PRODUCT MONOGRAPH. Levofloxacin Tablets. 250 mg, 500 mg and 750 mg Levofloxacin (anhydrous) as Levofloxacin Hemihydrate. Antibacterial Agent

Transcription

1 PRODUCT MONOGRAPH Pr SANDOZ LEVOFLOXACIN Tblets 250 mg, 500 mg nd 750 mg (nhydrous) s Hemihydrte Antibcteril Agent Sndoz Cnd Inc. Dte of Revision: June 25, Jules-Léger Boucherville, QC, Cnd J4B 7K8 Submission Control No: Sndoz Pge 1 of 60

2 Tble of Contents PART I: HEALTH PROFESSIONAL INFORMATION... 3 SUMMARY PRODUCT INFORMATION... 3 INDICATIONS AND CLINICAL USE... 3 CONTRAINDICATIONS... 4 WARNINGS AND PRECAUTIONS... 5 ADVERSE REACTIONS DRUG INTERACTIONS DOSAGE AND ADMINISTRATION OVERDOSAGE ACTION AND CLINICAL PHARMACOLOGY STORAGE AND STABILITY DOSAGE FORMS, COMPOSITION AND PACKAGING PART II: SCIENTIFIC INFORMATION PHARMACEUTICAL INFORMATION CLINICAL TRIALS DETAILED PHARMACOLOGY MICROBIOLOGY TOXICOLOGY REFERENCES PART III: CONSUMER INFORMATION Sndoz Pge 2 of 60

3 Pr SANDOZ LEVOFLOXACIN tblets PART I: HEALTH PROFESSIONAL INFORMATION SUMMARY PRODUCT INFORMATION Route of Administrtion Orl Dosge Form/ Strength Tblet/250 mg, 500 mg nd 750 mg Cliniclly Relevnt Nonmedicinl Ingredients Lctose For complete listing see DOSAGE FORMS, COMPOSITION AND PACKAGING section. INDICATIONS AND CLINICAL USE Sndoz (levofloxcin tblets) is indicted for the tretment of dults with bcteril infections cused by susceptible strins of the designted microorgnisms in the infections listed below. Upper Respirtory Trct Acute sinusitis (mild to moderte) due to Streptococcus pneumonie, Hemophilus influenze, or Morxell (Brnhmell) ctrrhlis. Lower Respirtory Trct Acute bcteril excerbtions of chronic bronchitis (mild to moderte) due to Stphylococcus ureus, Streptococcus pneumonie, Hemophilus influenze, Hemophilus prinfluenze, or Morxell (Brnhmell) ctrrhlis. Community-cquired pneumoni (mild, moderte nd severe infections) due to Stphylococcus ureus, Streptococcus pneumonie (including penicillin-resistnt strins), Hemophilus influenze, Hemophilus prinfluenze, Klebsiell pneumonie, Morxell (Brnhmell) ctrrhlis, Chlmydi pneumonie, Legionell pneumophil, or Mycoplsm pneumonie (see DOSAGE AND ADMINISTRATION, nd CLINICAL TRIALS). Nosocomil pneumoni due to methicillin-susceptible Stphylococcus ureus, Pseudomons eruginos, Serrti mrcescens, Escherichi coli, Klebsiell pneumonie, Hemophilus influenze or Streptococcus pneumonie. Adjunctive therpy should be used s cliniclly indicted. Where Pseudomons eruginos is documented or presumptive pthogen, combintion therpy with n nti-pseudomonl β-lctm is recommended. Skin nd Skin Structure Uncomplicted skin nd skin structure infections (mild to moderte) due to Stphylococcus ureus or Streptococcus pyogenes. Sndoz Pge 3 of 60

4 Complicted skin nd skin structure infections (mild to moderte), excluding burns, due to Enterococcus feclis, methicillin-sensitive Stphylococcus ureus, Streptococcus pyogenes, Proteus mirbilis, or Streptococcus glctie. Urinry Trct Complicted urinry trct infections (mild to moderte) due to Enterococcus (Streptococcus) feclis, Enterobcter cloce, Escherichi coli, Klebsiell pneumonie, Proteus mirbilis, or Pseudomons eruginos (see DOSAGE AND ADMINISTRATION nd CLINICAL TRIALS). Uncomplicted urinry trct infections (mild to moderte) due to Escherichi coli, Klebsiell pneumonie or Stphylococcus sprophyticus. Acute pyelonephritis (mild to moderte) cused by Escherichi coli (see DOSAGE AND ADMINISTRATION nd CLINICAL TRIALS). Chronic bcteril prosttitis due to Escherichi coli, Enterococcus feclis or Stphylococcus epidermidis. Approprite culture nd susceptibility tests should be performed before tretment in order to isolte nd identify the orgnisms cusing the infection, nd to determine their susceptibility to levofloxcin. Therpy with levofloxcin my be initited before the results of these tests re known; once results become vilble, pproprite therpy should be continued. As with other drugs in this clss, some strins of Pseudomons eruginos my develop resistnce firly rpidly during tretment with levofloxcin. Culture nd susceptibility testing performed periodiclly during therpy, will revel not only the therpeutic effect of the ntimicrobil gent, but lso the possible emergence of bcteril resistnce. Geritrics ( 65 yers of ge): Drug bsorption ppers to be unffected by ge. Dose djustment bsed on ge lone is not necessry (see WARNINGS AND PRECAUTIONS, Specil Popultions nd ACTION AND CLINICAL PHARMACOLOGY, Specil Popultions nd Conditions). Peditrics (<18 yers of ge): Sfety nd effectiveness in children under 18 yers of ge hve not been estblished (see WARNINGS AND PRECAUTIONS, Specil Popultions). CONTRAINDICATIONS is contrindicted in persons with history of hypersensitivity to levofloxcin, quinolone ntimicrobil gents, or ny other components of this product. For complete listing, see the DOSAGE FORMS, COMPOSITION AND PACKAGING section of the Product Monogrph. Sndoz Pge 4 of 60

