak and trough plasma concentrations attained following multiple once-daily IV regimens were approximately 6.4 0.8 and 0.6 0.2 mcg/mL after the 500 mg doses, and 12.1 4.1 and 1.3 0.71 mcg/mL after the 750 mg doses, respectively. Oral administration of a 500 mg dose of levofloxacin with food prolongs the time to peak concentration by approximately 1 hour and decreases the peak concentration by approximately 14% following tablet and approximately 25% following oral solution administration. Therefore, levofloxacin tablets can be administered without regard to food. It is recommended that levofloxacin oral solution be taken 1 hour before or 2 hours after eating. The plasma concentration profile of levofloxacin after IV administration is similar and comparable in extent of exposure (AUC) to that observed for levofloxacin tablets when equal doses (mg/mg) are administered. Therefore, the oral and IV routes of administration can be considered interchangeable ( see Figure 2 and Figure 3 ). Figure 2: Mean Levofloxacin Plasma Concentration vs.Time Profile: 750 mg Figure 3: Mean Levofloxacin Plasma Concentration vs.Time Profile: 500 mg Distribution The mean volume of distribution of levofloxacin generally ranges from 74 to 112 L after single and multiple 500 mg or 750 mg doses, indicating widespread distribution into body tissues. Levofloxacin reaches its peak levels in skin tissues and in blister fluid of healthy subjects at approximately 3 hours after dosing. The skin tissue biopsy to plasma AUC ratio is approximately 2 and the blister fluid to plasma AUC ratio is approximately 1 following multiple once-daily oral administration of 750 mg and 500 mg doses of levofloxacin, respectively, to healthy subjects. Levofloxacin also penetrates well into lung tissues. Lung tissue concentrations were generally 2- to 5-fold higher than plasma concentrations and ranged from approximately 2.4 to 11.3 mcg/g over a 24-hour period after a single 500 mg oral dose. In vitro, over a clinically relevant range (1 to 10 mcg/mL) of serum/plasma levofloxacin concentrations, levofloxacin is approximately 24 to 38% bound to serum proteins across all species studied, as determined by the equilibrium dialysis method. Levofloxacin is mainly bound to serum albumin in humans. Levofloxacin binding to serum proteins is independent of the drug concentration. Metabolism Levofloxacin is stereochemically stable in plasma and urine and does not invert metabolically to its enantiomer, D-ofloxacin. Levofloxacin undergoes limited metabolism in humans and is primarily excreted as unchanged drug in the urine. Following oral administration, approximately 87% of an administered dose was recovered as unchanged drug in urine within 48 hours, whereas less than 4% of the dose was recovered in feces in 72 hours. Less than 5% of an administered dose was recovered in the urine as the desmethyl and N-oxide metabolites, the only metabolites identified in humans. These metabolites have little relevant pharmacological activity. Excretion Levofloxacin is excreted largely as unchanged drug in the urine. The mean terminal plasma elimination half-life of levofloxacin ranges from approximately 6 to 8 hours following single or multiple doses of levofloxacin given orally or intravenously. The mean apparent total body clearance and renal clearance range from approximately 144 to 226 mL/min and 96 to 142 mL/min, respectively. Renal clearance in excess of the glomerular filtration rate suggests that tubular secretion of levofloxacin occurs in addition to its glomerular filtration. Concomitant administration of either cimetidine or probenecid results in approximately 24% and 35% reduction in the levofloxacin renal clearance, respectively, indicating that secretion of levofloxacin occurs in the renal proximal tubule. No levofloxacin crystals were found in any of the urine samples freshly collected from subjects receiving levofloxacin. Geriatric There are no significant differences in levofloxacin pharmacokinetics between young and elderly subjects when the subjects' differences in creatinine clearance are taken into consideration. Following a 500 mg oral dose of levofloxacin to healthy elderly subjects (66 to 80 years of age), the mean terminal plasma elimination half-life of levofloxacin was about 7.6 hours, as compared to approximately 6 hours in younger adults. The difference was attributable to the variation in renal function status of the subjects and was not believed to be clinically significant. Drug absorption appears to be unaffected by age. Levofloxacin dose adjustment based on age alone is not necessary [see Use in Specific Populations ( 8.5)] . Pediatrics The pharmacokinetics of levofloxacin following a single 7 mg/kg intravenous dose were investigated in pediatric patients ranging in age from 6 months to 16 years. Pediatric patients cleared levofloxacin faster than adult patients, resulting in lower plasma exposures than adults for a given mg/kg dose. Subsequent pharmacokinetic analyses predicted that a dosage regimen of 8 mg/kg every 12 hours (not to exceed 250 mg per dose) for pediatric patients 6 months to 17 years of age would achieve comparable steady state plasma exposures (AUC 0 to 24 and C max) to those observed in adult patients administered 500 mg of levofloxacin once every 24 hours. Gender There are no significant differences in levofloxacin pharmacokinetics between male and female subjects when subjects' differences in creatinine clearance are taken into consideration. Following a 500 mg oral dose of levofloxacin to healthy male subjects, the mean terminal plasma elimination half-life of levofloxacin was about 7.5 hours, as compared to approximately 6.1 hours in female subjects. This difference was attributable to the variation in renal function status of the male and female subjects and was not believed to be clinically significant. Drug absorption appears to be unaffected by the gender of the subjects. Dose adjustment based on gender alone is not necessary. Race The effect of race on levofloxacin pharmacokinetics was examined through a covariate analysis performed on data from 72 subjects: 48 white and 24 non-white. The apparent total body clearance and apparent volume of distribution were not affected by the race of the subjects. Renal Impairment Clearance of levofloxacin is substantially reduced and plasma elimination half-life is substantially prolonged in adult patients with impaired renal function (creatinine clearance < 50 mL/min), requiring dosage adjustment in such patients to avoid accumulation. Neither hemodialysis nor continuous ambulatory peritoneal dialysis (CAPD) is effective in removal of levofloxacin from the body, indicating that supplemental doses of levofloxacin are not required following hemodialysis or CAPD [see Dosage and Administration ( 2.3), Use in Specific Populations ( 8.6)] . Hepatic Impairment Pharmacokinetic studies in hepatically impaired patients have not been conducted. Due to the limited extent of levofloxacin metabolism, the pharmacokinetics of levofloxacin are not expected to be affected by hepatic impairment [see Use in Specific Populations ( 8.7)] . Bacterial Infection The pharmacokinetics of levofloxacin in patients with serious community-acquired bacterial infections are comparable to those observed in healthy subjects. Drug-Drug Interactions The potential for pharmacokinetic drug interactions between levofloxacin and antacids, warfarin, theophylline, cyclosporine, digoxin, probenecid, and cimetidine has been evaluated [see Drug Interactions ( 7)] .

