Duration (days) Type of Infection Dose Every 24 hours Inhalational Anthrax (Post-Exposure) (1.13)

Transcription

1 HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights d nt include all the infrmatin needed t use LEVAQUIN safely and effectively. See full prescribing infrmatin fr LEVAQUIN. LEVAQUIN (levflxacin) Tablet, Film Cated fr Oral use LEVAQUIN (levflxacin) Slutin fr Oral use LEVAQUIN (levflxacin) Injectin, Slutin fr Intravenus use Initial U.S. Apprval: 1996 WARNING: See full prescribing infrmatin fr cmplete bxed warning. Flurquinlnes, including LEVAQUIN, are assciated with an increased risk f tendinitis and tendn rupture in all ages. This risk is further increased in lder patients usually ver 60 years f age, in patients taking crticsterid drugs, and in patients with kidney, heart r lung transplants [see Warnings and Precautins (5.1)]. Flurquinlnes, including LEVAQUIN, may exacerbate muscle weakness in persns with myasthenia gravis. Avid LEVAQUIN in patients with a knwn histry f myasthenia gravis [see Warnings and Precautins (5.2)]. T reduce the develpment f drug-resistant bacteria and maintain the effectiveness f LEVAQUIN and ther antibacterial drugs, LEVAQUIN shuld be used nly t treat r prevent infectins that are prven r strngly suspected t be caused by bacteria. RECENT MAJOR CHANGES Warnings and Precautins Peripheral Neurpathy (5.8) 09/2013 INDICATIONS AND USAGE LEVAQUIN is a flurquinlne antibacterial indicated in adults ( 18 years f age) with infectins caused by designated, susceptible bacteria (1, 12.4). Pneumnia: nscmial (1.1) and cmmunity acquired (1.2, 1.3) Acute bacterial sinusitis (1.4) Acute bacterial exacerbatin f chrnic brnchitis (1.5) Skin and skin structure infectins: cmplicated (1.6) and uncmplicated (1.7) Chrnic bacterial prstatitis (1.8) Urinary tract infectins: cmplicated (1.9, 1.10) and uncmplicated (1.12) Acute pyelnephritis (1.11) Inhalatinal anthrax, pst-expsure (1.13) Plague (1.14) DOSAGE AND ADMINISTRATION Dsage in patients with nrmal renal functin (2.1) Type f Infectin Dse Every 24 hurs Duratin (days) Nscmial Pneumnia (1.1) 750 mg 7 14 Cmmunity Acquired Pneumnia (1.2) 500 mg 7 14 Cmmunity Acquired Pneumnia (1.3) 750 mg 5 Acute Bacterial Sinusitis (1.4) 750 mg mg Acute Bacterial Exacerbatin f Chrnic Brnchitis (1.5) 500 mg 7 Cmplicated Skin and Skin Structure Infectins (SSSI) (1.6) 750 mg 7 14 Uncmplicated SSSI (1.7) 500 mg 7 10 Chrnic Bacterial Prstatitis (1.8) 500 mg 28 Cmplicated Urinary Tract Infectin (1.9) r Acute Pyelnephritis (1.11) 750 mg 5 Cmplicated Urinary Tract Infectin (1.10) r Acute Pyelnephritis (1.11) 250 mg 10 Uncmplicated Urinary Tract Infectin (1.12) 250 mg 3 Type f Infectin Dse Every 24 hurs Inhalatinal Anthrax (Pst-Expsure) (1.13) Duratin (days) Adults and Pediatric Patients > 50 kg 500 mg 60 8 mg/kg BID Pediatric Patients < 50 kg and 6 mnths f (nt t exceed 60 age 250 mg/dse) Plague (1.14) Adults and Pediatric Patients > 50 kg 500 mg 10 t 14 8 mg/kg BID Pediatric Patients < 50 kg and 6 mnths f (nt t exceed age 250 mg/dse) 10 t 14 Adjust dse fr creatinine clearance < 50 ml/min (2.3, 8.6, 12.3) IV Injectin Premix: Slw IV infusin nly, ver 60 r 90 minutes depending n dse. Avid rapid r blus IV (2.5) D nt mix with ther medicatins in IV line (2.6) DOSAGE FORMS AND STRENGTHS Frmulatin (3) Tablets Oral Slutin Injectin: premix single-use flexible cntainers Strength 250 mg, 500 mg, and 750 mg 25 mg/ml 250 mg in 50 ml 500 mg in 100 ml 750 mg in 150 ml CONTRAINDICATIONS Knwn hypersensitivity t LEVAQUIN r ther quinlnes (4, 5.3) WARNINGS AND PRECAUTIONS Risk f tendinitis and tendn rupture is increased. This risk is further increased in lder patients usually ver 60 years f age, in patients taking crticsterids, and in patients with kidney, heart r lung transplants. Discntinue if pain r inflammatin in a tendn ccurs (5.1, 8.5) May exacerbate muscle weakness in persns with myasthenia gravis. Avid use in patients with a knwn histry f myasthenia gravis (5.2) Anaphylactic reactins and allergic skin reactins, serius, ccasinally fatal, may ccur after first dse (4, 5.3) Hematlgic (including agranulcytsis, thrmbcytpenia), and renal txicities may ccur after multiple dses (5.4) Hepattxicity: Severe, and smetimes fatal, hepatxicity has been reprted. Discntinue immediately if signs and symptms f hepatitis ccur (5.5) Central nervus system effects, including cnvulsins, anxiety, cnfusin, depressin, and insmnia may ccur after the first dse. Use with cautin in patients with knwn r suspected disrders that may predispse them t seizures r lwer the seizure threshld. Increased intracranial pressure (pseudtumr cerebri) has been reprted (5.6) Clstridium difficile-assciated clitis: evaluate if diarrhea ccurs (5.7) Peripheral neurpathy: discntinue immediately if symptms ccur in rder t prevent irreversibility (5.8) Prlngatin f the QT interval and islated cases f trsade de pintes have been reprted. Avid use in patients with knwn prlngatin, thse with hypkalemia, and with ther drugs that prlng the QT interval (5.9, 8.5) ADVERSE REACTIONS The mst cmmn reactins ( 3%) were nausea, headache, diarrhea, insmnia, cnstipatin and dizziness (6.2). T reprt SUSPECTED ADVERSE REACTIONS, cntact Janssen Pharmaceuticals, Inc. at r FDA at FDA-1088 r DRUG INTERACTIONS Interacting Drug Interactin Multivalent catincntaining prducts tablet r ral slutin frmulatin is taken within 2 Absrptin f levflxacin is decreased when the including antacids, metal hurs f these prducts. D nt c-administer the 1