5 is lso contrindicted in persons with history of tendinitis or tendon rupture ssocited with the use of ny member of the quinolone group of ntimicrobil gents. WARNINGS AND PRECAUTIONS Serious Wrnings nd Precutions hs been shown to prolong the QT intervl of the electrocrdiogrm in some ptients (see WARNINGS AND PRECAUTIONS, Crdiovsculr). Serious hypersensitivity nd/or nphylctic rections hve been reported in ptients receiving quinolone therpy, including levofloxcin (see WARNINGS AND PRECAUTIONS, Immune). Seizures my occur with quinolone therpy. should be used with cution in ptients with known or suspected CNS disorders which my predispose to seizures or lower the seizure threshold (see WARNINGS AND PRECAUTIONS, Neurologic). Fluoroquinolones, including levofloxcin, my excerbte muscle wekness in persons with mystheni grvis. Avoid levofloxcin in ptients with known history of mystheni grvis (see WARNINGS AND PRECAUTIONS, Musculoskeletl). Fluoroquinolones, including levofloxcin, re ssocited with n incresed risk of tendinitis nd tendon rupture in ll ges. This risk is further incresed in older ptients usully over 60 yers of ge, in ptients tking corticosteroid drugs, nd in ptients with kidney, hert or lung trnsplnts (see WARNINGS AND PRECAUTIONS, Musculoskeletl). Generl The dministrtion of levofloxcin incresed the incidence nd severity of osteochondrosis in immture rts nd dogs. Other quinolones lso produce similr erosions in the weight-bering joints nd other signs of rthropthy in immture nimls of vrious species. Consequently, levofloxcin should not be used in pre-pubertl ptients (see TOXICOLOGY). Although levofloxcin is soluble, dequte hydrtion of ptients receiving levofloxcin should be mintined to prevent the formtion of highly concentrted urine. Crystlluri hs been observed rrely in ptients receiving other quinolones, when ssocited with high doses nd n lkline urine. Although crystlluri ws not observed in clinicl trils with levofloxcin, ptients re encourged to remin dequtely hydrted. As with ny ntimicrobil drug, periodic ssessment of orgn system functions, including renl, heptic, nd hemtopoietic, is dvisble during prolonged therpy (see ADVERSE REACTIONS). Use of levofloxcin hemihydrte with other drugs my led to drug-drug interctions (see DRUG INTERACTIONS, Drug-Drug Interctions). Sexully Trnsmitted Diseses is not indicted for the tretment of syphilis or gonorrhe. is not Sndoz Pge 5 of 60

6 effective in the tretment of syphilis. Antimicrobil gents used in high doses for short periods of time to tret gonorrhe my msk or dely the symptoms of incubting syphilis. All ptients with gonorrhe should hve serologic test for syphilis t the time of dignosis. Ptients treted with ntimicrobil gents with limited or no ctivity ginst Treponem pllidum should hve follow-up serologic test for syphilis fter 3 months. Crdiovsculr QT Prolongtion Some quinolones, including levofloxcin, hve been ssocited with prolongtion of the QT intervl on the electrocrdiogrm nd infrequent cses of rrhythmi. During post-mrketing surveillnce, very rre cses of torsdes de pointes hve been reported in ptients tking levofloxcin. These reports generlly involved ptients with concurrent medicl conditions or concomitnt medictions tht my hve been contributory. The risk of rrhythmis my be reduced by voiding concurrent use with other drugs tht prolong the QT intervl including mcrolide ntibiotics, ntipsychotics, tricyclic ntidepressnts, Clss IA (e.g., quinidine, procinmide) or Clss III (e.g., miodrone, sotlol) ntirrhythmic gents, nd cispride. In ddition, use of levofloxcin in the presence of risk fctors for torsdes de pointes such s hypoklemi, significnt brdycrdi, crdiomyopthy, ptients with myocrdil ischemi, nd ptients with congenitl prolongtion of the QT intervl should be voided (see DETAILED PHARMACOLOGY, Humn Phrmcology, Studies Mesuring Effects on QT nd Corrected QT (QTc) Intervls). Endocrine nd Metbolism Disturbnces of Blood Glucose Disturbnces of blood glucose, including symptomtic hyper- nd hypoglycemi, hve been reported with the use of quinolones, including levofloxcin. In ptients treted with levofloxcin, some of these cses were serious. Blood glucose disturbnces were usully in dibetic ptients receiving concomitnt tretment with n orl hypoglycemic gent (e.g., glyburide/glibenclmide) nd/or with insulin. In these ptients, creful monitoring of blood glucose is recommended. If hypoglycemic rection occurs in ptient being treted with levofloxcin, discontinue levofloxcin immeditely nd initite pproprite therpy. Serious hypoglycemi nd hyperglycemi hve lso occurred in ptients without history of dibetes (see ADVERSE REACTIONS nd DRUG INTERACTIONS, Drug-Drug Interctions, Antidibetic Agents). Hypoglycemic com hs been observed in dibetic ptients with the use of levofloxcin. Ftl outcomes hve been reported. All cses of hypoglycemic com hd multiple confounding fctors; temporl reltionship with the use of levofloxcin ws identified (onset of ltered consciousness occurred within 3 dys in most cses). Cution should be exercised when using levofloxcin in dibetic ptients tking concomitnt tretment with n orl hypoglycemic gent nd/or insulin, especilly those who re elderly or who hve renl impirment (see WARNINGS AND PRECAUTIONS, Renl nd DRUG INTERACTIONS, Drug-Drug Interctions, Antidibetic Agents). Sndoz Pge 6 of 60

7 Gstrointestinl Clostridium difficile-ssocited disese Clostridium difficile-ssocited disese (CDAD) hs been reported with use of mny ntibcteril gents, including levofloxcin. CDAD my rnge in severity from mild dirrhe to ftl colitis. It is importnt to consider this dignosis in ptients who present with dirrhe or symptoms of colitis, pseudomembrnous colitis, toxic megcolon, or perfortion of the colon subsequent to the dministrtion of ny ntibcteril gent. CDAD hs been reported to occur over 2 months fter the dministrtion of ntibcteril gents. Tretment with ntibcteril gents my lter the norml flor of the colon nd my permit overgrowth of Clostridium difficile. C. difficile produces toxins A nd B, which contribute to the development of CDAD. CDAD my cuse significnt morbidity nd mortlity. CDAD cn be refrctory to ntimicrobil therpy. If the dignosis of CDAD is suspected or confirmed, pproprite therpeutic mesures should be initited. Mild cses of CDAD usully respond to discontinution of ntibcteril gents not directed ginst Clostridium difficile. In moderte to severe cses, considertion should be given to mngement with fluids nd electrolytes, protein supplementtion, nd tretment with n ntibcteril gent cliniclly effective ginst Clostridium difficile. Surgicl evlution should be instituted s cliniclly indicted since surgicl intervention my be required in certin severe cses (see ADVERSE REACTIONS). Heptic Very rre post-mrketing reports of severe heptotoxicity (including cute heptitis nd ftl events) hve been received for ptients treted with levofloxcin. No evidence of serious drugssocited heptotoxicity ws detected in clinicl trils of over 7000 ptients. Severe heptotoxicity generlly occurred within 14 dys of initition of therpy nd most cses occurred within 6 dys. Most cses of severe heptotoxicity were not ssocited with hypersensitivity. The mjority of ftl heptotoxicity reports occurred in ptients 65 yers of ge or older nd most were not ssocited with hypersensitivity. should be discontinued immeditely if the ptient develops signs nd symptoms of heptitis (see ADVERSE REACTIONS, Post- Mrket Adverse Drug Rections). Immune Hypersensitivity Serious nd occsionlly ftl hypersensitivity nd/or nphylctic rections hve been reported in ptients receiving therpy with quinolones, including levofloxcin. These rections often occur following the first dose. Some rections hve been ccompnied by crdiovsculr collpse, hypotension/shock, seizure, loss of consciousness, tingling, ngioedem (including tongue, lryngel, throt or fcil edem/swelling), irwy obstruction (including bronchospsm, shortness of breth, nd cute respirtory distress), dyspne, urticri, itching, nd other serious skin rections. should be discontinued immeditely t the first ppernce of skin rsh or ny other sign of hypersensitivity. Serious cute hypersensitivity rections my require tretment with epinephrine nd other resuscittive mesures, including oxygen, intrvenous fluids, ntihistmines, corticosteroids, pressor, mines nd irwy mngement, s cliniclly indicted (see ADVERSE REACTIONS). Sndoz Pge 7 of 60