Mechanism of Action Levofloxacin is the L-isomer of the racemate, ofloxacin, a quinolone antimicrobial agent. The antibacterial activity of ofloxacin resides primarily in the L-isomer. The mechanism of action of levofloxacin and other fluoroquinolone antimicrobials involves inhibition of bacterial topoisomerase IV and DNA gyrase (both of which are type II topoisomerases), enzymes required for DNA replication, transcription, repair and recombination. Mechanism of Resistance Fluoroquinolone resistance can arise through mutations in defined regions of DNA gyrase or topoisomerase IV, termed the Quinolone-Resistance Determining Regions (QRDRs), or through altered efflux. Fluoroquinolones, including levofloxacin, differ in chemical structure and mode of action from aminoglycosides, macrolides and -lactam antibiotics, including penicillins. Fluoroquinolones may, therefore, be active against bacteria resistant to these antimicrobials. Resistance to levofloxacin due to spontaneous mutation in vitro is a rare occurrence (range: 10 -9 to 10 -10). Cross-resistance has been observed between levofloxacin and some other fluoroquinolones, some microorganisms resistant to other fluoroquinolones may be susceptible to levofloxacin. Activity in vitro and in vivo Levofloxacin has in vitro activity against Gram-negative and Gram-positive bacteria. Levofloxacin has been shown to be active against most isolates of the following bacteria both in vitro and in clinical infections as described in Indications and Usage ( 1) : Gram-Positive Bacteria Enterococcus faecalis Staphylococcus aureus (methicillin-susceptible isolates) Staphylococcus epidermidis (methicillin-susceptible isolates) Staphylococcus saprophyticus Streptococcus pneumoniae (including multi-drug resistant isolates [MDRSP] 1) Streptococcus pyogenes Gram-Negative Bacteria Enterobacter cloacae Escherichia coli Haemophilus influenzae Haemophilus parainfluenzae Klebsiella pneumoniae Legionella pneumophila Moraxella catarrhalis Proteus mirabilis Pseudomonas aeruginosa Serratia marcescens Other Bacteria Chlamydophila pneumoniae Mycoplasma pneumonia 1 MDRSP (Multi-drug resistant Streptococcus pneumoniae) isolates are isolates resistant to two or more of the following antibiotics: penicillin (MIC 2 mcg/mL), 2 nd generation cephalosporins, e.g., cefuroxime; macrolides, tetracyclines and trimethoprim/sulfamethoxazole. The following in vitro data are available, but their clinical significance is unknown: Levofloxacin exhibits in vitro minimum inhibitory concentrations (MIC values) of 2 mcg/mL or less against most ( 90%) isolates of the following microorganisms; however, the safety and effectiveness of levofloxacin in treating clinical infections due to these bacteria have not been established in adequate and well-controlled clinical trials. Gram-Positive Bacteria Staphylococcus haemolyticus -hemolytic Streptococcus (Group C/F) -hemolytic Streptococcus (Group G) Streptococcus agalactiae Streptococcus milleri Viridans group streptococci Bacillus anthracis Gram-Negative Bacteria Acinetobacter baumannii Acinetobacter lwoffii Bordetella pertussis Citrobacter koseri Citrobacter freundii Enterobacter aerogenes Enterobacter sakazakii Klebsiella oxytoca Morganella morganii Pantoea agglomerans Proteus vulgaris Providencia rettgeri Providencia stuartii Pseudomonas fluorescens Yersinia pestis Anaerobic Gram-Positive Bacteria Clostridium perfringens Susceptibility Tests When available, the clinical microbiology laboratory should provide the results of in vitro susceptibility test results for antimicrobial drug products used in the resident hospitals to the physician as periodic reports that describe the susceptibility profile of nosocomial and community-acquired pathogens. These reports should aid the physician in selecting an antibacterial drug product for treatment. Dilution techniques: Quantitative methods are used to determine antimicrobial minimal inhibitory concentrations (MICs). These MICs provide estimates of the susceptibility of bacteria to antimicrobial compounds. The MIC values should be determined using a standardized procedure. Standardized procedures are based on a dilution method 1,2,4 (broth or agar) or equivalent with standardized inoculum concentrations and standardized concentrations of levofloxacin powder. The MIC values should be interpreted according to the criteria outlined in Table 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 procedure 2,3 requires the use of standardized inoculum concentrations. This procedure uses paper disks impregnated with 5 mcg levofloxacin to test the susceptibility of bacteria to levofloxacin. Reports from the laboratory providing results of the standard single-disk susceptibility test with a 5 mcg levofloxacin disk should be interpreted according to the criteria outlined in Table 9. Table 9: Susceptibility Test Interpretive Criteria for Levofloxacin Minimum Inhibitory Concentrations (mcg/mL) Disk Diffusion (zone diameter in mm) Pathogen S I R S I R Enterobacteriaceae 2 4 8 17 14-16 13 Enterococcus faecalis 2 4 8 17 14-16 13 Staphylococcus species 2 4 8 17 14-16 13 Pseudomonas aeruginosa 2 4 8 17 14-16 13 Haemophilus influenzae 2 -- -- 17 -- -- Haemophilus parainfluenzae 2 -- -- 17 -- -- Streptococcus pneumoniae 2 4 8 17 14-16 13 Streptococcus pyogenes 2 4 8 17 14-16 13 Yersinia pestis 4 0.25 -- -- -- -- -- Bacillus anthracis 4 0.25 -- -- -- -- -- S = Susceptible, I = Intermediate, R = Resistant The current absence of data on resistant isolates precludes defining any categories other than "Susceptible." Isolates yielding MIC/zone diameter results suggestive of a "nonsusceptible" category should be submitted to a reference laboratory for further testing. A report of Susceptible indicates that the pathogen is likely to be inhibited if the antimicrobial compound in the blood reaches the concentrations usually achievable. A report of Intermediate indicates that the result should be considered equivocal, and, if the microorganism is not fully susceptible to alternative, clinically feasible drugs, the test should be repeated. This category implies possible clinical applicability in body sites where the drug is physiologically concentrated or in situations where a high dosage of drug can be used. This category also provides a buffer zone which prevents small uncontrolled technical factors from causing major discrepancies in interpretation. A report of Resistant indicates that the pathogen is not likely to be inhibited if the antimicrobial compound in the blood reaches the concentrations usually achievable; other therapy should be selected. Quality Control: Standardized susceptibility test procedures require the use of laboratory controls to monitor and ensure the accuracy and precision of supplies and reagents used in the assay, and the techniques of the individuals performing the test. 1,2,3,4 Standard levofloxacin powder should provide the range of MIC values noted in Table 10. For the diffusion technique using the 5 mcg disk, the criteria in Table 10 should be achieved. Table 10: Quality Control Ranges for Susceptibility Testing Microorganism Microorganism QC Number MIC (mcg/mL) Disk Diffusion (zone diameter in mm) Enterococcus faecalis ATCC 29212 0.25 2 -- Escherichia coli ATCC 25922 0.008 0.06 29 37 Escherichia coli ATCC 35218 0.015 0.06 -- Haemophilus influenzae ATCC 49247 0.008 0.03 32 40 Pseudomonas aeruginosa ATCC 27853 0.5 4 19 26 Staphylococcus aureus ATCC 29213 0.06 0.5 -- Staphylococcus aureus ATCC 25923 -- 25 30 Streptococcus pneumoniae ATCC 49619 0.5 2 20 25

Levofloxacin and other quinolones have been shown to cause arthropathy in immature animals of most species tested [see Warnings and Precautions ( 5.11)] . In immature dogs (4 to 5 months old), oral doses of 10 mg/kg/day for 7 days and intravenous doses of 4 mg/kg/day for 14 days of levofloxacin resulted in arthropathic lesions. Administration at oral doses of 300 mg/kg/day for 7 days and intravenous doses of 60 mg/kg/day for 4 weeks produced arthropathy in juvenile rats. Three-month old beagle dogs dosed orally with levofloxacin at 40 mg/kg/day exhibited clinically severe arthrotoxicity resulting in the termination of dosing at Day 8 of a 14-day dosing routine. Slight musculoskeletal clinical effects, in the absence of gross pathological or histopathological effects, resulted from the lowest dose level of 2.5 mg/kg/day (approximately 0.2-fold the pediatric dose based upon AUC comparisons). Synovitis and articular cartilage lesions were observed at the 10 and 40 mg/kg dose levels (approximately 0.7-fold and 2.4-fold the pediatric dose, respectively, based on AUC comparisons). Articular cartilage gross pathology and histopathology persisted to the end of the 18-week recovery period for those dogs from the 10 and 40 mg/kg/day dose levels. When tested in a mouse ear swelling bioassay, levofloxacin exhibited phototoxicity similar in magnitude to ofloxacin, but less phototoxicity than other quinolones. While crystalluria has been observed in some intravenous rat studies, urinary crystals are not formed in the bladder, being present only after micturition and are not associated with nephrotoxicity. In mice, the CNS stimulatory effect of quinolones is enhanced by concomitant administration of non-steroidal anti-inflammatory drugs. In dogs, levofloxacin administered at 6 mg/kg or higher by rapid intravenous injection produced hypotensive effects. These effects were considered to be related to histamine release. In vitro and in vivo studies in animals indicate that levofloxacin is neither an enzyme inducer nor inhibitor in the human therapeutic plasma concentration range; therefore, no drug metabolizing enzyme-related interactions with other drugs or agents are anticipated.