2 Interacting Drug Interactin catins r didansine intravenus frmulatin in the same IV line with a multivalent catin, e.g., magnesium (2.4, 7.1) Warfarin Effect may be enhanced. Mnitr prthrmbin time, INR, watch fr bleeding (7.2) Antidiabetic agents Carefully mnitr bld glucse (5.11, 7.3) USE IN SPECIFIC POPULATIONS Geriatrics: Severe hepattxicity has been reprted. The majrity f reprts describe patients 65 years f age r lder (5.5, 8.5, 17). May have increased risk f tendinpathy (including rupture), especially with cncmitant crticsterid use (5.1, 8.5, 17). May be mre susceptible t prlngatin f the QT interval. (5.9, 8.5, 17). Pediatrics: Musculskeletal disrders (arthralgia, arthritis, tendinpathy, and gait abnrmality) seen in mre LEVAQUIN - treated patients than in cmparatr. Shwn t cause arthrpathy and stechndrsis in juvenile animals (5.10, 8.4, 13.2). Safety in pediatric patients treated fr mre than 14 days has nt been studied. Risk-benefit apprpriate nly fr the treatment f inhalatinal anthrax (pst-expsure) (1.13, 2.2, 8.4, 14.9) and plague (1.14, 2.2, 8.4, 14.10) See 17 fr PATIENT COUNSELING INFORMATION and the FDAapprved Medicatin Guide Revised: 06/2014 FULL PRESCRIBING INFORMATION: CONTENTS* WARNING: 1 INDICATIONS AND USAGE 1.1 Nscmial Pneumnia 1.2 Cmmunity-Acquired Pneumnia: 7 14 day Treatment Regimen 1.3 Cmmunity-Acquired Pneumnia: 5-day Treatment Regimen 1.4 Acute Bacterial Sinusitis: 5-day and day Treatment Regimens 1.5 Acute Bacterial Exacerbatin f Chrnic Brnchitis 1.6 Cmplicated Skin and Skin Structure Infectins 1.7 Uncmplicated Skin and Skin Structure Infectins 1.8 Chrnic Bacterial Prstatitis 1.9 Cmplicated Urinary Tract Infectins: 5-day Treatment Regimen 1.10 Cmplicated Urinary Tract Infectins: 10-day Treatment Regimen 1.11 Acute Pyelnephritis: 5 r 10-day Treatment Regimen 1.12 Uncmplicated Urinary Tract Infectins 1.13 Inhalatinal Anthrax (Pst-Expsure) 1.14 Plague 2 DOSAGE AND ADMINISTRATION 2.1 Dsage in Adult Patients with Nrmal Renal Functin 2.2 Dsage in Pediatric Patients 2.3 Dsage Adjustment in Adults with Renal Impairment 2.4 Drug Interactin With Chelatin Agents: Antacids, Sucralfate, Metal Catins, Multivitamins 2.5 Administratin Instructins 2.6 Preparatin f Intravenus Prduct 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 5.1 Tendinpathy and Tendn Rupture 5.2 Exacerbatin f Myasthenia Gravis 5.3 Hypersensitivity Reactins 5.4 Other Serius and Smetimes Fatal Reactins 5.5 Hepattxicity 5.6 Central Nervus System Effects 5.7 Clstridium difficile-assciated Diarrhea 5.8 Peripheral Neurpathy 5.9 Prlngatin f the QT Interval 5.10 Musculskeletal Disrders in Pediatric Patients and Arthrpathic Effects in Animals 5.11 Bld Glucse Disturbances 5.12 Phtsensitivity/Phttxicity 5.13 Develpment f Drug Resistant Bacteria 6 ADVERSE REACTIONS 6.1 Serius and Otherwise Imprtant Adverse Reactins 6.2 Clinical Trial Experience 6.3 Pstmarketing Experience 7 DRUG INTERACTIONS 7.1 Chelatin Agents: Antacids, Sucralfate, Metal Catins, Multivitamins 7.2 Warfarin 7.3 Antidiabetic Agents 7.4 Nn-Steridal Anti-Inflammatry Drugs 7.5 Thephylline 7.6 Cyclsprine 7.7 Digxin 7.8 Prbenecid and Cimetidine 7.9 Interactins with Labratry r Diagnstic Testing 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.3 Nursing Mthers 8.4 Pediatric Use 8.5 Geriatric Use 8.6 Renal Impairment 8.7 Hepatic Impairment 10 OVERDOSAGE 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12.1 Mechanism f Actin 12.3 Pharmackinetics 12.4 Micrbilgy 13 NONCLINICAL TOXICOLOGY 13.1 Carcingenesis, Mutagenesis, Impairment f Fertility 13.2 Animal Txiclgy and/r Pharmaclgy 14 CLINICAL STUDIES 14.1 Nscmial Pneumnia 14.2 Cmmunity-Acquired Pneumnia: 7 14 day Treatment Regimen 14.3 Cmmunity-Acquired Pneumnia: 5-day Treatment Regimen 14.4 Acute Bacterial Sinusitis: 5-day and day Treatment Regimens 14.5 Cmplicated Skin and Skin Structure Infectins 14.6 Chrnic Bacterial Prstatitis 14.7 Cmplicated Urinary Tract Infectins and Acute Pyelnephritis: 5-day Treatment Regimen 14.8 Cmplicated Urinary Tract Infectins and Acute Pyelnephritis: 10-day Treatment Regimen 14.9 Inhalatinal Anthrax (Pst-Expsure) Plague 15 REFERENCES 16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 LEVAQUIN Tablets 16.2 LEVAQUIN Oral Slutin 16.3 LEVAQUIN Injectin Pre-Mixed Slutin, Single-Use in Flexible Cntainer 17 PATIENT COUNSELING INFORMATION 17.1 Antibacterial Resistance 17.2 Administratin with Fd, Fluids, and Cncmitant Medicatins 17.3 Serius and Ptentially Serius Adverse Reactins 17.4 Drug Interactins with Insulin, Oral Hypglycemic Agents, and Warfarin 17.5 Plague and Anthrax Studies 17.6 FDA-Apprved Medicatin Guide 2

3 *Sectins r subsectins mitted frm the full prescribing infrmatin are nt listed FULL PRESCRIBING INFORMATION WARNING: Flurquinlnes, including LEVAQUIN, are assciated with an increased risk f tendinitis and tendn rupture in all ages. This risk is further increased in lder patients usually ver 60 years f age, in patients taking crticsterid drugs, and in patients with kidney, heart r lung transplants [see Warnings and Precautins (5.1)]. Flurquinlnes, including LEVAQUIN, may exacerbate muscle weakness in persns with myasthenia gravis. Avid LEVAQUIN in patients with a knwn histry f myasthenia gravis [see Warnings and Precautins (5.2)]. 1 INDICATIONS AND USAGE T reduce the develpment f drug-resistant bacteria and maintain the effectiveness f LEVAQUIN and ther antibacterial drugs, LEVAQUIN shuld be used nly t treat r prevent infectins that are prven r strngly suspected t be caused by susceptible bacteria. When culture and susceptibility infrmatin are available, they shuld be cnsidered in selecting r mdifying antibacterial therapy. In the absence f such data, lcal epidemilgy and susceptibility patterns may cntribute t the empiric selectin f therapy. LEVAQUIN Tablets/Injectin and Oral Slutin are indicated fr the treatment f adults ( 18 years f age) with mild, mderate, and severe infectins caused by susceptible islates f the designated micrrganisms in the cnditins listed in this sectin. LEVAQUIN Injectin is indicated when intravenus administratin ffers a rute f administratin advantageus t the patient (e.g., patient cannt tlerate an ral dsage frm). Culture and susceptibility testing Apprpriate culture and susceptibility tests shuld be perfrmed befre treatment in rder t islate and identify rganisms causing the infectin and t determine their susceptibility t levflxacin [see Micrbilgy (12.4)]. Therapy with LEVAQUIN may be initiated befre results f these tests are knwn; nce results becme available, apprpriate therapy shuld be selected. As with ther drugs in this class, sme islates f Pseudmnas aeruginsa may develp resistance fairly rapidly during treatment with LEVAQUIN. Culture and susceptibility testing 3