8 Serious nd sometimes ftl events, some due to hypersensitivity nd some due to uncertin etiology, hve rrely been reported in ptients receiving therpy with quinolones, including levofloxcin. These events my be severe, nd generlly occur following the dministrtion of multiple doses. Clinicl mnifesttions my include one or more of the following: fever; rsh or severe dermtologic rections (e.g., toxic epiderml necrolysis, Stevens-Johnson syndrome); vsculitis; rthrlgi; mylgi; serum sickness; llergic pneumonitis; interstitil nephritis; cute renl insufficiency or filure; heptitis, including cute heptitis; jundice; cute heptic necrosis or filure; nemi, including hemolytic nd plstic; thrombocytopeni, including thrombotic thrombocytopenic purpur; leukopeni; grnulocytosis; pncytopeni; nd/or other hemtologic bnormlities. The dministrtion of levofloxcin should be discontinued immeditely, t the first ppernce of skin rsh or ny other sign of hypersensitivity, nd supportive mesures instituted (see ADVERSE REACTIONS). Musculoskeletl Tendinitis Rupture of the shoulder, hnd nd Achilles tendons tht required surgicl repir or resulted in prolonged disbility hve been reported in ptients receiving quinolones, including levofloxcin. should be discontinued if the ptient experiences pin, inflmmtion or rupture of tendon. Ptients should rest nd refrin from exercise until the dignosis of tendinitis or tendon rupture hs been confidently excluded. The risk of developing fluoroquinolone-ssocited tendinitis nd tendon rupture is further incresed in older ptients usully over 60 yers of ge, in ptients tking corticosteroid drugs, nd in ptients with kidney, hert or lung trnsplnts. Fctors, in ddition to ge nd corticosteroid use, tht my independently increse the risk of tendon rupture include strenuous physicl ctivity, renl filure, nd previous tendon disorders such s rheumtoid rthritis. Tendinitis nd tendon rupture hve lso occurred in ptients tking fluoroquinolones who do not hve the bove risk fctors. Tendon rupture cn occur during or fter completion of therpy; cses occurring up to severl months fter completion of therpy hve been reported. should be discontinued if the ptient experiences pin, swelling, inflmmtion or rupture of tendon. Ptients should be dvised to rest t the first sign of tendinitis or tendon rupture, nd to contct their helthcre provider regrding chnging to non-quinolone ntimicrobil drug (see ADVERSE REACTIONS). should not be used in ptients with history of tendon disese/disorder relted to previous quinolone tretment (see CONTRAINDICATIONS). Mystheni Grvis Fluoroquinolones hve neuromusculr blocking ctivity nd my excerbte muscle wekness in persons with mystheni grvis. Postmrketing serious dverse events, including deths nd requirement for ventiltory support, hve been ssocited with fluoroquinolone use (including levofloxcin) in persons with mystheni grvis. Avoid levofloxcin in ptients with known history of mystheni grvis (see ADVERSE REACTIONS, Post-Mrket Adverse Drug Rections). Sndoz Pge 8 of 60

9 Neurologic CNS nd Psychitric Effects Convulsions, toxic psychoses nd incresed intrcrnil pressure (including pseudotumor cerebri) hve been reported in ptients receiving quinolones, including levofloxcin. Quinolones including levofloxcin, my lso cuse centrl nervous system stimultion which my led to tremors, restlessness, nxiety, lighthededness, dizziness, confusion nd hllucintions, prnoi, depression, nightmres, insomni, nd rrely, suicidl thoughts or cts. These rections my occur following the first dose. If these rections occur in ptients receiving levofloxcin, the drug should be discontinued nd pproprite mesures instituted. As with ll quinolones, levofloxcin should be used with cution in ptients with known or suspected CNS disorder tht my predispose to seizures or lower the seizure threshold (e.g., severe cerebrl rteriosclerosis, epilepsy), or in the presence of other risk fctors tht my predispose to seizures or lower the seizure threshold (e.g., lcohol buse, certin drug therpies such s NSAIDs nd theophylline, renl dysfunction). should be used with cution in ptients with unstble psychitric illness (see DRUG INTERACTIONS nd ADVERSE REACTIONS). Peripherl Neuropthy Rre cses of sensory or sensorimotor xonl polyneuropthy ffecting smll nd/or lrge xons resulting in presthesis, hypoesthesis, dysesthesis nd wekness hve been reported in ptients receiving quinolones, including levofloxcin. Symptoms my occur soon fter initition of tretment nd my be irreversible. should be discontinued immeditely if the ptient experiences symptoms of neuropthy including pin, burning, tingling, numbness, nd/or wekness or other ltertions of senstion including light touch, pin, temperture, position sense, nd vibrtory senstion in order to prevent the development of n irreversible condition. Renl Sfety nd efficcy of levofloxcin in ptients with impired renl function (cretinine clernce 80 ml/min) hve not been studied. Since levofloxcin is known to be substntilly excreted by the kidney, the risk of toxic rections to this drug my be greter in ptients with impired renl function. The potentil effects of levofloxcin ssocited with possible incresed serum/tissue levels in renl impired ptients, such s effect on QTc intervl, hve not been studied. Adjustment of the dosge regimen my be necessry to void the ccumultion of levofloxcin due to decresed clernce. Creful clinicl observtion nd pproprite lbortory studies should be performed prior to nd during therpy, since elimintion of levofloxcin my be reduced. Becuse elderly ptients re more likely to hve decresed renl function, cre should be tken in dose selection, nd it my be useful to monitor renl function. Administer levofloxcin with cution in the presence of renl insufficiency (see DOSAGE AND ADMINISTRATION, Recommended Dose nd Dosge Adjustment, Ptients with Impired Renl Function nd DETAILED PHARMACOLOGY, Fctors Influencing the Phrmcokinetics, Specil Popultions, Renl Insufficiency). Skin Phototoxicity Moderte to severe phototoxicity rections hve been observed in ptients exposed to direct sunlight or ultrviolet (UV) light while receiving drugs in this clss. Excessive exposure to sunlight or UV light should be voided. However, in clinicl trils with levofloxcin, Sndoz Pge 9 of 60