Adult patients with clinically and radiologically documented nosocomial pneumonia were enrolled in a multicenter, randomized, open-label study comparing intravenous levofloxacin (750 mg once daily) followed by oral levofloxacin (750 mg once daily) for a total of 7 to 15 days to intravenous imipenem/cilastatin (500 to 1000 mg every 6 to 8 hours daily) followed by oral ciprofloxacin (750 mg every 12 hours daily) for a total of 7 to 15 days. Levofloxacin-treated patients received an average of 7 days of intravenous therapy (range: 1 to 16 days); comparator-treated patients received an average of 8 days of intravenous therapy (range: 1 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 7 days in the levofloxacin arm and 7 days in the comparator. In clinically and microbiologically evaluable patients with documented Pseudomonas aeruginosa infection, 15 of 17 (88.2%) received ceftazidime (N=11) or piperacillin/tazobactam (N=4) in the levofloxacin arm and 16 of 17 (94.1%) received an aminoglycoside in the comparator arm. Overall, in clinically and microbiologically evaluable patients, vancomycin was added to the treatment regimen of 37 of 93 (39.8%) patients in the levofloxacin arm and 28 of 94 (29.8%) patients in the comparator arm for suspected methicillin-resistant S. aureus infection. Clinical success rates in clinically and microbiologically evaluable patients at the posttherapy visit (primary study endpoint assessed on day 3 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 11. Table 11: Clinical Success Rates and Bacteriological Eradication Rates (Nosocomial Pneumonia) Pathogen N Levofloxacin No. (%) of Patients Microbiologic/ Clinical Outcomes N Imipenem/Cilastatin No. (%) of Patients Microbiologic/ Clinical Outcomes MSSA * 21 14 (66.7)/13 (61.9) 19 13 (68.4)/15 (78.9) P. aeruginosa 17 10 (58.8)/11 (64.7) 17 5 (29.4)/7 (41.2) S. marcescens 11 9 (81.8)/7 (63.6) 7 2 (28.6)/3 (42.9) E. coli 12 10 (83.3)/7 (58.3) 11 7 (63.6 )/8 (72.7) K. pneumoniae 11 9 (81.8)/5 (45.5) 7 6 (85.7)/3 (42.9) H. influenzae 16 13 (81.3)/10 (62.5) 15 14 (93.3)/11 (73.3) S. pneumoniae 4 3 (75)/3 (75) 7 5 (71.4)/4 (57.1) *Methicillin-susceptible S. aureus See above text for use of combination therapy The observed differences in rates for the clinical and microbiological outcomes may reflect other factors that were not accounted for in the study

Adult inpatients and outpatients with a diagnosis of community-acquired bacterial pneumonia were evaluated in 2 pivotal clinical studies. In the first study, 590 patients were enrolled in a prospective, multi-center, unblinded randomized trial comparing levofloxacin 500 mg once daily orally or intravenously for 7 to 14 days to ceftriaxone 1 to 2 grams intravenously once or in equally divided doses twice daily followed by cefuroxime axetil 500 mg orally twice daily for a total of 7 to 14 days. Patients assigned to treatment with the control regimen were allowed to receive erythromycin (or doxycycline if intolerant of erythromycin) if an infection due to atypical pathogens was suspected or proven. Clinical and microbiologic evaluations were performed during treatment, 5 to 7 days posttherapy, and 3 to 4 weeks posttherapy. Clinical success (cure plus improvement) with levofloxacin at 5 to 7 days posttherapy, the primary efficacy variable in this study, was superior (95%) to the control group (83%). The 95% CI for the difference of response rates (levofloxacin minus comparator) was [-6, 19]. In the second study, 264 patients were enrolled in a prospective, multi-center, noncomparative trial of 500 mg levofloxacin administered orally or intravenously once daily for 7 to 14 days. Clinical success for clinically evaluable patients was 93%. For both studies, the clinical success rate in patients with atypical pneumonia due to Chlamydophila pneumoniae, Mycoplasma pneumoniae, and Legionella pneumophila were 96%, 96%, and 70%, respectively. Microbiologic eradication rates across both studies are presented in Table 12. Table 12: Bacteriological Eradication Rates Across 2 Community Acquired Pneumonia Clinical Studies Pathogen No. Pathogens Bacteriological Eradication Rate (%) H. influenzae 55 98 S. pneumoniae 83 95 S. aureus 17 88 M. catarrhalis 18 94 H. parainfluenzae 19 95 K. pneumoniae 10 100 Community-Acquired Pneumonia Due to Multi-Drug Resistant Streptococcus pneumoniae Levofloxacin was effective for the treatment of community-acquired pneumonia caused by multi-drug resistant Streptococcus pneumoniae (MDRSP). MDRSP isolates are isolates resistant to two or more of the following antibacterials: penicillin (MIC 2 mcg/mL), 2 nd generation cephalosporins (e.g., cefuroxime, macrolides, tetracyclines and trimethoprim/sulfamethoxazole). Of 40 microbiologically evaluable patients with MDRSP isolates, 38 patients (95%) achieved clinical and bacteriologic success at post-therapy. The clinical and bacterial success rates are shown in Table 13. Table 13: Clinical and Bacterial Success Rates for Levofloxacin-Treated MDRSP in Community Acquired Pneumonia Patients (Population Valid for Efficacy) Screening Susceptibility Clinical Success Bacteriological Success * n/N % n/N % Penicillin-resistant 16/17 94.1 16/17 94.1 2nd generation Cephalosporin resistant 31/32 96.9 31/32 96.9 Macrolide-resistant 28/29 96.6 28/29 96.6 Trimethoprim/Sulfamethoxazole resistant 17/19 89.5 17/19 89.5 Tetracycline-resistant 12/12 100 12/12 100 *One patient had a respiratory isolate that was resistant to tetracycline, cefuroxime, macrolides and TMP/SMX and intermediate to penicillin and a blood isolate that was intermediate to penicillin and cefuroxime and resistant to the other classes. The patient is included in the database based on respiratory isolate. n=the number of microbiologically evaluable patients who were clinical successes; N=number of microbiologically evaluable patients in the designated resistance group. n=the number of MDRSP isolates eradicated or presumed eradicated in microbiologically evaluable patients; N=number of MDRSP isolates in a designated resistance group. Not all isolates were resistant to all antimicrobial classes tested. Success and eradication rates are summarized in Table 14. Table 14: Clinical Success and Bacteriologic Eradication Rates for Resistant Streptococcus pneumoniae (Community Acquired Pneumonia) Type of Resistance Clinical Success Bacteriologic Eradication Resistant to 2 antibacterials 17/18 (94.4%) 17/18 (94.4%) Resistant to 3 antibacterials 14/15 (93.3%) 14/15 (93.3%) Resistant to 4 antibacterials 7/7 (100%) 7/7 (100%) Resistant to 5 antibacterials 0 0 Bacteremia with MDRSP 8/9 (89%) 8/9 (89%)

Adult patients with a clinical diagnosis of prostatitis and microbiological culture results from urine sample collected after prostatic massage (VB 3) or expressed prostatic secretion (EPS) specimens obtained via the Meares-Stamey procedure were enrolled in a multicenter, randomized, double-blind study comparing oral levofloxacin 500 mg, once daily for a total of 28 days to oral ciprofloxacin 500 mg, twice daily for a total of 28 days. The primary efficacy endpoint was microbiologic efficacy in microbiologically evaluable patients. A total of 136 and 125 microbiologically evaluable patients were enrolled in the levofloxacin and ciprofloxacin groups, respectively. The microbiologic eradication rate by patient infection at 5 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 17. Table 17: Bacteriological Eradication Rates (Chronic Bacterial Prostatitis) Levofloxacin (N=136) Ciprofloxacin (N=125) Pathogen N Eradication N Eradication E. coli 15 14 (93.3%) 11 9 (81.8%) E. faecalis 54 39 (72.2%) 44 33 (75%) S. epidermidis * 11 9 (81.8%) 14 11 (78.6%) *Eradication rates shown are for patients who had a 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 5 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).