4 perfrmed peridically during therapy will prvide infrmatin abut the cntinued susceptibility f the pathgens t the antimicrbial agent and als the pssible emergence f bacterial resistance. 1.1 Nscmial Pneumnia LEVAQUIN is indicated fr the treatment f nscmial pneumnia due t methicillinsusceptible Staphylcccus aureus, Pseudmnas aeruginsa, Serratia marcescens, Escherichia cli, Klebsiella pneumniae, Haemphilus influenzae, r Streptcccus pneumniae. Adjunctive therapy shuld be used as clinically indicated. Where Pseudmnas aeruginsa is a dcumented r presumptive pathgen, cmbinatin therapy with an antipseudmnal β-lactam is recmmended [see Clinical Studies (14.1)]. 1.2 Cmmunity-Acquired Pneumnia: 7 14 day Treatment Regimen LEVAQUIN is indicated fr the treatment f cmmunity-acquired pneumnia due t methicillin-susceptible Staphylcccus aureus, Streptcccus pneumniae (including multidrug-resistant Streptcccus pneumniae [MDRSP]), Haemphilus influenzae, Haemphilus parainfluenzae, Klebsiella pneumniae, Mraxella catarrhalis, Chlamydphila pneumniae, Leginella pneumphila, r Mycplasma pneumniae [see Dsage and Administratin (2.1) and Clinical Studies (14.2)]. MDRSP islates are islates resistant t tw r mre f the fllwing antibacterials: penicillin (MIC 2 mcg/ml), 2 nd generatin cephalsprins, e.g., cefurxime, macrlides, tetracyclines and trimethprim/sulfamethxazle. 1.3 Cmmunity-Acquired Pneumnia: 5-day Treatment Regimen LEVAQUIN is indicated fr the treatment f cmmunity-acquired pneumnia due t Streptcccus pneumniae (excluding multi-drug-resistant islates [MDRSP]), Haemphilus influenzae, Haemphilus parainfluenzae, Mycplasma pneumniae, r Chlamydphila pneumniae [see Dsage and Administratin (2.1) and Clinical Studies (14.3)]. 1.4 Acute Bacterial Sinusitis: 5-day and day Treatment Regimens LEVAQUIN is indicated fr the treatment f acute bacterial sinusitis due t Streptcccus pneumniae, Haemphilus influenzae, r Mraxella catarrhalis [see Clinical Studies (14.4)]. 1.5 Acute Bacterial Exacerbatin f Chrnic Brnchitis LEVAQUIN is indicated fr the treatment f acute bacterial exacerbatin f chrnic brnchitis due t methicillin-susceptible Staphylcccus aureus, Streptcccus pneumniae, Haemphilus influenzae, Haemphilus parainfluenzae, r Mraxella catarrhalis. 4

5 1.6 Cmplicated Skin and Skin Structure Infectins LEVAQUIN is indicated fr the treatment f cmplicated skin and skin structure infectins due t methicillin-susceptible Staphylcccus aureus, Entercccus faecalis, Streptcccus pygenes, r Prteus mirabilis [see Clinical Studies (14.5)]. 1.7 Uncmplicated Skin and Skin Structure Infectins LEVAQUIN is indicated fr the treatment f uncmplicated skin and skin structure infectins (mild t mderate) including abscesses, cellulitis, furuncles, impetig, pyderma, wund infectins, due t methicillin-susceptible Staphylcccus aureus, r Streptcccus pygenes. 1.8 Chrnic Bacterial Prstatitis LEVAQUIN is indicated fr the treatment f chrnic bacterial prstatitis due t Escherichia cli, Entercccus faecalis, r methicillin-susceptible Staphylcccus epidermidis [see Clinical Studies (14.6)]. 1.9 Cmplicated Urinary Tract Infectins: 5-day Treatment Regimen LEVAQUIN is indicated fr the treatment f cmplicated urinary tract infectins due t Escherichia cli, Klebsiella pneumniae, r Prteus mirabilis [see Clinical Studies (14.7)] Cmplicated Urinary Tract Infectins: 10-day Treatment Regimen LEVAQUIN is indicated fr the treatment f cmplicated urinary tract infectins (mild t mderate) due t Entercccus faecalis, Enterbacter clacae, Escherichia cli, Klebsiella pneumniae, Prteus mirabilis, r Pseudmnas aeruginsa [see Clinical Studies (14.8)] Acute Pyelnephritis: 5 r 10-day Treatment Regimen LEVAQUIN is indicated fr the treatment f acute pyelnephritis caused by Escherichia cli, including cases with cncurrent bacteremia [see Clinical Studies (14.7, 14.8)] Uncmplicated Urinary Tract Infectins LEVAQUIN is indicated fr the treatment f uncmplicated urinary tract infectins (mild t mderate) due t Escherichia cli, Klebsiella pneumniae, r Staphylcccus saprphyticus Inhalatinal Anthrax (Pst-Expsure) LEVAQUIN is indicated fr inhalatinal anthrax (pst-expsure) t reduce the incidence r prgressin f disease fllwing expsure t aerslized Bacillus anthracis. The effectiveness f LEVAQUIN is based n plasma cncentratins achieved in humans, a surrgate endpint reasnably likely t predict clinical benefit. LEVAQUIN has nt been tested in humans fr the pst-expsure preventin f inhalatin anthrax. The safety f LEVAQUIN in adults fr duratins f therapy beynd 28 days r in pediatric patients fr duratins f therapy beynd 5

6 14 days has nt been studied. Prlnged LEVAQUIN therapy shuld nly be used when the benefit utweighs the risk [see Dsage and Administratin (2.1, 2.2) and Clinical Studies (14.9)] Plague LEVAQUIN is indicated fr treatment f plague, including pneumnic and septicemic plague, due t Yersinia pestis (Y. pestis) and prphylaxis fr plague in adults and pediatric patients, 6 mnths f age and lder. Efficacy studies f LEVAQUIN culd nt be cnducted in humans with plague fr ethical and feasibility reasns. Therefre, apprval f this indicatin was based n an efficacy study cnducted in animals [see Dsage and Administratin (2.1, 2.2) and Clinical Studies (14.10)]. 2 DOSAGE AND ADMINISTRATION 2.1 Dsage in Adult Patients with Nrmal Renal Functin The usual dse f LEVAQUIN Tablets r Oral Slutin is 250 mg, 500 mg, r 750 mg administered rally every 24 hurs, as indicated by infectin and described in Table 1. The usual dse f LEVAQUIN Injectin is 250 mg r 500 mg administered by slw infusin ver 60 minutes every 24 hurs r 750 mg administered by slw infusin ver 90 minutes every 24 hurs, as indicated by infectin and described in Table 1. These recmmendatins apply t patients with creatinine clearance 50 ml/min. Fr patients with creatinine clearance <50 ml/min, adjustments t the dsing regimen are required [see Dsage and Administratin (2.3)]. Table 1: Dsage in Adult Patients with Nrmal Renal Functin (creatinine clearance 50 ml/min) Type f Infectin * Dsed Every 24 hurs Duratin (days) Nscmial Pneumnia 750 mg 7 14 Cmmunity Acquired Pneumnia 500 mg 7 14 Cmmunity Acquired Pneumnia 750 mg 5 Acute Bacterial Sinusitis 750 mg mg Acute Bacterial Exacerbatin f Chrnic Brnchitis 500 mg 7 Cmplicated Skin and Skin Structure Infectins (SSSI) 750 mg 7 14 Uncmplicated SSSI 500 mg 7 10 Chrnic Bacterial Prstatitis 500 mg 28 Cmplicated Urinary Tract Infectin (cuti) r 750 mg 5 Acute Pyelnephritis (AP) Cmplicated Urinary Tract Infectin (cuti) r 250 mg 10 Acute Pyelnephritis (AP) # 6