10 phototoxicity hs been observed in less thn 0.1% of ptients. Therpy should be discontinued if phototoxicity (e.g., skin eruption) occurs. Specil Popultions The sfety nd efficcy of levofloxcin in children, dolescents (under the ge of 18 yers), pregnnt women, nd nursing mothers hve not been estblished. Pregnnt Women: There re no dequte nd well-controlled studies in pregnnt women. should be used during pregnncy only if the potentil benefit justifies the potentil risk to the fetus (see TOXICOLOGY). Nursing Women: hs not been mesured in humn milk. Bsed upon dt from ofloxcin, it cn be presumed tht levofloxcin cn be excreted in humn milk. Becuse of the potentil for serious dverse rections from levofloxcin in nursing infnts, decision should be mde whether to discontinue nursing or to discontinue the drug, tking into ccount the importnce of the drug to the mother (see TOXICOLOGY). Peditrics (<18 yers of ge): is not indicted for the tretment of ptients younger thn 18 yers of ge. Quinolones, including levofloxcin, cuse rthropthy in juvenile nimls of severl species (see TOXICOLOGY). The incidence of protocol-defined musculoskeletl disorders in prospective long-term surveillnce study ws higher in children treted for pproximtely 10 dys with levofloxcin thn in children treted with nonfluoroquinolone ntibiotics for pproximtely 10 dys (see ADVERSE REACTIONS). Geritrics ( 65 yers of ge): The phrmcokinetic properties of levofloxcin in younger dults nd elderly dults do not differ significntly when cretinine clernce is tken into considertion. However, since the drug is known to be substntilly excreted by the kidney, the risk of toxic rections to this drug my be greter in ptients with impired renl function. Becuse elderly ptients re more likely to hve decresed renl function, cre should be tken in dose selection. It my lso be useful to monitor renl function. Elderly ptients my be more susceptible to drug-ssocited effects on the QT intervl (see WARNINGS AND PRECAUTIONS, Crdiovsculr). Geritric ptients re t incresed risk for developing severe tendon disorders including tendon rupture when being treted with fluoroquinolone such s levofloxcin. This risk is further incresed in ptients receiving concomitnt corticosteroid therpy (see WARNINGS AND PRECAUTIONS, Musculoskeletl). Severe nd sometimes ftl cses of heptotoxicity hve been reported post-mrketing in ssocition with levofloxcin. The mjority of ftl heptotoxicity reports occurred in ptients 65 yers of ge or older nd most were not ssocited with hypersensitivity (see WARNINGS AND PRECAUTIONS, Heptic). Sndoz Pge 10 of 60

11 Effects on Ability to Drive nd Use Mchines Neurologic dverse effects such s dizziness nd lighthededness my occur. Therefore, ptients should know how they rect to levofloxcin before operting n utomobile or mchinery or engging in other ctivities requiring mentl lertness nd coordintion. ADVERSE REACTIONS Adverse Drug Rection Overview In North Americn Phse III clinicl trils involving 7537 subjects, the incidence of tretmentemergent dverse events in ptients treted with levofloxcin tblets nd injection ws comprble to comprtors. The mjority of dverse events were considered to be mild to moderte, with 5.6%of ptients considered to hve severe dverse events. Among ptients receiving multiple-dose therpy, 4.2% discontinued therpy with levofloxcin due to dverse experiences. The incidence of drug-relted dverse rections ws 6.7%. In clinicl trils, the most frequently reported dverse drug rections occurring in > 3% of the study popultion were nuse, hedche, dirrhe, insomni, dizziness nd constiption. Serious nd otherwise importnt dverse drug rections re discussed in greter detil in other sections (see WARNINGS AND PRECAUTIONS). Clinicl Tril Adverse Drug Rections Becuse clinicl trils re conducted under very specific conditions the dverse rection rtes observed in the clinicl trils my not reflect the rtes observed in prctice nd should not be compred to the rtes in the clinicl trils of nother drug. Adverse drug rection informtion from clinicl trils is useful for identifying drug-relted dverse events nd for pproximting rtes. The dt described below reflect exposure to levofloxcin in 7537 ptients in 29 pooled Phse III clinicl trils. The popultion studied hd men ge of 49.6 yers (74.2% of the popultion ws < 65 yers), 50.1% were mle, 71.0% were Cucsin nd 18.8% were Blck. Ptients were treted with levofloxcin for wide vriety of infectious diseses (See INDICATIONS AND CLINICAL USE). Tretment durtion ws usully 3-14 dys, the men number of dys on therpy ws 9.6 dys nd the men number of doses ws Ptients received levofloxcin doses of 750 mg once dily, 250 mg once dily, or 500 mg once or twice dily. The overll incidence, type nd distribution of dverse rections were similr in ptients receiving levofloxcin doses of 750 mg once dily, 250 mg once dily, nd 500 mg once or twice dily. Adverse rections (chrcterized s likely relted to drug-therpy) occurring in 1% of levofloxcin-treted ptients re shown in Tble 1.1 below. Sndoz Pge 11 of 60

12 Tble 1.1: Common ( 1%) Adverse Rections Reported in Clinicl Trils with System/Orgn Clss Adverse Rection % (N=7537) Infections nd Infesttions monilisis 1 Psychitric Disorders insomni 4 Nervous System Disorders hedche dizziness 6 3 Respirtory, Thorcic nd Medistinl dyspne 1 Disorders Gstrointestinl Disorders Skin nd Subcutneous Tissue Disorders Reproductive System nd Brest Disorders Generl Disorders nd Administrtion Site Conditions N = 7274 b N = 3758 (women) nuse dirrhe constiption bdominl pin vomiting dyspepsi rsh pruritus vginitis edem injection site rection chest pin b Less Common Clinicl Tril Adverse Drug Rections (<1%) Less common dverse rections occurring in 0.1 to <1% of levofloxcin-treted ptients re shown in Tble 1.2 below. Tble 1.2: Less Common (0.1 to <1%) Adverse Rections Reported in Clinicl Trils with System/Orgn Clss Adverse Rection Infections nd Infesttions genitl monilisis Blood nd Lymphtic System nemi, thrombocytopeni, grnulocytopeni Disorders Immune System Disorders llergic rection Metbolism nd Nutrition Disorders hyperglycemi, hypoglycemi, hyperklemi Psychitric Disorders nxiety, gittion, confusion, depression, hllucintion, nightmre, sleep disorder, norexi, bnorml dreming Nervous System Disorders tremor, convulsions, presthesi, vertigo, hypertoni, hyperkinesis, bnorml git, somnolence, syncope Respirtory, Thorcic nd Medistinl epistxis Disorders Crdic Disorders crdic rrest, plpittion, ventriculr tchycrdi, ventriculr rrhythmi Vsculr Disorders phlebitis Gstrointestinl Disorders gstritis, stomtitis, pncretitis, esophgitis, gstroenteritis, glossitis, pseudomembrneous/ C.difficile colitis Heptobiliry Disorders bnorml heptic function, incresed heptic enzymes, incresed lkline phosphtse Sndoz Pge 12 of 60