To evaluate the safety and efficacy of the higher dose and shorter course of levofloxacin, 1109 patients with cUTI and AP were enrolled in a randomized, double-blind, multicenter clinical trial conducted in the US from November 2004 to April 2006 comparing levofloxacin 750 mg IV or orally once daily for 5 days (546 patients) with ciprofloxacin 400 mg IV or 500 mg orally twice daily for 10 days (563 patients). Patients with AP complicated by underlying renal diseases or conditions such as complete obstruction, surgery, transplantation, concurrent infection or congenital malformation were excluded. Efficacy was measured by bacteriologic eradication of the baseline organism(s) at the post-therapy visit in patients with a pathogen identified at baseline. The post-therapy (test-of-cure) visit occurred 10 to 14 days after the last active dose of levofloxacin and 5 to 9 days after the last dose of active ciprofloxacin. The bacteriologic cure rates overall for levofloxacin and control at the test-of-cure (TOC) visit for the group of all patients with a documented pathogen at baseline (modified intent to treat or mITT) and the group of patients in the mITT population who closely followed the protocol (Microbiologically Evaluable) are summarized in Table 18. Table 18: Bacteriological Eradication at Test-of-Cure Levofloxacin 750 mg orally or IV once daily for 5 days Ciprofloxacin 400 mg IV/ 500 mg orally twice daily for 10 days Overall Difference [95% CI] n/N % n/N % Levofloxacin- Ciprofloxacin mITT Population * Overall (cUTI or AP) 252/333 75.7 239/318 75.2 0.5 (-6.1, 7.1) cUTI 168/230 73 157/213 73.7 AP 84/103 81.6 82/105 78.1 Microbiologically Evaluable Population Overall (cUTI or AP) 228/265 86 215/241 89.2 -3.2 [-8.9, 2.5] cUTI 154/185 83.2 144/165 87.3 AP 74/80 92.5 71/76 93.4 *The mITT population included patients who received study medication and who had a positive ( 10 5 CFU/mL) urine culture with no more than 2 uropathogens at baseline. Patients with missing response were counted as failures in this analysis. The Microbiologically Evaluable population included patients with a confirmed diagnosis of cUTI or AP, a causative organism(s) at baseline present at 10 5 CFU/mL, a valid test-of-cure urine culture, no pathogen isolated from blood resistant to study drug, no premature discontinuation or loss to follow-up, and compliance with treatment (among other criteria). Microbiologic eradication rates in the Microbiologically Evaluable population at TOC for individual pathogens recovered from patients randomized to levofloxacin treatment are presented in Table 19. Table 19: Bacteriological Eradication Rates for Individual Pathogens Recovered From Patients Randomized to Levofloxacin 750 mg QD for 5 Days Treatment Pathogen Bacteriological Eradication Rate (n/N) % Escherichia coli * 155/172 90 Klebsiella pneumoniae 20/23 87 Proteus mirabilis 12/12 100 *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.

The effectiveness of levofloxacin for this indication is based on plasma concentrations achieved in humans, a surrogate endpoint reasonably likely to predict clinical benefit. Levofloxacin has not been tested in humans for the post-exposure prevention of inhalation anthrax. The mean plasma concentrations of levofloxacin associated with a statistically significant improvement in survival over placebo in the rhesus monkey model of inhalational anthrax are reached or exceeded in adult and pediatric patients receiving the recommended oral and intravenous dosage regimens [see Indications and Usage ( 1.13); Dosage and Administration ( 2.1, 2.2)] .Levofloxacin pharmacokinetics have been evaluated in adult and pediatric patients. The mean ( SD) steady state peak plasma concentration in human adults receiving 500 mg orally or intravenously once daily is 5.7 1.4 and 6.4 0.8 mcg/mL, respectively; and the corresponding total plasma exposure (AUC 0 to 24) is 47.5 6.7 and 54.6 11.1 mcg.h/mL, respectively. The predicted steady-state pharmacokinetic parameters in pediatric patients ranging in age from 6 months to 17 years receiving 8 mg/kg orally every 12 hours (not to exceed 250 mg per dose) were calculated to be comparable to those observed in adults receiving 500 mg orally once daily [see Clinical Pharmacology ( 12.3)] . In adults, the safety of levofloxacin for treatment durations of up to 28 days is well characterized. However, information pertaining to extended use at 500 mg daily up to 60 days is limited. Prolonged levofloxacin therapy in adults should only be used when the benefit outweighs the risk. In pediatric patients, the safety of levofloxacin for treatment durations of more than 14 days has not been studied. An increased incidence of musculoskeletal adverse events (arthralgia, arthritis, tendinopathy, gait abnormality) compared to controls has been observed in clinical studies with treatment duration of up to 14 days. Long-term safety data, including effects on cartilage, following the administration of levofloxacin to pediatric patients is limited [see Warnings and Precautions ( 5.10), Use in Specific Populations ( 8.4)] . A placebo-controlled animal study in rhesus monkeys exposed to an inhaled mean dose of 49 LD 50 (~2.7 x 10 6) spores (range 17 to 118 LD 50) of B. anthracis (Ames strain) was conducted. The minimal inhibitory concentration (MIC) of levofloxacin for the anthrax strain used in this study was 0.125 mcg/mL. In the animals studied, mean plasma concentrations of levofloxacin achieved at expected T max (1 hour post-dose) following oral dosing to steady state ranged from 2.79 to 4.87 mcg/mL. Steady state trough concentrations at 24 hours post-dose ranged from 0.107 to 0.164 mcg/mL. Mean (SD) steady state AUC 0 to 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 a 30 day regimen of oral levofloxacin beginning 24 hrs post exposure was significantly lower (1/10), compared to the placebo group (9/10) [P=0.0011, 2-sided Fisher's Exact Test]. The one levofloxacin treated animal that died of anthrax did so following the 30-day drug administration period.

Efficacy studies of levofloxacin could not be conducted in humans with pneumonic plague for ethical and feasibility reasons. Therefore, approval of this indication was based on an efficacy study conducted in animals. The mean plasma concentrations of levofloxacin associated with a statistically significant improvement in survival over placebo in an African green monkey model of pneumonic plague are reached or exceeded in adult and pediatric patients receiving the recommended oral and intravenous dosage regimens [see Indications and Usage ( 1.14), Dosage and Administration ( 2.1), ( 2.2)] . Levofloxacin pharmacokinetics have been evaluated in adult and pediatric patients. The mean ( SD) steady state peak plasma concentration in human adults receiving 500 mg orally or intravenously once daily is 5.7 1.4 and 6.4 0.8 mcg/mL, respectively; and the corresponding total plasma exposure (AUC 0 to 24) is 47.5 6.7 and 54.6 11.1 mcg.h/mL, respectively. The predicted steady-state pharmacokinetic parameters in pediatric patients ranging in age from 6 months to 17 years receiving 8 mg/kg orally every 12 hours (not to exceed 250 mg per dose) were calculated to be comparable to those observed in adults receiving 500 mg orally once daily [see Clinical Pharmacology ( 12.3)] . A placebo-controlled animal study in African green monkeys exposed to an inhaled mean dose of 65 LD 50 (range 3 to 145 LD 50) of Yersinia pestis (CO92 strain) was conducted. The minimal inhibitory concentration (MIC) of levofloxacin for the Y. pestis strain used in this study was 0.03 mcg/mL. Mean plasma concentrations of levofloxacin achieved at the end of a single 30-min infusion ranged from 2.84 to 3.50 mcg/mL in African green monkeys. Trough concentrations at 24 hours post-dose ranged from <0.03 to 0.06 mcg/mL. Mean (SD) AUC 0 to 24 was 11.9 (3.1) mcg.h/mL (range 9.50 to 16.86 mcg.h/mL). Animals were randomized to receive either a 10-day regimen of i.v. levofloxacin or placebo beginning within 6 hrs of the onset of telemetered fever ( 39 C for more than 1 hour). Mortality in the levofloxacin group was significantly lower (1/17) compared to the placebo group (7/7) [p<0.001, Fisher's Exact Test; exact 95% confidence interval (-99.9%, -55.5%) for the difference in mortality]. One levofloxacin-treated animal was euthanized on Day 9 post-exposure to Y. pestis due to a gastric complication; it had a blood culture positive for Y. pestis on Day 3 and all subsequent daily blood cultures from Day 4 through Day 7 were negative.