7 Table 1: Dsage in Adult Patients with Nrmal Renal Functin (creatinine clearance 50 ml/min) Type f Infectin * Dsed Every 24 hurs Duratin (days) Uncmplicated Urinary Tract Infectin 250 mg 3 Inhalatinal Anthrax (Pst-Expsure), adult and pediatric patients > 50 kg Þ,ß Pediatric patients < 50 kg and 6 mnths f age Þ,ß Plague, adult and pediatric patients > 50 kg à Pediatric patients < 50 kg and 6 mnths f age 500 mg see Table 2 belw (2.2) 500 mg see Table 2 belw (2.2) 60 ß 60 ß 10 t t 14 * Due t the designated pathgens [see Indicatins and Usage (1)]. Sequential therapy (intravenus t ral) may be instituted at the discretin f the physician. Due t methicillin-susceptible Staphylcccus aureus, Streptcccus pneumniae (including multi-drug-resistant islates [MDRSP]), Haemphilus influenzae, Haemphilus parainfluenzae, Klebsiella pneumniae, Mraxella catarrhalis, Chlamydphila pneumniae, Leginella pneumphila, r Mycplasma pneumniae [see Indicatins and Usage (1.2)]. Due t Streptcccus pneumniae (excluding multi-drug-resistant islates [MDRSP]), Haemphilus influenzae, Haemphilus parainfluenzae, Mycplasma pneumniae, r Chlamydphila pneumniae [see Indicatins and Usage (1.3)]. This regimen is indicated fr cuti due t Escherichia cli, Klebsiella pneumniae, Prteus mirabilis and AP due t E. cli, including cases with cncurrent bacteremia. # This regimen is indicated fr cuti due t Entercccus faecalis, Entercccus clacae, Escherichia cli, Klebsiella pneumniae, Prteus mirabilis, Pseudmnas aeruginsa; and fr AP due t E. cli. Þ Drug administratin shuld begin as sn as pssible after suspected r cnfirmed expsure t aerslized B. anthracis. This indicatin is based n a surrgate endpint. Levflxacin plasma cncentratins achieved in humans are reasnably likely t predict clinical benefit [see Clinical Studies (14.9)]. ß à The safety f LEVAQUIN in adults fr duratins f therapy beynd 28 days r in pediatric patients fr duratins beynd 14 days has nt been studied. An increased incidence f musculskeletal adverse events cmpared t cntrls has been bserved in pediatric patients [see Warnings and Precautins (5.10), Use in Specific Ppulatins (8.4), and Clinical Studies (14.9)]. Prlnged LEVAQUIN therapy shuld nly be used when the benefit utweighs the risk. Drug administratin shuld begin as sn as pssible after suspected r cnfirmed expsure t Yersinia pestis. Higher dses f LEVAQUIN typically used fr treatment f pneumnia can be used fr treatment f plague, if clinically indicated. 2.2 Dsage in Pediatric Patients The dsage in pediatric patients 6 mnths f age is described belw in Table 2. Table 2: Dsage in Pediatric Patients 6 mnths f age Type f Infectin * Dse Freq. Once every Duratin Inhalatinal Anthrax (pst-expsure), Pediatric patients > 50 kg 500 mg 24 hr 60 days Pediatric patients < 50 kg and 6 mnths f age Plague 8 mg/kg (nt t exceed 250 mg per dse) 12 hr 60 days Pediatric patients > 50 kg 500 mg 24 hr 10 t 14 days Pediatric patients < 50 kg and 6 mnths f age 8 mg/kg (nt t exceed 250 mg per dse) 12 hr 10 t 14 days 7

8 Table 2: Dsage in Pediatric Patients 6 mnths f age * Due t Bacillus anthracis [see Indicatins and Usage (1.13)] and Yersinia pestis [see Indicatins and Usage (1.14)]. Sequential therapy (intravenus t ral) may be instituted at the discretin f the physician. Drug administratin shuld begin as sn as pssible after suspected r cnfirmed expsure t aerslized B. anthracis. This indicatin is based n a surrgate endpint. Levflxacin plasma cncentratins achieved in humans are reasnably likely t predict clinical benefit [see Clinical Studies (14.9)] The safety f LEVAQUIN in pediatric patients fr duratins f therapy beynd 14 days has nt been studied. An increased incidence f musculskeletal adverse events cmpared t cntrls has been bserved in pediatric patients [see Warnings and Precautins (5.10), Use in Specific Ppulatins (8.4), and Clinical Studies (14.9)]. Prlnged LEVAQUIN therapy shuld nly be used when the benefit utweighs the risk. Drug administratin shuld begin as sn as pssible after suspected r cnfirmed expsure t Yersinia pestis. 2.3 Dsage Adjustment in Adults with Renal Impairment Administer LEVAQUIN with cautin in the presence f renal insufficiency. Careful clinical bservatin and apprpriate labratry studies shuld be perfrmed prir t and during therapy since eliminatin f levflxacin may be reduced. N adjustment is necessary fr patients with a creatinine clearance 50 ml/min. In patients with impaired renal functin (creatinine clearance < 50 ml/min), adjustment f the dsage regimen is necessary t avid the accumulatin f levflxacin due t decreased clearance [see Use in Specific Ppulatins (8.6)]. Table 3 shws hw t adjust dse based n creatinine clearance. Table 3: Dsage Adjustment in Adult Patients with Renal Impairment (creatinine clearance < 50 ml/min) Dsage in Nrmal Renal Functin Every 24 hurs Creatinine Clearance 20 t 49 ml/min Creatinine Clearance 10 t 19 ml/min Hemdialysis r Chrnic Ambulatry Peritneal Dialysis (CAPD) 750 mg 750 mg every 48 hurs 750 mg initial dse, then 500 mg every 48 hurs 750 mg initial dse, then 500 mg every 48 hurs 500 mg 500 mg initial dse, then 250 mg every 24 hurs 500 mg initial dse, then 250 mg every 48 hurs 500 mg initial dse, then 250 mg every 48 hurs 250 mg N dsage adjustment required 250 mg every 48 hurs. If treating uncmplicated UTI, then n dsage adjustment is required N infrmatin n dsing adjustment is available 2.4 Drug Interactin With Chelatin Agents: Antacids, Sucralfate, Metal Catins, Multivitamins LEVAQUIN Tablets and Oral Slutin LEVAQUIN Tablets and Oral Slutin shuld be administered at least tw hurs befre r tw hurs after antacids cntaining magnesium, aluminum, as well as sucralfate, metal catins such as irn, and multivitamin preparatins with zinc r didansine chewable/buffered tablets 8