13 Skin nd Subcutneous Tissue Disorders Musculoskeletl nd Connective Tissue Disorders Renl nd Urinry Disorders N = 7274 urticri tendinitis, rthrlgi, mylgi, skeletl pin bnorml renl function, cute renl filure Rre (<0.1%) dverse rections from Phse III studies include dyspne nd rsh mculo-ppulr. In clinicl trils using multiple-dose therpy, ophthlmologic bnormlities, including ctrcts nd multiple punctte lenticulr opcities, hve been noted in ptients undergoing tretment with other quinolones. The reltionship of the drugs to these events is not presently estblished. Crystlluri nd cylindruri hve been reported with other quinolones. Abnorml Hemtologic nd Clinicl Chemistry Findings Lbortory bnormlities seen in > 2% of ptients receiving multiple doses of levofloxcin: decresed glucose 2.1% It is not known whether this bnormlity ws cused by the drug or the underlying condition being treted. Peditric Dt In group of 1534 peditric ptients (6 months to 16 yers of ge) treted with levofloxcin for respirtory infections, children 6 months to 5 yers of ge received 10 mg/kg of levofloxcin twice dy for pproximtely 10 dys nd children greter thn 5 yers of ge received 10 mg/kg to mximum of 500 mg of levofloxcin once dy for pproximtely 10 dys. The dverse rection profile ws similr to tht reported in dult ptients. Vomiting nd dirrhe were reported more frequently in children thn reported in dults. However, the frequency of vomiting nd dirrhe ws similr in levofloxcin-treted nd non-fluoroquinolone ntibiotic comprtor-treted children. A subset of 1340 of these children treted with levofloxcin for pproximtely 10 dys ws enrolled in prospective, long-term, surveillnce study to ssess the incidence of protocoldefined musculoskeletl disorders (rthrlgi, rthritis, tendonopthy, git bnormlity) during 60 dys nd 1 yer following the first dose of levofloxcin. During the 60-dy period following the first dose, the incidence of protocol-defined musculoskeletl disorders ws greter in levofloxcin-treted children thn in nonfluoroquinolone ntibiotic comprtor-treted children (2.1% vs. 0.9%, respectively [p=0.038]). In 22/28 (78%) of these children, reported disorders were chrcterized s rthrlgi. A similr observtion ws mde during the one-yer period, with greter incidence of protocol-defined musculoskeletl disorders in levofloxcin-treted children thn in non-fluoroquinolone ntibiotic comprtor-treted children (3.4% vs. 1.8%, respectively [p=0.025]). The mjority of these disorders occurring in children treted with levofloxcin were mild nd resolved within 7 dys. Disorders were moderte in 8 children nd mild in 35 (76%) children. Sndoz Pge 13 of 60

14 Post-Mrket Adverse Drug Rections Tble 1.3 lists dverse rections tht hve been identified during post-pprovl use of levofloxcin. Becuse these rections re reported voluntrily from popultion of uncertin size, relibly estimting their frequency or estblishing cusl reltionship to drug exposure is not lwys possible. Tble 1.3: Post-Mrketing Reports of Adverse Drug Rections System Orgn Clss Adverse Rection Blood nd Lymphtic System pncytopeni, plstic nemi, leucopeni, hemolytic nemi, Disorders eosinophili, thrombocytopeni including thrombotic thrombocytopenic purpur, grnulocytosis Immune System Disorders hypersensitivity rections, sometimes ftl including: nphylctic/nphylctoid rections, nphylctic shock, ngioneurotic edem, serum sickness Psychitric Disorders psychosis, prnoi, isolted reports of suicide ttempt nd suicidl idetion Nervous System Disorders nosmi, geusi, prosmi, dysgeusi, peripherl neuropthy (my be irreversible), isolted reports of encephlopthy, bnorml EEG, dysphoni, excerbtion of mystheni grvis, mnesi, pseudotumor cerebri Eye Disorders uveitis, vision disturbnce (including diplopi), visul cuity reduced, vision blurred, scotom Er nd Lbyrinth Disorders hypocusis, tinnitus Crdic Disorders isolted reports of torsdes de pointes, electrocrdiogrm QT prolonged, tchycrdi Vsculr Disorders vsodiltion, vsculitis, DIC Respirtory, Thorcic nd isolted reports of llergic pneumonitis, interstitil pneumoni, lryngel Medistinl Disorders edem, pne Heptobiliry Disorders Skin nd Subcutneous Tissue Disorders Musculoskeletl nd Connective Tissue Disorders Renl nd Urinry Disorders heptic filure (including ftl cses), heptitis, jundice, heptic necrosis bullous eruptions to include: Stevens-Johnson Syndrome, toxic epiderml necrolysis, erythem multiforme, photosensitivity/phototoxicity rection, leukocytoclstic vsculitis tendon rupture, muscle injury (including rupture), rhbdomyolysis, myositis, mylgi interstitil nephritis, nephrosis, glomerulonephritis Generl Disorders nd Administrtion Site Conditions Investigtions multi-orgn filure, pyrexi, rsh prothrombin time prolonged, interntionl normlized rtio (INR) prolonged, muscle enzymes incresed (CPK) DRUG INTERACTIONS Overview undergoes limited metbolism in humns nd is primrily excreted s unchnged drug in the urine. The P450 system is not involved in the levofloxcin metbolism, nd is not ffected by levofloxcin. is unlikely to lter the phrmcokinetics of drugs metbolized by these enzymes. Disturbnces of blood glucose hve been reported in ptients treted concomitntly with levofloxcin nd n ntidibetic gent. Therefore, creful monitoring Sndoz Pge 14 of 60

