ZYVOXID MRSA susceptibility ZYVOXID Tissue penetration Zyvoxid anemi

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					                                                                                                                                                                              ZYVOXID ® Efficacy in cSSTI and NP

                                    PUBLICATION                                                             NUMBER OF                          DESIGN                     TREATMENT                                                  MAIN RESULTS

                        Efficacy and safety of linezolid                Itani K, Weigelt J,           ITT pop, 1052 pts                  Randomised, open-              • Linezolid at 600mg         Efficacy results
                        versus vancomycin for the treatment            Stevens D et al.              • 537 linezolid                    label, controlled,               IV/PO q12h                 PP pop:
                                                                       Clin Microbiol Infect 2008;                                      multicentre, phase 4           • Vancomycin 15mg/kg IV      • Linezolid was at least as effective as vancomycin at EOS (7–10 days after
                        of complicated skin and soft-tissue            14: Abstract O80.             • 515 vancomycin                   study, to determine the          q12h, adjusted for CRCL      last dose) with clinical success rates of 83.2% vs 79.5%, respectively; p=ns,
                        infections proven to be due to                                                                                  non-inferiority of linezolid                                  demonstrating that lin ezolid was not inferior to vancomycin
                        methicillin-resistant Staphylococcus                                         mITT pop, 654 pts                  vs. vancomycin for the
                                                                                                                                                                                                    • Superiority was not demonstrated
                        aureus.                                                                      • 329 linezolid                    treatment of cSSTIs
                                                                                                                                        proven to be due to MRSA                                    MSR:
                                                                                                     • 325 vancomycin
                                                                                                                                                                                                    • At EOS: linezolid 74.4% vs vancomycin 68.4% p=ns
                                                                                                                                                                                                    • At EOT: linezolid 85.8% vs vancomycin 69.3% p=0.000
                                                                                                     PP pop, 452 pts                    A nested superiority
                                                                                                     • 235 linezolid                    analysis was included                                       • Mean duration of IV treatment was shorter for linezolid-treated pts at 5.4 days
                                                                                                     • 217 vancomycin                                                                                 compared with 10.3 days for vancomycin treated pts
                                                                                                                                                                                                    Safety results
                                                                                                     All pts with defined, proven                                                                    • Both linezolid and vancomycin were generally well tolerated
                                                                                                     MRSA cSSTI                                                                                     • The three most common side-effects were gastrointestinal,
                                                                                                                                                                                                      infection/infestation and skin/subcutaneous tissue disorder

                        Linezolid versus vancomycin in                 Weigelt J, Itani K,           ITT pop, 1180 adult pts            Randomized, open-label,        • Oral or IV linezolid       Efficacy results
                                                                       Stevens D, et al.                                                comparator-controlled,           600mg q12h                 ITT pop at TOC (7–14 days after EOT):
                        treatment of complicated skin and              Antimicrob Agents
                                                                                                     with suspected or proven           multicentre, multinational     • IV vanco. 1g q12h
                        soft-tissue infections.                                                      Gram-positive cSSTIs                                                                           • CCR: 92.2% with linezolid Tt vs 88.5% with vancomycin p=0.057
                                                                       Chemother                                                        trial to determine if                                       • The primary endpoint in this population (superiority of clinical cure in the ITT
                                                                       2005; 49: 2260–66.            requiring hospitalisation:         linezolid is superior                                         population) was not met
                                                                                                     • 592 linezolid                    to vancomycin for the
                                                                                                                                        treatment of cSSTIs                                         Safety results
                                                                                                     • 588 vancomycin
                                                                                                                                                                                                    • NS difference in frequency of DRAEs
                                                                                                                                                                                                    • NS difference in the frequency of adverse events leading to discontinuation
                                                                                                                                                                                                      5.1% vs 5.8%; p=0.588

                                                                                                                                                                                                    • Results from sub-analyses suggest the need for definitive study in culture-proven
                                                                                                                                                                                                      MRSA cSSTIs

                        Linezolid compared with teicoplanin            Wilcox M,                     ITT pop, 430 pts with NP           Randomized, controlled,        • IV or oral linezolid       Efficacy results
                                                                       Nathwani D,                                                      open-label, multicentre,         600mg q12h                 ITT pop
                        for the treatment of suspected or              Dryden M.
                                                                                                     (109 pts) and cSSTI (228 pts):     Phase IIIb trial               • IV or IM teico. as
                        proven Gram-positive infections.                                             • 215 linezolid                                                                                • CCR all infections: 95.5% linezolid vs 87.6% teicoplanin p=0.005
                                                                       J Antimicrob Chemother                                                                            approved by local          • CCR NP: 96.2% linezolid vs 92.9% vancomycin p=ns
                                                                       2004; 53: 335–44.             • 215 teicoplanin                                                   prescribing information    • CCR cSSTI: 96.6% linezolid vs 92.8% vancomycin p=ns
                                                                                                                                                                                                    Safety results
                                                                                                                                                                                                    • Most AEs mild-to-moderate and resolved after Tt
                                                                                                                                                                                                    • ≥ 1 DRAE 56.3% linezolid vs 51.2% teicoplanin p=ns
                                                                                                                                                                                                    • GI disorders 13% linezolid vs 1.9% teicoplanin p=0.001
                                                                                                                                                                                                    • Nervous system 9% linezolid vs 4% teicoplanin p=0.03
                                                                                                                                                                                                    • < 5% in either group discontinued Tt for AEs
                                                                                                                                                                                                    • Hæmatological disorders similar; 3 discontinuation linezolid