9 r the pediatric pwder fr ral slutin [see Drug Interactins (7.1) and Patient Cunseling Infrmatin (17.2)]. LEVAQUIN Injectin LEVAQUIN Injectin shuld nt be c-administered with any slutin cntaining multivalent catins, e.g., magnesium, thrugh the same intravenus line [see Dsage and Administratin (2.6)]. 2.5 Administratin Instructins Fd and LEVAQUIN Tablets and Oral Slutin LEVAQUIN Tablets can be administered withut regard t fd. It is recmmended that LEVAQUIN Oral Slutin be taken 1 hur befre r 2 hurs after eating. LEVAQUIN Injectin Cautin: Rapid r blus intravenus infusin f LEVAQUIN has been assciated with hyptensin and must be avided. LEVAQUIN Injectin shuld be infused intravenusly slwly ver a perid f nt less than 60 r 90 minutes, depending n the dsage. LEVAQUIN Injectin shuld be administered nly by intravenus infusin. It is nt fr intramuscular, intrathecal, intraperitneal, r subcutaneus administratin. Hydratin fr Patients Receiving LEVAQUIN Tablets, Oral Slutin, and Injectin Adequate hydratin f patients receiving ral r intravenus LEVAQUIN shuld be maintained t prevent the frmatin f highly cncentrated urine. Crystalluria and cylindruria have been reprted with quinlnes [see Adverse Reactins (6.1) and Patient Cunseling Infrmatin (17.2)]. 2.6 Preparatin f Intravenus Prduct Parenteral drug prducts shuld be inspected visually fr particulate matter and disclratin prir t administratin, whenever slutin and cntainer permit. Because nly limited data are available n the cmpatibility f LEVAQUIN Injectin with ther intravenus substances, additives r ther medicatins shuld nt be added t LEVAQUIN Injectin Premix in Single-Use Flexible Cntainers, r infused simultaneusly thrugh the same intravenus line. If the same intravenus line is used fr sequential infusin f several different drugs, the line shuld be flushed befre and after infusin f LEVAQUIN Injectin with an infusin slutin cmpatible with LEVAQUIN Injectin and with any ther drug(s) administered via this cmmn line. 9

10 LEVAQUIN Injectin Premix in Single-Use Flexible Cntainers (5 mg/ml) LEVAQUIN Injectin is supplied in flexible cntainers within a fil verwrap. These cntain a premixed, ready t use levflxacin slutin in 5% dextrse (D5W) fr single-use. The 100 ml premixed flexible cntainers cntain either 250 mg/50 ml r 500 mg/100 ml f levflxacin slutin. The 150 ml flexible cntainer cntains 750 mg/150 ml f levflxacin slutin. The cncentratin f each cntainer is 5 mg/ml. N further dilutin f these preparatins is necessary. Because the premix flexible cntainers are fr single-use nly, any unused prtin shuld be discarded. Instructins fr the Use f LEVAQUIN Injectin Premix in Flexible Cntainers: 1. Tear uter wrap at the ntch and remve slutin cntainer. 2. Check the cntainer fr minute leaks by squeezing the inner bag firmly. If leaks are fund, r if the seal is nt intact, discard the slutin, as the sterility may be cmprmised. 3. D nt use if the slutin is cludy r a precipitate is present. 4. Use sterile equipment. 5. WARNING: D nt use flexible cntainers in series cnnectins. Such use culd result in air emblism due t residual air being drawn frm the primary cntainer befre administratin f the fluid frm the secndary cntainer is cmplete. Preparatin fr Administratin: 1. Clse flw cntrl clamp f administratin set. 2. Remve cver frm prt at bttm f cntainer. 3. Insert piercing pin f administratin set int prt with a twisting mtin until the pin is firmly seated. NOTE: See full directins n administratin set cartn. 4. Suspend cntainer frm hanger. 5. Squeeze and release drip chamber t establish prper fluid level in chamber during infusin f LEVAQUIN Injectin Premix in Flexible Cntainers. 6. Open flw cntrl clamp t expel air frm set. Clse clamp. 7. Regulate rate f administratin with flw cntrl clamp. 3 DOSAGE FORMS AND STRENGTHS TABLETS, Film-cated, capsule-shaped 250 mg terra ctta pink tablets, imprinted with "250" n ne side and "LEVAQUIN" n the ther 500 mg peach tablets, imprinted with "500" n ne side and "LEVAQUIN" n the ther 750 mg white tablets, imprinted with "750" n ne side and "LEVAQUIN" n the ther 10

11 ORAL SOLUTION, 25 mg/ml, clear yellw t clear greenish-yellw clr INJECTION (5 mg/ml in 5% Dextrse) Premix in Single-Use Flexible Cntainers, fr intravenus infusin 100 ml cntainer, fill vlume 50 ml (equivalent t 250 mg levflxacin) 100 ml cntainer, fill vlume 100 ml (equivalent t 500 mg levflxacin) 150 ml cntainer, fill vlume 150 ml (equivalent t 750 mg levflxacin) 4 CONTRAINDICATIONS LEVAQUIN is cntraindicated in persns with knwn hypersensitivity t levflxacin, r ther quinlne antibacterials [see Warnings and Precautins (5.3)]. 5 WARNINGS AND PRECAUTIONS 5.1 Tendinpathy and Tendn Rupture Flurquinlnes, including LEVAQUIN, are assciated with an increased risk f tendinitis and tendn rupture in all ages. This adverse reactin mst frequently invlves the Achilles tendn, and rupture f the Achilles tendn may require surgical repair. Tendinitis and tendn rupture in the rtatr cuff (the shulder), the hand, the biceps, the thumb, and ther tendn sites have als been reprted. The risk f develping flurquinlne-assciated tendinitis and tendn rupture is further increased in lder patients usually ver 60 years f age, in thse taking crticsterid drugs, and in patients with kidney, heart r lung transplants. Factrs, in additin t age and crticsterid use, that may independently increase the risk f tendn rupture include strenuus physical activity, renal failure, and previus tendn disrders such as rheumatid arthritis. Tendinitis and tendn rupture have been reprted in patients taking flurquinlnes wh d nt have the abve risk factrs. Tendn rupture can ccur during r after cmpletin f therapy; cases ccurring up t several mnths after cmpletin f therapy have been reprted. LEVAQUIN shuld be discntinued if the patient experiences pain, swelling, inflammatin r rupture f a tendn. Patients shuld be advised t rest at the first sign f tendinitis r tendn rupture, and t cntact their healthcare prvider regarding changing t a nn-quinlne antimicrbial drug. [see Adverse Reactins (6.3); Patient Cunseling Infrmatin (17.3)]. 5.2 Exacerbatin f Myasthenia Gravis Flurquinlnes, including LEVAQUIN, have neurmuscular blcking activity and may exacerbate muscle weakness in persns with myasthenia gravis. Pstmarketing serius adverse events, including deaths and requirement fr ventilatry supprt, have been assciated with flurquinlne use in persns with myasthenia gravis. Avid LEVAQUIN in patients with a 11