15 of blood glucose is recommended when these gents, including levofloxcin, re codministered. As with ll other quinolones, iron nd ntcids significntly reduced biovilbility of levofloxcin. Drug-Drug Interctions Tble 1.4: Estblished or Potentil Drug-Drug Interctions Proper nme Ref Effect Clinicl comment Antidibetic Agents C Disturbnces of blood glucose, including hyperglycemi nd hypoglycemi, hve been reported in ptients treted concomitntly with levofloxcin nd n ntidibetic gent. Some of these cses were serious including hypoglycemic com. Creful monitoring of blood glucose is recommended when these gents, including levofloxcin, re codministered. Antcids, Sucrlfte, Metl Ctions, Multi-Vitmins T Tblets: Due to the cheltion of levofloxcin by multivlent ctions, concurrent dministrtion of levofloxcin tblets with ntcids contining clcium, mgnesium, or luminum, s well s sucrlfte, metl ctions such s iron, multivitmin preprtions with zinc, or ny products contining ny of these components my interfere with the gstrointestinl bsorption of levofloxcin, resulting in systemic levels considerbly lower thn desired. Cyclosporine CT No significnt effect of levofloxcin on the pek plsm concentrtions, AUC, nd other disposition prmeters for cyclosporine ws detected in clinicl study involving helthy volunteers. However, elevted serum levels of cyclosporine hve been reported in the ptient popultion when co-dministered with some other quinolones. C mx nd k e were slightly lower, while T mx nd t ½ were slightly longer in the presence of cyclosporine, thn those observed in other studies without concomitnt mediction. The differences, however, re not considered to be cliniclly significnt. Digoxin CT No significnt effect of levofloxcin on the pek plsm concentrtions, AUC, nd, other disposition prmeters for digoxin ws detected in clinicl study involving helthy volunteers. bsorption nd disposition kinetics were similr in the presence or bsence of digoxin. These gents should be tken t lest 2 hours before or 2 hours fter levofloxcin tblet dministrtion. No dosge djustment is required for levofloxcin or cyclosporine when dministered concomitntly. No dosge djustment for levofloxcin or digoxin is required when dministered concomitntly. Digoxin levels should be closely monitored in ptients receiving concomitnt therpy with digoxin. Sndoz Pge 15 of 60

16 Proper nme Ref Effect Clinicl comment Non-Steroidl Anti- Inflmmtory Drugs (NSAIDs) T Although not observed with levofloxcin in clinicl trils, some quinolones hve been reported to hve proconvulsnt ctivity tht is excerbted with concominnt use of NSAIDs. The concomitnt dministrtion of non-steroidl nti-inflmmtory drug with quinolone, including levofloxcin, my increse the risk of CNS stimultion nd convulsive seizures (see WARNINGS AND PRECAUTIONS, Neurologic nd DETAILED PHARMACOLOGY, Animl Phrmcology). Probenecid nd Cimetidine CT No significnt effect of probenecid or cimetidine on the rte nd extent of levofloxcin bsorption ws observed in clinicl study involving helthy volunteers. The AUC nd t ½ of levofloxcin were 27-38% nd 30% higher, respectively, while CL/F nd Cl r were 21-35% lower during concomitnt tretment with probenecid or cimetidine compred to levofloxcin lone..no dosge djustment for levofloxcin is required when dministered concomitntly with probenecid or cimetidine except dosge djustment for levofloxcin my be required bsed on the renl function of the ptient. Theophylline CT/T No significnt effect of levofloxcin on the plsm concentrtions, AUC, nd other disposition prmeters for theophylline ws detected in clinicl study involving 14 helthy volunteers. Similrly, no pprent effect of theophylline on levofloxcin bsorption nd disposition ws observed. However, concomitnt dministrtion of other quinolones with theophylline hs resulted in prolonged elimintion, elevted serum theophylline levels, nd subsequent increse in the risk of theophylline-relted dverse rections in the ptient popultion. Wrfrin T Certin quinolones, including levofloxcin, my enhnce the effects of orl nticogulnt wrfrin or its derivtives. Zidovudine CT bsorption nd disposition in HIVinfected subjects, with or without concomitnt zidovudine tretment, were similr. The effect of levofloxcin on zidovudine phrmcokinetics hs not been studied. Legend: C = Cse Study; CT = Clinicl Tril; T = Theoreticl Theophylline levels should be closely monitored, nd theophylline dosge djustments mde if pproprite, when levofloxcin is codministered. Adverse rections, including seizures, my occur with or without n elevtion in serum theophylline level (see WARNINGS AND PRECAUTIONS, Neurologic). When these products re dministered concomitntly, prothrombin time, Interntionl Normlized Rtio (INR), or other suitble cogultion tests should be monitored closely, especilly in elderly ptients. No dosge djustment for levofloxcin ppers to be required when co-dministered with zidovudine. Drug-Food Interctions my be tken with or without food. Drug-Herb Interctions Interctions with herbl products hve not been estblished. Drug-Lbortory Interctions Some quinolones, including levofloxcin, my produce flse-positive urine screening results for Sndoz Pge 16 of 60

17 opites using commercilly vilble immunossy kits. Confirmtion of positive opite screens by more specific methods my be necessry. DOSAGE AND ADMINISTRATION Dosing Considertions The dosge of Sndoz tblets for ptients with norml renl function (i.e., Cl Cr > 80 ml/min) is described in the following dosing chrt. For ptients with ltered renl function (i.e., Cl Cr 80 ml/min), see Ptients with Impired Renl Function subsection. Recommended Dose nd Dosge Adjustment Ptients with Norml Renl Function Infection* Dose Freq. Durtion** Acute Bcteril Excerbtion of Chronic Bronchitis 500 mg 750 mg q24h q24h 7 dys 5 dys Comm.-Acquired Pneumoni 500 mg 750 mg*** q24h q24h 7-14 dys (10-14 dys for severe infections) 5 dys Sinusitis 500 mg 750 mg**** q24h q24h dys 5 dys Nosocomil Pneumoni 750 mg q24h 7-14 dys Uncomplicted SSSI 500 mg q24h 7-10 dys Complicted SSSI 750 mg q24h 7-14 dys Chronic Bcteril Prosttitis 500 mg q24h 28 dys Complicted UTI 250 mg 750 mg q24h q24h 10 dys 5 dys Acute Pyelonephritis 250 mg 750 mg q24h q24h 10 dys 5 dys Uncomplicted UTI 250 mg q24h 3 dys * DUE TO THE DESIGNATED PATHOGENS (see INDICATIONS AND CLINICAL USE). ** TOTAL THERAPY DURATION. When pproprite, ptients my be converted from levofloxcin injection to n equivlent dose of levofloxcin tblets. *** Efficcy of this lterntive regimen hs only been documented for infections cused by penicillin-susceptible Streptococcus pneumonie, Hemophilus influenze, Hemophilus prinfluenze, Mycoplsm pneumonie, Chlmydi pneumonie, nd Legionell pneumophil. **** The efficcy of regimen of 750 mg dily for 5 dys hs been demonstrted to be non-inferior to regimen of 500 mg dily for 10 dys. The 750 mg dily 5-dy regimen hs not been compred to regimen of 500 mg dily for dys. The efficcy of this lterntive regimen hs been documented for infections cused by Escherichi coli, Klebsiell pneumonie, nd Proteus mirbilis. Efficcy ginst infections cused by Enterococcus feclis, Enterobcter cloce, or Pseudomons eruginos hs not been demonstrted with this regimen. Ptients with Impired Renl Function On the bsis of the ltered levofloxcin disposition phrmcokinetics in subjects with impired renl function, dose djustment is recommended for ptients with impired renl function s given below (see WARNINGS AND PRECAUTIONS, Renl; ACTION AND CLINICAL PHARMACOLOGY, Specil Popultions nd Conditions, Renl Insufficiency nd DETAILED PHARMACOLOGY, Fctors Influencing the Phrmcokinetics, Specil Popultions, Renl Insufficiency). Sndoz Pge 17 of 60