Advise patients to stop taking levofloxacin if they experience an adverse reaction and to call their healthcare provider for advice on completing the full course of treatment with another antibacterial drug. Inform patients of the following serious adverse reactions that have been associated with levofloxacin or other fluoroquinolone use: Disabling and Potentially Irreversible Serious Adverse Reactions That May Occur Together: Inform patients that disabling and potentially irreversible serious adverse reactions, including tendinitis and tendon rupture, peripheral neuropathies, and central nervous system effects, have been associated with use of levofloxacin and may occur together in the same patient. Inform patients to stop taking levofloxacin immediately if they experience an adverse reaction and to call their healthcare provider. Tendinitis and Tendon Rupture: Instruct patients to contact their healthcare provider if they experience pain, swelling, or inflammation of a tendon, or weakness or inability to use one of their joints; rest and refrain from exercise; and discontinue levofloxacin treatment. Symptoms may be irreversible. The risk of severe tendon disorder 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. Peripheral Neuropathies: Inform patients that peripheral neuropathies have 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, immediately discontinue levofloxacin and tell them to contact their physician. Central Nervous System Effects (for example, convulsions, dizziness, lightheadedness, increased intracranial pressure): Inform patients that convulsions have been reported in patients receiving fluoroquinolones, including levofloxacin. Instruct patients to notify their physician before taking this drug if they have a history of convulsions. Inform patients that they should know how they react to levofloxacin before they operate an automobile or machinery or engage in other activities requiring mental alertness and coordination. Instruct patients to notify their physician if persistent headache with or without blurred vision occurs. Exacerbation of Myasthenia Gravis: Instruct patients to inform their physician of any history of myasthenia gravis. Instruct patients to notify their physician if they experience any symptoms of muscle weakness, including respiratory difficulties. Hypersensitivity Reactions: Inform patients that levofloxacin can cause hypersensitivity reactions, even following a single dose, and to discontinue the drug at the first sign of a skin rash, hives or other skin reactions, a rapid heartbeat, difficulty in swallowing or breathing, any swelling suggesting angioedema (for example, swelling of the lips, tongue, face, tightness of the throat, hoarseness), or other symptoms of an allergic reaction. Hepatotoxicity: Inform patients that severe hepatotoxicity (including acute hepatitis and fatal events) has been reported in patients taking levofloxacin. Instruct patients to inform their physician 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. Diarrhea: Diarrhea is a common problem caused by antibiotics which usually ends when the antibiotic is discontinued. Sometimes after starting treatment with antibiotics, patients can develop watery and bloody stools (with or without stomach cramps and fever) even as late as two or more months after having taken the last dose of the antibiotic. If this occurs, instruct patients to contact their physician as soon as possible. Prolongation of the QT Interval: Instruct patients to 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. Instruct patients to notify their physician if they have any symptoms of prolongation of the QT interval, including prolonged heart palpitations or a loss of consciousness. Musculoskeletal Disorders in Pediatric Patients: Instruct parents to inform their child s physician if the child has a history of joint-related problems before taking this drug. Inform parents of pediatric patients to notify their child s physician of any joint-related problems that occur during or following levofloxacin therapy [ see Warnings and Precautions ( 5.11) and Use in Specific Populations ( 8.4) ]. Photosensitivity/Phototoxicity: Inform patients that photosensitivity/phototoxicity has been reported in patients receiving fluoroquinolones. Inform patients to minimize or avoid exposure to natural or artificial sunlight (tanning beds or UVA/B treatment) while taking fluoroquinolones. If patients need to be outdoors while using fluoroquinolones, instruct them to wear loose-fitting clothes that protect skin from sun exposure and discuss other sun protection measures with their physician. If a sunburn-like reaction or skin eruption occurs, instruct patients to contact their physician.

MEDICATION GUIDE Levofloxacin (LEE-voe-FLOX-a-sin) Tablets Read this Medication Guide before you start taking levofloxacin and each time you get a refill. There may be new information. This Medication Guide does not take the place of talking to your healthcare provider about your medical condition or your treatment. What is the most important information I should know about levofloxacin? Levofloxacin, a fluoroquinolone antibiotic, can cause serious side effects. Some of these serious side effects can happen at the same time and could result in death. If you have any of the following serious side effects while you take levofloxacin, you should stop taking levofloxacin immediately and get medical help right away. 1. Tendon rupture or swelling of the tendon (tendinitis). Tendon problems can happen in people of all ages who take levofloxacin. Tendons are tough cords of tissue that connect muscles to bones. Some tendon problems include pain, swelling, tears, and swelling of tendons including the back of the ankle (Achilles), shoulder, hand, or other tendon sites. The risk of getting tendon problems while you take levofloxacin is higher if you: o are over 60 years of age o are taking steroids (corticosteroids) o have had a kidney, heart or lung transplant. Tendon problems can happen in people who do not have the above risk factors when they take levofloxacin. Other reasons that can increase your risk of tendon problems can include: o physical activity or exercise o kidney failure o tendon problems in the past, such as in people with rheumatoid arthritis (RA) Stop taking levofloxacin immediately and get medical help right away at the first sign of tendon pain, swelling or inflammation. 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. You may need a different antibiotic that is not a fluoroquinolone to treat your infection. Tendon rupture can happen while you are taking or after you have finished taking levofloxacin. Tendon ruptures can happen within hours or days of taking levofloxacin and have happened up to several months after people have finished taking their fluoroquinolone. Stop taking levofloxacin immediately and get medical help right away if you get any of the following signs or symptoms of a tendon rupture: o hear or feel a snap or pop in a tendon area o bruising right after an injury in a tendon area o unable to move the affected area or bear weight 2. Changes in sensation and possible nerve damage (Peripheral Neuropathy). Damage to the nerves in arms, hands, legs, or feet can happen in people who take fluoroquinolones, including levofloxacin. Stop taking levofloxacin immediately and talk to your healthcare provider right away if you get any of the following symptoms of peripheral neuropathy in your arms, hands, legs, or feet: pain numbness burning weakness tingling The nerve damage may be permanent. 3. Central Nervous System (CNS) effects. Seizures have been reported in people who take fluoroquinolone antibacterial medicines, including levofloxacin. Tell your healthcare provider if you have a history of seizures before you start taking levofloxacin. CNS side effects may happen as soon as after taking the first dose of levofloxacin. Stop taking levofloxacin immediately and talk to your healthcare provider right away if you get any of these side effects, or other changes in mood or behavior: seizures trouble sleeping hear voices, see things, or sense things that are not there (hallucinations) nightmares feel restless feel lightheaded or dizzy tremors feel more suspicious (paranoia) feel anxious or nervous suicidal thoughts or acts confusion headaches that will not go away, with or without blurred vision depression 4. Worsening of myasthenia gravis (a problem that causes muscle weakness). Fluoroquinolones like levofloxacin may cause worsening of myasthenia gravis symptoms, including muscle weakness and breathing problems. Tell your healthcare provider if you have a history of myasthenia gravis before you start taking levofloxacin. Call your healthcare provider right away if you have any worsening muscle weakness or breathing problems. What is levofloxacin? Levofloxacin is a fluoroquinolone antibiotic medicine used in adults age 18 years or older to treat certain infections caused by certain germs called bacteria. These bacterial infections include: nosocomial pneumonia chronic prostate infection acquired pneumonia urinary tract infections, complicated and uncomplicated acute sinus infection acute kidney infection (pyelonephritis) acute