12 knwn histry f myasthenia gravis [see Adverse Reactins (6.3); Patient Cunseling Infrmatin (17.3)]. 5.3 Hypersensitivity Reactins Serius and ccasinally fatal hypersensitivity and/r anaphylactic reactins have been reprted in patients receiving therapy with flurquinlnes, including LEVAQUIN. These reactins ften ccur fllwing the first dse. Sme reactins have been accmpanied by cardivascular cllapse, hyptensin/shck, seizure, lss f cnsciusness, tingling, angiedema (including tngue, laryngeal, thrat, r facial edema/swelling), airway bstructin (including brnchspasm, shrtness f breath, and acute respiratry distress), dyspnea, urticaria, itching, and ther serius skin reactins. LEVAQUIN shuld be discntinued immediately at the first appearance f a skin rash r any ther sign f hypersensitivity. Serius acute hypersensitivity reactins may require treatment with epinephrine and ther resuscitative measures, including xygen, intravenus fluids, antihistamines, crticsterids, pressr amines, and airway management, as clinically indicated [see Adverse Reactins (6); Patient Cunseling Infrmatin (17.3)]. 5.4 Other Serius and Smetimes Fatal Reactins Other serius and smetimes fatal events, sme due t hypersensitivity, and sme due t uncertain etilgy, have been reprted rarely in patients receiving therapy with flurquinlnes, including LEVAQUIN. These events may be severe and generally ccur fllwing the administratin f multiple dses. Clinical manifestatins may include ne r mre f the fllwing: fever, rash, r severe dermatlgic reactins (e.g., txic epidermal necrlysis, Stevens- Jhnsn Syndrme); vasculitis; arthralgia; myalgia; serum sickness; allergic pneumnitis; interstitial nephritis; acute renal insufficiency r failure; hepatitis; jaundice; acute hepatic necrsis r failure; anemia, including hemlytic and aplastic; thrmbcytpenia, including thrmbtic thrmbcytpenic purpura; leukpenia; agranulcytsis; pancytpenia; and/r ther hematlgic abnrmalities. The drug shuld be discntinued immediately at the first appearance f skin rash, jaundice, r any ther sign f hypersensitivity and supprtive measures instituted [see Adverse Reactins (6); Patient Cunseling Infrmatin (17.3)]. 12

13 5.5 Hepattxicity Pst-marketing reprts f severe hepattxicity (including acute hepatitis and fatal events) have been received fr patients treated with LEVAQUIN. N evidence f serius drug-assciated hepattxicity was detected in clinical trials f ver 7,000 patients. Severe hepattxicity generally ccurred within 14 days f initiatin f therapy and mst cases ccurred within 6 days. Mst cases f severe hepattxicity were nt assciated with hypersensitivity [see Warnings and Precautins (5.4)]. The majrity f fatal hepattxicity reprts ccurred in patients 65 years f age r lder and mst were nt assciated with hypersensitivity. LEVAQUIN shuld be discntinued immediately if the patient develps signs and symptms f hepatitis [see Adverse Reactins (6); Patient Cunseling Infrmatin (17.3)]. 5.6 Central Nervus System Effects Cnvulsins, txic psychses, increased intracranial pressure (including pseudtumr cerebri) have been reprted in patients receiving flurquinlnes, including LEVAQUIN. Flurquinlnes may als cause central nervus system stimulatin which may lead t tremrs, restlessness, anxiety, lightheadedness, cnfusin, hallucinatins, parania, depressin, nightmares, insmnia, and, rarely, suicidal thughts r acts. These reactins may ccur fllwing the first dse. If these reactins ccur in patients receiving LEVAQUIN, the drug shuld be discntinued and apprpriate measures instituted. As with ther flurquinlnes, LEVAQUIN shuld be used with cautin in patients with a knwn r suspected central nervus system (CNS) disrder that may predispse them t seizures r lwer the seizure threshld (e.g., severe cerebral arterisclersis, epilepsy) r in the presence f ther risk factrs that may predispse them t seizures r lwer the seizure threshld (e.g., certain drug therapy, renal dysfunctin). [see Adverse Reactins (6); Drug Interactins (7.4, 7.5); Patient Cunseling Infrmatin (17.3)]. 5.7 Clstridium difficile-assciated Diarrhea Clstridium difficile-assciated diarrhea (CDAD) has been reprted with use f nearly all antibacterial agents, including LEVAQUIN, and may range in severity frm mild diarrhea t fatal clitis. Treatment with antibacterial agents alters the nrmal flra f the cln leading t vergrwth f C. difficile. C. difficile prduces txins A and B which cntribute t the develpment f CDAD. Hypertxin prducing strains f C. difficile cause increased mrbidity and mrtality, as these infectins can be refractry t antimicrbial therapy and may require clectmy. CDAD must be cnsidered in all patients wh present with diarrhea fllwing antibitic use. Careful medical histry is necessary since CDAD has been reprted t ccur ver tw mnths after the administratin f antibacterial agents. 13

14 If CDAD is suspected r cnfirmed, nging antibitic use nt directed against C. difficile may need t be discntinued. Apprpriate fluid and electrlyte management, prtein supplementatin, antibitic treatment f C. difficile, and surgical evaluatin shuld be instituted as clinically indicated [see Adverse Reactins (6.2), Patient Cunseling Infrmatin (17.3)]. 5.8 Peripheral Neurpathy Cases f sensry r sensrimtr axnal plyneurpathy affecting small and/r large axns resulting in paresthesias, hypesthesias, dysesthesias and weakness have been reprted in patients receiving flurquinlnes, including LEVAQUIN. Symptms may ccur sn after initiatin f LEVAQUIN and may be irreversible. LEVAQUIN shuld be discntinued immediately if the patient experiences symptms f neurpathy including pain, burning, tingling, numbness, and/r weakness r ther alteratins f sensatin including light tuch, pain, temperature, psitin sense, and vibratry sensatin [see Adverse Reactins (6), Patient Cunseling Infrmatin (17.3)]. 5.9 Prlngatin f the QT Interval Sme flurquinlnes, including LEVAQUIN, have been assciated with prlngatin f the QT interval n the electrcardigram and infrequent cases f arrhythmia. Rare cases f trsade de pintes have been spntaneusly reprted during pstmarketing surveillance in patients receiving flurquinlnes, including LEVAQUIN. LEVAQUIN shuld be avided in patients with knwn prlngatin f the QT interval, patients with uncrrected hypkalemia, and patients receiving Class IA (quinidine, prcainamide), r Class III (amidarne, stall) antiarrhythmic agents. Elderly patients may be mre susceptible t drug-assciated effects n the QT interval [see Adverse Reactins (6.3), Use in Specific Ppulatins (8.5), and Patient Cunseling Infrmatin (17.3)] Musculskeletal Disrders in Pediatric Patients and Arthrpathic Effects in Animals LEVAQUIN is indicated in pediatric patients (6 mnths f age and lder) nly fr the preventin f inhalatinal anthrax (pst-expsure) and fr plague [see Indicatins and Usage (1.13, 1.14)]. An increased incidence f musculskeletal disrders (arthralgia, arthritis, tendinpathy, and gait abnrmality) cmpared t cntrls has been bserved in pediatric patients receiving LEVAQUIN [see Use in Specific Ppulatins (8.4)]. In immature rats and dgs, the ral and intravenus administratin f levflxacin resulted in increased stechndrsis. Histpathlgical examinatin f the weight-bearing jints f immature dgs dsed with levflxacin revealed persistent lesins f the cartilage. Other flurquinlnes als prduce similar ersins in the weight-bearing jints and ther signs f 14