18 Dosing recommendtions for renlly impired ptients re bsed on dt collected from clinicl sfety nd phrmcokinetic study in renlly impired ptients treted with single 500 mg orl dose of levofloxcin. There is no clinicl experience vilble in this ptient popultion for the 250 mg dose or 750 mg dose. Phrmcokinetic modelling ws used to determine recommended dosing regimen which would provide equivlent drug exposures for which clinicl efficcy hs been demonstrted. The potentil effects of levofloxcin ssocited with possible incresed serum/tissue levels in renl impired ptients, such s effect on QTc intervl, hve not been studied. Renl Sttus Initil Dose Subsequent Dose Acute Sinusitis/Acute Bcteril Excerbtion of Chronic Bronchitis/Community Acquired Pneumoni/Uncomplicted SSSI/Chronic Bcteril Prosttitis Cl Cr from 50 to 80 ml/min No dosge djustment required Cl Cr from 20 to 49 ml/min 500 mg 250 mg q24h Cl Cr from 10 to 19 ml/min 500 mg 250 mg q48h Hemodilysis 500 mg 250 mg q48h CAPD 500 mg 250 mg q48h Complicted UTI/Acute Pyelonephritis Cl Cr 20 ml/min No dosge djustment required Cl Cr from 10 to 19 ml/min 250 mg 250 mg q48h Complicted SSSI/Nosocomil Pneumoni/Community Acquired Pneumoni/Acute Bcteril Excerbtion of Chronic Bronchitis/Acute Sinusitis/Complicted UTI/Acute Pyelonephritis Cl Cr from 50 to 80 ml/min No dosge djustment required Cl Cr from 20 to 49 ml/min 750 mg 750 mg q48h Cl Cr from 10 to 19 ml/min 750 mg 500 mg q48h Hemodilysis 750 mg 500 mg q48h CAPD 750 mg 500 mg q48h Uncomplicted UTI No dosge djustment required Cl Cr = cretinine clernces CAPD = chronic mbultory peritonel dilysis When only the serum cretinine is known, the following formul my be used to estimte cretinine clernce. Men: Women: Cretinine Clernce (ml/min) = Weight (kg) x (140- ge) x 1.2 serum cretinine (mcmol/l) 0.85 x the vlue clculted for men. The serum cretinine should represent stedy stte of renl function. Missed Dose More thn the prescribed dose of levofloxcin should not be tken, even if dose is missed. Administrtion Sndoz cn be dministered without regrd to food. Doses should be dministered t lest 2 hours before or 2 hours fter ntcids contining clcium, mgnesium, luminum, Sndoz Pge 18 of 60

19 sucrlfte, metl ctions such s iron, multi-vitmin preprtions with zinc, or products contining ny of these components. OVERDOSAGE In the event of n cute overdosge, ctivted chrcol my be dministered to id in the removl of unbsorbed drug. Generl supportive mesures re recommended. The ptient should be observed, including ECG monitoring (see ACTION AND CLINICAL PHARMACOLOGY, Phrmcodynmics, Studies Mesuring Effects on QT nd Corrected QT (QTc) Intervls), nd pproprite hydrtion mintined. Tretment should be supportive. is not efficiently removed by hemodilysis or peritonel dilysis. exhibits low potentil for cute toxicity. Mice, rts, dogs nd monkeys exhibited the following clinicl signs fter receiving single high dose of levofloxcin: txi, ptosis, decresed locomotor ctivity, dyspne, prostrtion, tremors, nd convulsions. Doses in excess of 1500 mg/kg orlly nd 250 mg/kg IV produced significnt mortlity in rodents. For mngement of suspected drug overdose, contct your regionl Poison Control Centre. ACTION AND CLINICAL PHARMACOLOGY Mechnism of Action is synthetic brod-spectrum ntibcteril gent for orl nd intrvenous dministrtion. is the L-isomer of the rcemte, ofloxcin, quinolone ntibcteril gent. The ntibcteril ctivity of ofloxcin resides primrily in the L-isomer. The mechnism of ction of levofloxcin nd other quinolone ntibcterils involves inhibition of bcteril topoisomerse II (DNA gyrse) nd topoisomerse IV. Topoisomerses re essentil in controlling the topologicl stte of DNA, nd re vitl for DNA repliction, trnscription, repir nd recombintion. Fluoroquinolones, including levofloxcin, differ in chemicl structure nd mode of ction from other clsses of ntimicrobil gents, such s β-lctm ntibiotics, minoglycosides, nd mcrolides. Therefore, microorgnisms resistnt to these ltter clsses of ntimicrobil gents my be susceptible to fluoroquinolones. For exmple, β-lctmse production nd ltertions in penicillin-binding proteins hve no effect on levofloxcin ctivity. Conversely, microorgnisms resistnt to fluoroquinolones my be susceptible to other clsses of ntimicrobil gents. Phrmcodynmics Studies Mesuring Effects on QT nd Corrected QT (QTc) Intervls Two studies hve been conducted to ssess specificlly the effect of levofloxcin on QT nd corrected QT (QTc) intervls in helthy dult volunteers. In dose escltion study (n=48) where the effect on verge QTc, fter single doses of 500, 1000, nd 1500 mg of levofloxcin, ws mesured between the bseline QTc (clculted s the verge QTc mesured 24, 20, Sndoz Pge 19 of 60

20 16 hours nd immeditely before tretment) nd the verge post-dose QTc intervl (clculted from mesurements tken every hlf hour for two hours nd t 4, 8, 12 nd 24 hours fter tretment), n effect on the verge QTc (Bzett) ws 1.84, 1.55 nd 6.40 msec, respectively. In study which compred the effect of 3 ntimicrobils (n=48) where the difference ws mesured between the bseline QTc (clculted s the verge QTc mesured 24, 20, 16 hours nd immeditely before tretment) nd the verge post-dose QTc intervl (clculted from mesurements tken every hlf hour for four hours nd t 8, 12 nd 24 hours fter tretment), n effect on the verge QTc ws n increse of 3.58 msec fter the 1000 mg dose of levofloxcin. The men increse compred to bseline of QTc t Cmx in these two trils ws 7.82 msec nd 5.32 msec fter single 1000 mg dose. In these trils, no effect on QT intervls compred to plcebo ws evident t ny of the doses studied. The clinicl relevnce of the results of these studies is not known (see DETAILED PHARMACOLOGY, Humn Phrmcology, Studies Mesuring the Effects on QT nd Corrected QT (QTc) Intervls). Phrmcokinetics The men (± SD) phrmcokinetic prmeters of levofloxcin determined under single nd stedy-stte conditions following orl (PO) or intrvenous (IV) doses of levofloxcin re summrized in Tble 1.5. Sndoz Pge 20 of 60