worsening of chronic bronchitis inhalational anthrax skin infections, complicated and uncomplicated plague Studies of levofloxacin for use in the treatment of plague and anthrax were done in animals only, because plague and anthrax could not be studied in people. Levofloxacin should not be used in patients with uncomplicated urinary tract infections, acute bacterial exacerbation of chronic bronchitis, or acute bacterial sinusitis if there are other treatment options available. Levofloxacin is also used to treat children who are 6 months of age or older and may have breathed in anthrax germs, have plague, or been exposed to plague germs. It is not known if levofloxacin is safe and effective in children under 6 months of age. The safety and effectiveness in children treated with levofloxacin for more than 14 days is not known. Who should not take levofloxacin? Do not take levofloxacin if you have ever had a severe allergic reaction to an antibiotic known as a fluoroquinolone, or if you are allergic to levofloxacin or any of the ingredients in levofloxacin. See the end of this leaflet for a complete list of ingredients in levofloxacin. What should I tell my healthcare provider before taking levofloxacin? Before you take levofloxacin, tell your healthcare provider if you: have tendon problems; levofloxacin should not be used in patients who have a history of tendon problems have a problem that causes muscle weakness (myasthenia gravis); levofloxacin should not be used in patients who have a known history of myasthenia gravis have central nervous system problems such as seizures (epilepsy) have nerve problems; levofloxacin should not be used in patients how have a history of a nerve problem called peripheral neuropathy have or anyone in your family has an irregular heartbeat, especially a condition called QT prolongation. have low blood potassium (hypokalemia) have bone problems have joint problems including rheumatoid arthritis (RA) have kidney problems. You may need a lower dose of levofloxacin if your kidneys do not work well. have liver problems have diabetes or problems with low blood sugar (hypoglycemia) are pregnant or plan to become pregnant. It is not known if levofloxacin will harm your unborn child. are breastfeeding or plan to breastfeed. It is not known if levofloxacin passes into your breast milk. You and your healthcare provider should decide if you will take levofloxacin or breastfeed. You should not do both. Tell your healthcare provider about all the medicines you take, including prescription and non-prescription medicines, vitamins, and herbal supplements. Levofloxacin and other medicines can affect each other causing side effects. Especially tell your healthcare provider if you take: a steroid medicine. an anti-psychotic medicine a tricyclic antidepressant a water pill (diuretic) certain medicines may keep levofloxacin from working correctly. Take levofloxacin tablets either 2 hours before or 2 hours after taking these medicines or supplements: o an antacid, multivitamin, or other medicines or supplements that have magnesium, aluminium, iron, or zinc. o sucralfate (Carafate ) o didanosine (Videx , Videx EC) a blood thinner (warfarin, Coumadin, Jantoven) an oral anti-diabetes medicine or insulin an NSAID (Non-Steroidal Anti-Inflammatory Drug). Many common medicines for pain relief are NSAIDs. Taking an NSAID while you take levofloxacin or other fluoroquinolones may increase your risk of central nervous system effects and seizures. theophylline (Theo-24 , Elixophyllin , Theochron , Uniphyl , Theolair ) a medicine to control your heart rate or rhythm (antiarrhythmics) Ask your healthcare provider if you are not sure if any of your medicines are listed above. Know the medicines you take. Keep a list of your medicines and show it to your healthcare provider and pharmacist when you get a new medicine. How should I take levofloxacin? Take levofloxacin exactly as your healthcare provider tells you to take it. Take levofloxacin at about the same time each day. Drink plenty of fluids while you take levofloxacin. Levofloxacin tablets can be taken with or without food. If you miss a dose of levofloxacin, take it as soon as you remember. Do not take more than 1 dose in 1 day. Do not skip any doses of levofloxacin or stop taking it, even if you begin to feel better, until you finish your prescribed treatment, unless: o you have tendon problems. See " What is the most important information I should know about levofloxacin?" o you have a nerve problem. See "What are the possible side effects of levofloxacin?". o you have a central nervous sytem problem. See " What are the possible side effects of levofloxacin?". o you have a serious allergic reaction. See " What are the possible side effects of levofloxacin?" o your healthcare provider tells you to stop taking levofloxacin. Taking all of your levofloxacin doses will help make sure that all of the bacteria are killed. Taking all of your levofloxacin doses will help you lower the chance that the bacteria will become resistant to levofloxacin. If your infection does not get better while you take levofloxacin, it may mean that the bacteria causing your infection may be resistant to levofloxacin. If your infection does not get better, call your healthcare provider. If your infection does not get better, levofloxacin and other similar antibiotic medicines may not work for you in the future. If you take too much levofloxacin, call your healthcare provider or get medical help right away. What should I avoid while taking levofloxacin? Levofloxacin can make you feel dizzy and lightheaded. Do not drive, operate machinery, or do other activities that require mental alertness or coordination until you know how levofloxacin affects you. Avoid sunlamps, tanning beds, and try to limit your time in the sun. Levofloxacin can make your skin sensitive to the sun (photosensitivity) and the light from sunlamps and tanning beds. You could get severe sunburn, blisters or swelling of your skin. If you get any of these symptoms while you take levofloxacin, call your healthcare provider right away. You should use a sunscreen and wear a hat and clothes that cover your skin if you have to be in sunlight. What are the possible side effects of levofloxacin? Levofloxacin can cause serious side effects, including: See "What is the most important information I should know about levofloxacin?" Serious allergic reactions. Allergic reactions can happen in people taking fluoroquinolones, including levofloxacin, even after only 1 dose. Stop taking levofloxacin and get emergency medical help right away if you have any of the following symptoms of a severe allergic reaction: o hives o trouble breathing or swallowing o swelling of the lips, tongue, face o throat tightness, hoarseness o rapid heartbeat o faint o skin rash Skin rash may happen in people taking levofloxacin, even after only 1 dose. Stop taking levofloxacin at the first sign of a skin rash and call your healthcare provider. Skin rash may be a sign of a more serious reaction to levofloxacin. Liver damage (hepatotoxicity): Hepatotoxicity can happen in people who take levofloxacin. Call your healthcare provider right away if you have unexplained symptoms such as: o nausea or vomiting o stomach pain o fever o weakness o abdominal pain or tenderness o itching o unusual tiredness o loss of appetite o light colored bowel movements o dark colored urine o yellowing of your skin or the whites of your eyes Stop taking levofloxacin and tell your healthcare provider right away if you have yellowing of your skin or white part of your eyes, or if you have dark urine. These can be signs of a serious reaction to levofloxacin (a liver problem). Intestine infection (Pseudomembranous colitis)Pseudomembranous colitis can happen with many antibiotics, including levofloxacin. Call your healthcare provider right away if you get watery diarrhea, diarrhea that does not go away, or bloody stools. You may have stomach cramps and a fever.Pseudomembranous colitis can happen 2 or more months after you have finished your antibiotic. Serious heart rhythm changes (QT prolongation and torsades de pointes)Tell your healthcare provider right away if you have a change in your heart beat (a fast or irregular heartbeat), or if you faint. Levofloxacin may cause a rare heart problem known as prolongation of the QT interval. This condition can cause an abnormal heartbeat and can be very dangerous. The chances of this happening are higher in people: o who are elderly o with a family history of prolonged QT interval o with low blood potassium (hypokalemia) o who take certain medicines to control heart rhythm (antiarrhythmics) Joint Problems Increased chance of problems with joints and tissues around joints in children can happen. Tell your child s healthcare provider if your child has any joint problems during or after treatment with levofloxacin. Changes in blood sugar People who take levofloxacin and other fluoroquinolone medicines with oral anti-diabetes medicines or with insulin can get low blood sugar (hypoglycemia) and high blood sugar (hyperglycemia). Follow your healthcare provider's instructions for how often to check your blood sugar. If you have diabetes and you get low blood sugar while taking levofloxacin, stop taking levofloxacin and call your healthcare provider right away. Your antibiotic medicine may need to be changed. Sensitivity to sunlight (photosensitivity) See "What should I avoid while taking levofloxacin?" The most common side effects of levofloxacin include: o nausea o headache o diarrhea o insomnia o constipation o dizziness In children 6 months and older who take levofloxacin to treat anthrax disease or plague, vomiting is also common. Levofloxacin may cause false-positive urine screening results for opiates when testing is done with some commercially available kits. A positive result should be confirmed using a more specific test. These are not all the possible side effects of levofloxacin. Tell your healthcare provider about any side effect that bothers you or that does not go away. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. How should I store levofloxacin? Store levofloxacin tablets at 20 to 25 C (68 to 77 F) [see USP Controlled Room Temperature]. Keep levofloxacin tablets in a tightly closed container Keep levofloxacin and all medicines out of the reach of children. General Information about the safe and effective use of levofloxacin Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use levofloxacin for a condition for which it is not prescribed. Do not give levofloxacin to other people, even if they have the same symptoms that you have. It may harm them. This Medication Guide summarizes the most important information about levofloxacin. If you would like more information about levofloxacin, talk with your healthcare provider. You can ask your healthcare provider or pharmacist for information about levofloxacin that is written for healthcare professionals. What are the ingredients in levofloxacin? Active ingredient: levofloxacin, USP Inactive ingredients: croscarmellose sodium, hypromellose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, polysorbate 80, povidone and titanium dioxide.Levofloxacin Tablets USP, 250 mg also contains iron oxide red. Levofloxacin Tablets USP, 500 mg also contains iron oxide red and iron oxide yellow. This Medication Guide has been approved by the U.S. Food and Drug Administration. Manufactured for: Camber Pharmaceuticals, Inc., Piscataway, NJ 08854 By: HETERO TM Hetero Labs Limited, Unit V, Polepally, Jadcherla, Mahaboob Nagar-509 301, India. Revised: September 2016

17.6 FDA-Approved Medication Guide MEDICATION GUIDE Levofloxacin (LEE-voe-FLOX-a-sin) Tablets Read this Medication Guide before you start taking levofloxacin and each time you get a refill. There may be new information. This Medication Guide does not take the place of talking to your healthcare provider about your medical condition or your treatment.What is the most important information I should know about levofloxacin? Levofloxacin, a fluoroquinolone antibiotic, can cause serious side effects. Some of these serious side effects can happen at the same time and could result in death. If you have any of the following serious side effects while you take levofloxacin, you should stop taking levofloxacin immediately and get medical help right away. 1. Tendon rupture or swelling of the tendon (tendinitis). Tendon problems can happen in people of all ages who take levofloxacin. Tendons are tough cords of tissue that connect muscles to bones. Some tendon problems include pain, swelling, tears, and swelling of tendons including the back of the ankle (Achilles), shoulder, hand, or other tendon sites. The risk of getting tendon problems while you take levofloxacin is higher if you: o are over 60 years of age o are taking steroids (corticosteroids) o have had a kidney, heart or lung transplant. Tendon problems can happen in people who do not have the above risk factors when they take levofloxacin. Other reasons that can increase your risk of tendon problems can include: o physical activity or exercise o kidney failure o tendon problems in the past, such as in people with rheumatoid arthritis (RA) Stop taking levofloxacin immediately and get medical help right away at the first sign of tendon pain, swelling or inflammation. 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. You may need a different antibiotic that is not a fluoroquinolone to treat your infection. Tendon rupture can happen while you are taking or after you have finished taking levofloxacin. Tendon ruptures can happen within hours or days of taking levofloxacin and have happened up to several months after people have finished taking their fluoroquinolone. Stop taking levofloxacin immediately and get medical help right away if you get any of the following signs or symptoms of a tendon rupture: o hear or feel a snap or pop in a tendon area o bruising right after an injury in a tendon area o unable to move the affected area or bear weight 2. Changes in sensation and possible nerve damage (Peripheral Neuropathy). Damage to the nerves in arms, hands, legs, or feet can happen in people who take fluoroquinolones, including levofloxacin. Stop taking levofloxacin immediately and talk to your healthcare provider right away if you get any of the following symptoms of peripheral neuropathy in your arms, hands, legs, or feet: pain numbness burning weakness tingling The nerve damage may be permanent. 3. Central Nervous System (CNS) effects. Seizures have been reported in people who take fluoroquinolone antibacterial medicines, including levofloxacin. Tell your healthcare provider if you have a history of seizures before you start taking levofloxacin. CNS side effects may happen as soon as after taking the first dose of levofloxacin. Stop taking levofloxacin immediately and talk to your healthcare provider right away if you get any of these side effects, or other changes in mood or behavior: seizures trouble sleeping hear voices, see things, or sense things that are not there (hallucinations) nightmares feel restless feel lightheaded or dizzy tremors feel more suspicious (paranoia) feel anxious or nervous suicidal thoughts or acts confusion headaches that will not go away, with or without blurred vision depression 4. Worsening of myasthenia gravis (a problem that causes muscle weakness). Fluoroquinolones like levofloxacin may cause worsening of myasthenia gravis symptoms, including muscle weakness and breathing problems. Tell your healthcare provider if you have a history of myasthenia gravis before you start taking levofloxacin. Call your healthcare provider right away if you have any worsening muscle weakness or breathing problems. What is levofloxacin? Levofloxacin is a fluoroquinolone antibiotic medicine used in adults age 18 years or older to treat certain infections caused by certain germs called bacteria. These bacterial infections include: nosocomial pneumonia chronic prostate infection acquired pneumonia urinary tract infections, complicated and uncomplicated acute sinus infection acute kidney infection (pyelonephritis) acute worsening of chronic bronchitis inhalational anthrax skin infections, complicated and uncomplicated plague Studies of levofloxacin for use in the treatment of plague and anthrax were done in animals only, because plague and anthrax could not be studied in people. Levofloxacin should not be used in patients with uncomplicated urinary tract infections, acute bacterial exacerbation of chronic bronchitis, or acute bacterial sinusitis if there are other treatment options available. Levofloxacin is also used to treat children who are 6 months of age or older and may have breathed in anthrax germs, have plague, or been exposed to plague germs. It is not known if levofloxacin is safe and effective in children under 6 months of age. The safety and effectiveness in children treated with levofloxacin for more than 14 days is not known. Who should not take levofloxacin? Do not take levofloxacin if you have ever had a severe allergic reaction to an antibiotic known as a fluoroquinolone, or if you are allergic to levofloxacin or any of the ingredients in levofloxacin. See the end of this leaflet for a complete list of ingredients in levofloxacin. What should I tell my healthcare provider before taking levofloxacin? Before you take levofloxacin, tell your healthcare provider if you: have tendon problems; levofloxacin should not be used in patients who have a history of tendon problems have a problem that causes muscle weakness (myasthenia gravis); levofloxacin should not be used in patients who have a known history of myasthenia gravis have central nervous system problems such as seizures (epilepsy) have nerve problems; levofloxacin should not be used in patients how have a history of a nerve problem called peripheral neuropathy have or anyone in your family has an irregular heartbeat, especially a condition called QT prolongation. have low blood potassium (hypokalemia) have bone problems have joint problems including rheumatoid arthritis (RA) have kidney problems. You may need a lower dose of levofloxacin if your kidneys do not work well. have liver problems have diabetes or problems with low blood sugar (hypoglycemia) are pregnant or plan to become pregnant. It is not known if levofloxacin will harm your unborn child. are breastfeeding or plan to breastfeed. It