15 arthrpathy in immature animals f varius species [see Animal Txiclgy and/r Pharmaclgy (13.2)] Bld Glucse Disturbances As with ther flurquinlnes, disturbances f bld glucse, including symptmatic hyperand hypglycemia, have been reprted with LEVAQUIN, usually in diabetic patients receiving cncmitant treatment with an ral hypglycemic agent (e.g., glyburide) r with insulin. In these patients, careful mnitring f bld glucse is recmmended. If a hypglycemic reactin ccurs in a patient being treated with LEVAQUIN, LEVAQUIN shuld be discntinued and apprpriate therapy shuld be initiated immediately [see Adverse Reactins (6.2); Drug Interactins (7.3); Patient Cunseling Infrmatin (17.4)] Phtsensitivity/Phttxicity Mderate t severe phtsensitivity/phttxicity reactins, the latter f which may manifest as exaggerated sunburn reactins (e.g., burning, erythema, exudatin, vesicles, blistering, edema) invlving areas expsed t light (typically the face, V area f the neck, extensr surfaces f the frearms, drsa f the hands), can be assciated with the use f flurquinlnes after sun r UV light expsure. Therefre, excessive expsure t these surces f light shuld be avided. Drug therapy shuld be discntinued if phtsensitivity/phttxicity ccurs [see Adverse Reactins (6.3); Patient Cunseling Infrmatin (17.3)] Develpment f Drug Resistant Bacteria Prescribing LEVAQUIN in the absence f a prven r strngly suspected bacterial infectin r a prphylactic indicatin is unlikely t prvide benefit t the patient and increases the risk f the develpment f drug-resistant bacteria [see Patient Cunseling Infrmatin (17.1)]. 6 ADVERSE REACTIONS 6.1 Serius and Otherwise Imprtant Adverse Reactins The fllwing serius and therwise imprtant adverse drug reactins are discussed in greater detail in ther sectins f labeling: Tendn Effects [see Warnings and Precautins (5.1)] Exacerbatin f Myasthenia Gravis [see Warnings and Precautins (5.2)] Hypersensitivity Reactins [see Warnings and Precautins (5.3)] Other Serius and Smetimes Fatal Reactins [see Warnings and Precautins (5.4)] Hepattxicity [see Warnings and Precautins (5.5)] Central Nervus System Effects [see Warnings and Precautins (5.6)] 15

16 Clstridium difficile-assciated Diarrhea [see Warnings and Precautins (5.7)] Peripheral Neurpathy that may be irreversible [see Warnings and Precautins (5.8)] Prlngatin f the QT Interval [see Warnings and Precautins (5.9)] Musculskeletal Disrders in Pediatric Patients [see Warnings and Precautins (5.10)] Bld Glucse Disturbances [see Warnings and Precautins (5.11)] Phtsensitivity/Phttxicity [see Warnings and Precautins (5.12)] Develpment f Drug Resistant Bacteria [see Warnings and Precautins (5.13)] Hyptensin has been assciated with rapid r blus intravenus infusin f LEVAQUIN. LEVAQUIN shuld be infused slwly ver 60 t 90 minutes, depending n dsage [see Dsage and Administratin (2.5)]. Crystalluria and cylindruria have been reprted with quinlnes, including LEVAQUIN. Therefre, adequate hydratin f patients receiving LEVAQUIN shuld be maintained t prevent the frmatin f a highly cncentrated urine [see Dsage and Administratin (2.5)]. 6.2 Clinical Trial Experience Because clinical trials are cnducted under widely varying cnditins, adverse reactin rates bserved in the clinical trials f a drug cannt be directly cmpared t rates in the clinical trials f anther drug and may nt reflect the rates bserved in practice. The data described belw reflect expsure t LEVAQUIN in 7537 patients in 29 pled Phase 3 clinical trials. The ppulatin studied had a mean age f 50 years (apprximately 74% f the ppulatin was < 65 years f age), 50% were male, 71% were Caucasian, 19% were Black. Patients were treated with LEVAQUIN fr a wide variety f infectius diseases [see Indicatins and Usage (1)]. Patients received LEVAQUIN dses f 750 mg nce daily, 250 mg nce daily, r 500 mg nce r twice daily. Treatment duratin was usually 3 14 days, and the mean number f days n therapy was 10 days. The verall incidence, type and distributin f adverse reactins was similar in patients receiving LEVAQUIN dses f 750 mg nce daily, 250 mg nce daily, and 500 mg nce r twice daily. Discntinuatin f LEVAQUIN due t adverse drug reactins ccurred in 4.3% f patients verall, 3.8% f patients treated with the 250 mg and 500 mg dses and 5.4% f patients treated with the 750 mg dse. The mst cmmn adverse drug reactins leading t discntinuatin with the 250 and 500 mg dses were gastrintestinal (1.4%), primarily nausea (0.6%); vmiting (0.4%); dizziness (0.3%); and headache (0.2%). The mst cmmn adverse drug reactins leading t discntinuatin with the 750 mg dse were gastrintestinal (1.2%), primarily nausea (0.6%), vmiting (0.5%); dizziness (0.3%); and headache (0.3%). 16

17 Adverse reactins ccurring in 1% f LEVAQUIN -treated patients and less cmmn adverse reactins, ccurring in 0.1 t <1% f LEVAQUIN -treated patients, are shwn in Table 4 and Table 5, respectively. The mst cmmn adverse drug reactins ( 3%) are nausea, headache, diarrhea, insmnia, cnstipatin, and dizziness. Table 4: Cmmn ( 1%) Adverse Reactins Reprted in Clinical Trials with LEVAQUIN System/Organ Class Adverse Reactin % (N = 7537) Infectins and Infestatins mniliasis 1 Psychiatric Disrders insmnia * [see Warnings and Precautins (5.6)] 4 Nervus System Disrders headache dizziness [see Warnings and Precautins (5.6)] 6 3 Respiratry, Thracic and Mediastinal Disrders Gastrintestinal Disrders Skin and Subcutaneus Tissue Disrders Reprductive System and Breast Disrders General Disrders and Administratin Site Cnditins * N = 7274 N = 3758 (wmen) dyspnea [see Warnings and Precautins (5.3)] 1 nausea diarrhea cnstipatin abdminal pain vmiting dyspepsia rash [see Warnings and Precautins (5.3)] pruritus vaginitis edema injectin site reactin chest pain Table 5: Less Cmmn (0.1 t 1%) Adverse Reactins Reprted in Clinical Trials with LEVAQUIN (N = 7537) System/Organ Class Adverse Reactin Infectins and Infestatins genital mniliasis Bld and Lymphatic System anemia Disrders thrmbcytpenia granulcytpenia [see Warnings and Precautins (5.4)] Immune System Disrders allergic reactin [see Warnings and Precautins (5.3, 5.4)] Metablism and Nutritin Disrders hyperglycemia hypglycemia [see Warnings and Precautins (5.11)] hyperkalemia 17