                        Clinical cure and survival in                  Kollef MH, Rello J,           ITT pop, 544 adult pts with        Retrospective subset           • IV linezolid 600mg q12h    Efficacy results
                        Gram-positive ventilator-associated            Cammarata SK et al.                                              analysis of two                  + aztreo 1–2g q8h          ITT VAP
                                                                       Intensive Care Med 2004;
                                                                                                     suspected Gram-positive VAP        prospective double-blind       • IV vanco. 1g q12h
                        pneumonia: retrospective analysis of                                         including 91 patients with                                                                     • CCR 45% linezolid vs 37% vancomycin p=ns
                                                                       30: 388–94.                                                      randomised trials                + aztreo 1–2g q8h
                        two double-blind studies comparing                                           MRSA VAP:                                                                                      MRSA VAP
                        linezolid with vancomycin.                                                   • 44 linezolid                                                                                 • CCR 62% linezolid vs 21% vancomycin p=0.001
                                                                                                     • 47 vancomycin

                        Efficacy and tolerability of linezolid          Chen YS, Lee SC, Kim WJ.      166 patients at 27 sites in        Open-label, single-arm,        • Linezolid IV at 600mg      Efficacy results
                        in treating severe skin and soft-tissue        J Form Med Assoc 2004;        7 countries                        multicentre study to             q12h then linezolid PO     ITT pop/CE
                                                                       103(5): 349–54.                                                  evaluate the efficacy and         600mg q12h                 • Clinical success rate was approx 93% at EOT and TOC in both ITT
                        infections caused by Gram-positive                                                                              tolerability of linezolid in                                  and CE populations
                        pathogens.                                                                                                      patients from the Asia
                                                                                                                                        Pacific region with severe                                   mITT pop ME
                                                                                                                                        Gram-positive skin and                                      • Microbiological success rate at TOC was 88.9% in the mITT population
                                                                                                                                        soft tissue infections                                        and 93.8% in the ME population
                                                                                                                                                                                                    Safety results
                                                                                                                                                                                                    • The most commonly reported treatment-emergent adverse effects were
                                                                                                                                                                                                      nausea (13%), anaemia (7%) and vomiting (5%)

                        Linezolid versus vancomycin:                   Wunderink RG, Rello J,        ITT pop, 1019 adult pts            Retrospective subset           • IV linezolid 600mg q12h    Efficacy results
                                                                       Cammarata SK et al.           with suspected                     analysis of data from two        + aztreo 1-2g q8h          ITT NP
                        Analysis of two double-blind studies           Chest 2003; 124: 1789–97.                                        prospective, randomised,       • IV vanco. 1g q12h
                        of patients with methicillin-resistant                                       Gram-positive NP, including                                                                    • CCR 53% linezolid vs 52% vancomycin p=ns
                                                                                                                                        double-blind, registration       + aztreo 1-2g q8h
                        Staphylococcus aureus nosocomial                                             160 pts with MRSA NP               studies                                                     MRSA NP
                        pneumonia.                                                                                                                                                                  • CCR : 59% linezolid vs 36% vancomycin p<0.01

                        Continuation of a randomised,                  Wunderink RG,                 ITT pop, 623 adult pts with NP:    Continuation of a              • IV linezolid 600mg q12h    Efficacy results
                        double-blind, multicentre study of             Cammarata SK,                 • 321 linezolid                    randomised, double-blind,        + aztreo 1-2g q8h          CE pop
                                                                       Oliphant TH et al.                                               registration study             • IV vanco. 1g q12h          • CCR equivalent 67.9% linezolid vs 64.9% vancomycin p=ns
                        linezolid versus vancomycin in the             Clin Ther 2003; 25: 980–92.   • 302 vancomycin                                                    + aztreo 1-2g q8h          • MSR 61.8% linezolid vs 53.2% vancomycin p=ns
                        treatment of patients with nosocomial                                        CE pop, 339 pts:
                        pneumonia.                                                                   • 168 linezolid                                                                                Safety results
                                                                                                                                                                                                    • NS differences between 2 groups in Rt of AEs, seriousness or discontinuation of Tt
                                                                                                     • 171 vancomycin                                                                               • Drug related AEs 14% of pts from each group
                                                                                                                                                                                                    • SAEs occurred in 3 pts on linezolid and 6 on vancomycin
                                                                                                                                                                                                    • Haematology NS different between Tt groups