21 Tble 1.5: Summry of Phrmcokinetic Prmeters (men ± SD) Regimen N Cmx (mcg/ml) Single dose 250 mg PO ± mg PO * ± mg IV ± mg PO cc ± mg IV c ± 1.2 b Multiple dose 500 mg q24h PO 500 mg q24h IV 500 mg or 250 mg q24h IV ptients with bcteril infections d 750 mg q24h PO cc 750 mg q24h IV c ± ± ± 4.0 i 8.6 ± ± 0.91 b Tmx (h) 1.6 ± ± ± ± 0.7 ND 1.1 ± 0.4 ND ND 1.4 ± 0.5 ND AUC j (mcg h/ml) 27.2 ± ± ± ± ± ± 6.7 x 54.6 ± 11.1 x 72.5 ± 51.2 i,x 90.7 ± ± 0.8 x 500 mg PO single dose, effects of gender nd ge: mle e femle f young g elderly h ± ± ± ± ± ± ± ± ± ± ± ± mg PO single dose, ptients with renl insufficiency: Cl Cr ml/min ± ± ± 11.8 Cl Cr ml/min ± ± ± 62.6 Cl Cr < 20 ml/min ± ± ± 72.5 Hemodilysis ± ± 2.2 ND CAPD ± ± 1.1 ND 750 mg IV single dose nd multiple dose, ptients with renl insufficiency: Single dose - Cl Cr ml/min k ± 3.6 ND 128 ± 37 Multiple q24h dose - Cl Cr ml/min k ± 3.2 ND 145 ± 36 helthy mles yers of ge; b 60 min infusion for 250 mg nd 500 mg doses, 90 min infusion for 750 mg dose; c helthy mle subjects yers of ge; cc helthy mle subjects yers of ge; d including 500 mg q48h for 8 ptients with moderte renl impirment (Cl Cr ml/min) nd infections of the respirtory trct or skin; CL/F (ml/min) 156 ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± 8 ND ND 104 ± ± 20 Vd/F (L) ND ND 90 ± ± ± ± ± ± ± ± ± ± ± ± 19 ND ND ND ND ND 62.7 ± ± 16.9 e helthy mles yers of ge; f helthy femles yers of ge; g young helthy mle nd femle subjects yers of ge; h helthy elderly mle nd femle subjects yers of ge; i dose-normlized vlues (to 500 mg dose), estimted by popultion phrmcokinetic modelling; j AUC for 0- reported, unless otherwise specified; k mle nd femle subjects yers of ge; x AUC 0-24 h ; * Absolute biovilbility; F = 0.99 ± 0.08 from 500 mg tblet nd F = 0.99 ± 0.06 from 750 mg tblet. ND = Not Determined t ½ (h) 7.3 ± ± ± ± ± ± ± 0.8 ND 8.8 ± ± ± ± ± ± ± ± ± 5 76 ± ± ± ± 2.0 Cl r (ml/min) 142 ± ± ± ± 28 ND 116 ± ± 28 ND 116 ± 28 ND 126 ± ± ± ± ± 8 26 ± ± 3 ND ND ND ND Sndoz Pge 21 of 60

22 Absorption: is rpidly nd essentilly completely bsorbed fter orl dministrtion. Pek plsm concentrtions re usully ttined 1 to 2 hours fter orl dosing. The bsolute biovilbility of 500 mg tblet nd 750 mg tblet of levofloxcin is pproximtely 99% in both cses, demonstrting complete orl bsorption of levofloxcin. phrmcokinetics re liner nd predictble fter single nd multiple orl dosing regimens. Stedy-stte conditions re reched within 48 hours following 500 mg or 750 mg once-dily dosge regimen. The pek nd trough plsm concentrtions ttined following multiple once-dily orl dosge regimens were pproximtely 5.7 mcg/ml nd 0.5 mcg/ml fter the 500 mg doses, nd 8.6 mcg/ml nd 1.1 mcg/ml fter the 750 mg doses, respectively. There ws no cliniclly significnt effect of food on the extent of bsorption of levofloxcin. Orl dministrtion with food slightly prolongs the time to pek concentrtion by pproximtely 1 hour, nd slightly decreses the pek concentrtion by pproximtely 14%. Therefore, levofloxcin cn be dministered without regrd to food. Distribution: The men volume of distribution of levofloxcin generlly rnges from 74 to 112 L fter single nd multiple 500 mg or 750 mg doses, indicting widespred distribution into body tissues. reches its pek levels in skin tissues (11.7 mcg/g for 750 mg dose) nd in blister fluid (4.33 mcg/g for 500 mg dose) t pproximtely 3-4 hours fter dosing. The skin tissue biopsy to plsm AUC rtio is pproximtely 2. The blister fluid to plsm AUC rtio is pproximtely 1, following multiple once-dily orl dministrtion of 750 mg nd 500 mg levofloxcin to helthy subjects, respectively. lso penetrtes into lung tissues. Lung tissue concentrtions were generlly 2- to 5-fold higher thn plsm concentrtions, nd rnged from pproximtely 2.4 to 11.3 mcg/g over 24-hour period fter single 500 mg orl dose. is 24 to 38% bound to serum proteins cross ll species studied. binding to serum proteins is independent of the drug concentrtion. Metbolism: is stereochemiclly stble in plsm nd urine, nd does not invert metboliclly to its enntiomer, D-ofloxcin. undergoes limited metbolism in humns, nd is primrily excreted s unchnged drug (87%) in the urine within 48 hours. Excretion: The mjor route of elimintion of levofloxcin in humns is s unchnged drug in the urine. The men terminl plsm elimintion hlf-life of levofloxcin rnges from pproximtely 6 to 8 hours following single or multiple doses of levofloxcin given orlly or intrvenously. Specil Popultions nd Conditions Peditrics: The phrmcokinetics of levofloxcin in peditric ptients hve not been studied. Geritrics: There re no significnt differences in levofloxcin phrmcokinetics between young nd elderly subjects when the subjects differences in cretinine clernce re tken into considertion. Drug bsorption ppers to be unffected by ge. dose djustment bsed on ge lone is not necessry. Gender: There re no significnt differences in levofloxcin phrmcokinetics between mle nd femle subjects when the differences in cretinine clernce re tken into considertion. Sndoz Pge 22 of 60