18 Table 5: Less Cmmn (0.1 t 1%) Adverse Reactins Reprted in Clinical Trials with LEVAQUIN (N = 7537) System/Organ Class Adverse Reactin Psychiatric Disrders anxiety agitatin cnfusin depressin hallucinatin nightmare * [see Warnings and Precautins (5.6)] Nervus System Disrders Respiratry, Thracic and Mediastinal Disrders Cardiac Disrders Vascular Disrders Gastrintestinal Disrders Hepatbiliary Disrders sleep disrder * anrexia abnrmal dreaming * tremr cnvulsins [see Warnings and Precautins (5.6)] paresthesia [see Warnings and Precautins (5.8)] vertig hypertnia hyperkinesias abnrmal gait smnlence * syncpe epistaxis cardiac arrest palpitatin ventricular tachycardia ventricular arrhythmia phlebitis gastritis stmatitis pancreatitis esphagitis gastrenteritis glssitis pseudmembranus/ C. difficile clitis [see Warnings and Precautins (5.7)] abnrmal hepatic functin increased hepatic enzymes increased alkaline phsphatase 18

19 Table 5: Less Cmmn (0.1 t 1%) Adverse Reactins Reprted in Clinical Trials with LEVAQUIN (N = 7537) System/Organ Class Adverse Reactin Skin and Subcutaneus Tissue urticaria [see Warnings and Precautins (5.3)] Disrders Musculskeletal and Cnnective arthralgia Tissue Disrders tendinitis [see Warnings and Precautins (5.1)] Renal and Urinary Disrders * N = 7274 myalgia skeletal pain abnrmal renal functin acute renal failure [see Warnings and Precautins (5.4)] In clinical trials using multiple-dse therapy, phthalmlgic abnrmalities, including cataracts and multiple punctate lenticular pacities, have been nted in patients underging treatment with quinlnes, including LEVAQUIN. The relatinship f the drugs t these events is nt presently established. 6.3 Pstmarketing Experience Table 6 lists adverse reactins that have been identified during pst-apprval use f LEVAQUIN. Because these reactins are reprted vluntarily frm a ppulatin f uncertain size, reliably estimating their frequency r establishing a causal relatinship t drug expsure is nt always pssible. Table 6: Pstmarketing Reprts Of Adverse Drug Reactins System/Organ Class Adverse Reactin Bld and Lymphatic System pancytpenia Disrders aplastic anemia leukpenia hemlytic anemia [see Warnings and Precautins (5.4)] Immune System Disrders Psychiatric Disrders esinphilia hypersensitivity reactins, smetimes fatal including: anaphylactic/anaphylactid reactins anaphylactic shck angineurtic edema serum sickness [see Warnings and Precautins (5.3, 5.4)] psychsis parania islated reprts f suicide attempt and suicidal ideatin [see Warnings and Precautins (5.6)] 19

20 Table 6: Pstmarketing Reprts Of Adverse Drug Reactins System/Organ Class Adverse Reactin Nervus System Disrders exacerbatin f myasthenia gravis [see Warnings and Precautins (5.2)] ansmia ageusia parsmia dysgeusia peripheral neurpathy (may be irreversible) [see Warnings and Precautins (5.8)] islated reprts f encephalpathy abnrmal electrencephalgram (EEG) dysphnia pseudtumr cerebri [see Warnings and Precautins (5.6)] Eye Disrders uveitis visin disturbance, including diplpia visual acuity reduced visin blurred sctma Ear and Labyrinth Disrders hypacusis tinnitus Cardiac Disrders islated reprts f trsade de pintes electrcardigram QT prlnged [see Warnings and Precautins (5.9)] Vascular Disrders Respiratry, Thracic and Mediastinal Disrders Hepatbiliary Disrders Skin and Subcutaneus Tissue Disrders tachycardia vasdilatatin islated reprts f allergic pneumnitis [see Warnings and Precautins (5.4)] hepatic failure (including fatal cases) hepatitis jaundice [see Warnings and Precautins (5.4), (5.5)] bullus eruptins t include: Stevens-Jhnsn Syndrme txic epidermal necrlysis erythema multifrme [see Warnings and Precautins (5.4)] Musculskeletal and Cnnective Tissue Disrders phtsensitivity/phttxicity reactin [see Warnings and Precautins (5.12)] leukcytclastic vasculitis tendn rupture [see Warnings and Precautins (5.1)] muscle injury, including rupture rhabdmylysis Renal and Urinary Disrders interstitial nephritis [see Warnings and Precautins (5.4)] General Disrders and multi-rgan failure Administratin Site Cnditins pyrexia Investigatins prthrmbin time prlnged internatinal nrmalized rati prlnged muscle enzymes increased 7 DRUG INTERACTIONS 7.1 Chelatin Agents: Antacids, Sucralfate, Metal Catins, Multivitamins LEVAQUIN Tablets and Oral Slutin 20

21 While the chelatin by divalent catins is less marked than with ther flurquinlnes, cncurrent administratin f LEVAQUIN Tablets and Oral Slutin with antacids cntaining magnesium, r aluminum, as well as sucralfate, metal catins such as irn, and multivitamin preparatins with zinc may interfere with the gastrintestinal absrptin f levflxacin, resulting in systemic levels cnsiderably lwer than desired. Tablets with antacids cntaining magnesium, aluminum, as well as sucralfate, metal catins such as irn, and multivitamin preparatins with zinc r didansine may substantially interfere with the gastrintestinal absrptin f levflxacin, resulting in systemic levels cnsiderably lwer than desired. These agents shuld be taken at least tw hurs befre r tw hurs after ral LEVAQUIN administratin. LEVAQUIN Injectin There are n data cncerning an interactin f intravenus flurquinlnes with ral antacids, sucralfate, multivitamins, didansine, r metal catins. Hwever, n flurquinlne shuld be c-administered with any slutin cntaining multivalent catins, e.g., magnesium, thrugh the same intravenus line [see Dsage and Administratin (2.5)]. 7.2 Warfarin N significant effect f LEVAQUIN n the peak plasma cncentratins, AUC, and ther dispsitin parameters fr R- and S- warfarin was detected in a clinical study invlving healthy vlunteers. Similarly, n apparent effect f warfarin n levflxacin absrptin and dispsitin was bserved. Hwever, there have been reprts during the pstmarketing experience in patients that LEVAQUIN enhances the effects f warfarin. Elevatins f the prthrmbin time in the setting f cncurrent warfarin and LEVAQUIN use have been assciated with episdes f bleeding. Prthrmbin time, Internatinal Nrmalized Rati (INR), r ther suitable anticagulatin tests shuld be clsely mnitred if LEVAQUIN is administered cncmitantly with warfarin. Patients shuld als be mnitred fr evidence f bleeding [see Adverse Reactins (6.3); Patient Cunseling Infrmatin (17.4)]. 7.3 Antidiabetic Agents Disturbances f bld glucse, including hyperglycemia and hypglycemia, have been reprted in patients treated cncmitantly with flurquinlnes and an antidiabetic agent. Therefre, careful mnitring f bld glucse is recmmended when these agents are c-administered [see Warnings and Precautins (5.11); Adverse Reactins (6.2), Patient Cunseling Infrmatin (17.4)]. 21