is not known if levofloxacin passes into your breast milk. You and your healthcare provider should decide if you will take levofloxacin or breastfeed. You should not do both. Tell your healthcare provider about all the medicines you take, including prescription and non-prescription medicines, vitamins, and herbal supplements. Levofloxacin and other medicines can affect each other causing side effects. Especially tell your healthcare provider if you take: a steroid medicine. an anti-psychotic medicine a tricyclic antidepressant a water pill (diuretic) certain medicines may keep levofloxacin from working correctly. Take levofloxacin tablets either 2 hours before or 2 hours after taking these medicines or supplements: o an antacid, multivitamin, or other medicines or supplements that have magnesium, aluminium, iron, or zinc. o sucralfate (Carafate ) o didanosine (Videx , Videx EC) a blood thinner (warfarin, Coumadin, Jantoven) an oral anti-diabetes medicine or insulin an NSAID (Non-Steroidal Anti-Inflammatory Drug). Many common medicines for pain relief are NSAIDs. Taking an NSAID while you take levofloxacin or other fluoroquinolones may increase your risk of central nervous system effects and seizures. theophylline (Theo-24 , Elixophyllin , Theochron , Uniphyl , Theolair ) a medicine to control your heart rate or rhythm (antiarrhythmics) Ask your healthcare provider if you are not sure if any of your medicines are listed above. Know the medicines you take. Keep a list of your medicines and show it to your healthcare provider and pharmacist when you get a new medicine. How should I take levofloxacin? Take levofloxacin exactly as your healthcare provider tells you to take it. Take levofloxacin at about the same time each day. Drink plenty of fluids while you take levofloxacin. Levofloxacin tablets can be taken with or without food. If you miss a dose of levofloxacin, take it as soon as you remember. Do not take more than 1 dose in 1 day. Do not skip any doses of levofloxacin or stop taking it, even if you begin to feel better, until you finish your prescribed treatment, unless: o you have tendon problems. See " What is the most important information I should know about levofloxacin?" o you have a nerve problem. See "What are the possible side effects of levofloxacin?". o you have a central nervous sytem problem. See "What are the possible side effects of levofloxacin?". o you have a serious allergic reaction. See " What are the possible side effects of levofloxacin?" o your healthcare provider tells you to stop taking levofloxacin. Taking all of your levofloxacin doses will help make sure that all of the bacteria are killed. Taking all of your levofloxacin doses will help you lower the chance that the bacteria will become resistant to levofloxacin. If your infection does not get better while you take levofloxacin, it may mean that the bacteria causing your infection may be resistant to levofloxacin. If your infection does not get better, call your healthcare provider. If your infection does not get better, levofloxacin and other similar antibiotic medicines may not work for you in the future. If you take too much levofloxacin, call your healthcare provider or get medical help right away. What should I avoid while taking levofloxacin? Levofloxacin can make you feel dizzy and lightheaded. Do not drive, operate machinery, or do other activities that require mental alertness or coordination until you know how levofloxacin affects you. Avoid sunlamps, tanning beds, and try to limit your time in the sun. Levofloxacin can make your skin sensitive to the sun (photosensitivity) and the light from sunlamps and tanning beds. You could get severe sunburn, blisters or swelling of your skin. If you get any of these symptoms while you take levofloxacin, call your healthcare provider right away. You should use a sunscreen and wear a hat and clothes that cover your skin if you have to be in sunlight. What are the possible side effects of levofloxacin? Levofloxacin can cause serious side effects, including: See "What is the most important information I should know about levofloxacin?" Serious allergic reactions. Allergic reactions can happen in people taking fluoroquinolones, including levofloxacin, even after only 1 dose. Stop taking levofloxacin and get emergency medical help right away if you have any of the following symptoms of a severe allergic reaction: o hives o trouble breathing or swallowing o swelling of the lips, tongue, face o throat tightness, hoarseness o rapid heartbeat o faint o skin rash Skin rash may happen in people taking levofloxacin, even after only 1 dose. Stop taking levofloxacin at the first sign of a skin rash and call your healthcare provider. Skin rash may be a sign of a more serious reaction to levofloxacin. Liver damage (hepatotoxicity): Hepatotoxicity can happen in people who take levofloxacin. Call your healthcare provider right away if you have unexplained symptoms such as: o nausea or vomiting o stomach pain o fever o weakness o abdominal pain or tenderness o itching o unusual tiredness o loss of appetite o light colored bowel movements o dark colored urine o yellowing of your skin or the whites of your eyes Stop taking levofloxacin and tell your healthcare provider right away if you have yellowing of your skin or white part of your eyes, or if you have dark urine. These can be signs of a serious reaction to levofloxacin (a liver problem). Intestine infection (Pseudomembranous colitis)Pseudomembranous colitis can happen with many antibiotics, including levofloxacin. Call your healthcare provider right away if you get watery diarrhea, diarrhea that does not go away, or bloody stools. You may have stomach cramps and a fever.Pseudomembranous colitis can happen 2 or more months after you have finished your antibiotic. Serious heart rhythm changes (QT prolongation and torsades de pointes)Tell your healthcare provider right away if you have a change in your heart beat (a fast or irregular heartbeat), or if you faint. Levofloxacin may cause a rare heart problem known as prolongation of the QT interval. This condition can cause an abnormal heartbeat and can be very dangerous. The chances of this happening are higher in people: o who are elderly o with a family history of prolonged QT interval o with low blood potassium (hypokalemia) o who take certain medicines to control heart rhythm (antiarrhythmics) Joint Problems Increased chance of problems with joints and tissues around joints in children can happen. Tell your child s healthcare provider if your child has any joint problems during or after treatment with levofloxacin. Changes in blood sugar People who take levofloxacin and other fluoroquinolone medicines with oral anti-diabetes medicines or with insulin can get low blood sugar (hypoglycemia) and high blood sugar (hyperglycemia). Follow your healthcare provider's instructions for how often to check your blood sugar. If you have diabetes and you get low blood sugar while taking levofloxacin, stop taking levofloxacin and call your healthcare provider right away. Your antibiotic medicine may need to be changed. Sensitivity to sunlight (photosensitivity) See "What should I avoid while taking levofloxacin?" The most common side effects of levofloxacin include: o nausea o headache o diarrhea o insomnia o constipation o dizziness In children 6 months and older who take levofloxacin to treat anthrax disease or plague, vomiting is also common. Levofloxacin may cause false-positive urine screening results for opiates when testing is done with some commercially available kits. A positive result should be confirmed using a more specific test. These are not all the possible side effects of levofloxacin. Tell your healthcare provider about any side effect that bothers you or that does not go away. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. How should I store levofloxacin? Store levofloxacin tablets at 20 to 25 C (68 to 77 F) [see USP Controlled Room Temperature]. Keep levofloxacin tablets in a tightly closed container Keep levofloxacin and all medicines out of the reach of children. General Information about the safe and effective use of levofloxacin Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use levofloxacin for a condition for which it is not prescribed. Do not give levofloxacin to other people, even if they have the same symptoms that you have. It may harm them. This Medication Guide summarizes the most important information about levofloxacin. If you would like more information about levofloxacin, talk with your healthcare provider. You can ask your healthcare provider or pharmacist for information about levofloxacin that is written for healthcare professionals. What are the ingredients in levofloxacin? Active ingredient: levofloxacin, USP Inactive ingredients: croscarmellose sodium, hypromellose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, polysorbate 80, povidone and titanium dioxide.Levofloxacin Tablets USP, 250 mg also contains iron oxide red. Levofloxacin Tablets USP, 500 mg also contains iron oxide red and iron oxide yellow. This Medication Guide has been approved by the U.S. Food and Drug Administration

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