                        Linezolid versus vancomycin for                Stevens DL, Herr D,           ITT pop, 460 pts with              Randomised,                    • IV linezolid 600mg q12h    Efficacy results
                                                                       Lampiris H et al.             presumed MRSA infection:           open-label, multinational,     • IV vanco. 1g q12h          • NS differences between groups in different pops
                        the treatment of methicillin-resistant         Clin Infect Dis                                                  multicentre trial
                        Staphylococcus aureus infections.                                            • 240 linezolid                                                                                Evaluable MRSA-ITT pop
                                                                       2002; 34: 1481–90.                                                                                                           • CCR 73.2% linezolid and 73.1% vancomycin p=ns
                                                                                                     • 220 vancomycin
                                                                                                                                                                                                    • MSR 58.9% linezolid and 63.2% vancomycin p=ns
                                                                                                     Evaluable MRSA-ITT pop,
                                                                                                                                                                                                    Safety results
                                                                                                     116 pts, met all study criteria,                                                               • Rts of SAEs and deaths between groups: NS differences
                                                                                                     no prohibited antibiotics,                                                                     • < 5% in either group discontinued Tt for AEs
                                                                                                     received adequate study Tt                                                                     • Higher proportion of pts with linezolid had ≥1 DRAE (mainly GI)
                                                                                                     (≥ 7 days and 13 doses) and                                                                    • More GI disorders linezolid than vancomycin e.g. diarrhoea p=0.004
                                                                                                     returned for follow-up                                                                         • No clinically relevant MAO inhibitor–related events
                                                                                                     • 56 linezolid                                                                                 • Serum chemical and haematological assays similar
                                                                                                     • 60 vancomycin                                                                                • Thrombocytopenia 10% linezolid treated and 2.9% vancomycin p=0.003
                                                                                                                                                                                                    • No drug-related bleeding events

                        Linezolid (PNU-100766) versus                  Rubinstein E,                 ITT pop, 396 adult pts             Multinational,                 • IV linezolid 600mg q12h    Efficacy results
                                                                       Cammarata SK,                 with suspected NP:                 randomised, double-blind,         + aztreo 1-2g q8h         CE pop
                        vancomycin in the treatment of                 Oliphant TH et al.                                               controlled trial               • IV vanco. 1g q12h
                        hospitalised patients with nosocomial                                        • 203 linezolid                                                                                • CCR equivalent 66.4% linezolid vs 68.1% vancomycin p=ns
                                                                       Clin Infect Dis                                                                                   + aztreo 1-2g q8h
                        pneumonia: a randomised, double-blind,         2001; 32: 402–12.             • 193 vancomycin                                                                               ME pop
                        multicentre study.                                                           CE pop, 204 pts:                                                                               • MSR 67.9% linezolid vs 71.8% vancomycin p=ns
                                                                                                                                                                                                    • No differences seen in the nb of TFs between groups
                                                                                                     • 108 linezolid
                                                                                                     • 96 vancomycin                                                                                Safety results
                                                                                                                                                                                                    • 70.4% linezolid and 74.1% vanco. with at least one 1 AE
                                                                                                     ME pop, 94 pts:                                                                                • Most AEs mild-to-moderate
                                                                                                     • 54 linezolid                                                                                 • Diarrhoea most common AE occurring in more than 1% of patients both groups
                                                                                                     • 40 vancomycin                                                                                • AEs leading to discontinuation of Tt 6.4% linezolid and 10.4% vanco.
                                                                                                                                                                                                    • No clinically relevant statistically significant differences between Tts for any
                                                                                                                                                                                                      haematology assay

                                                                                                                                                                                                   ZYVOXID ® Tissue penetration
                                    PUBLICATION                                                             NUMBER OF                          DESIGN                     TREATMENT                                                  MAIN RESULTS

                        Pharmacokinetics and intrapulmonary            Boselli E, Breilh D,          16 critically ill adult pts        Prospective, open-label        1h IV infusion               Results
                                                                       Rimmelé T et al.                                                 study                          linezolid 600mg bid as       • Linezolid ELF penetration ≈100%
                        concentrations of linezolid administered
                                                                       Crit Care Med 2005; 33(7):
                                                                                                     with late-onset VAP                                               antistaphylococcal
                        to critically ill patients with                                                                                                                                             • Linezolid concentrations plasma and ELF >MIC GP bacteria – including MRSA
                                                                       1529–33.                                                                                        empirical therapy
                        ventilator-associated pneumonia.                                                                                                               + antipseudomonal
                                                                                                                                                                       ß-lactam (ceftazidime or
                                                                                                                                                                       + amikacin

                        Penetration of linezolid into soft-tissues     Dehghanyar P,                 10 healthy volunteers              Single-centre,                 1x 600mg IV dose then        Results
                        of healthy volunteers after single and         Bürger C,                                                        pharmacokinetic study          oral linezolid 600mg q12h    • After single IV dose AUC0-8 soft tissues >plasma; p=0.007 adipose tissue,
                                                                       Zeitlinger M et al.
                        multiple doses.                                Antimicrob Agents
                                                                                                                                                                                                      p=0.02 skeletal muscle; therefore AUCtissue to AUCfree plasma >1
                                                                       Chemother                                                                                                                    • Complete equilibrium linezolid plasma and ISF after multiple doses mean
                                                                       2005; 49(6): 2367–71.                                                                                                          ratios AUCtissue to AUCfree plasma ≈ 1
                                                                                                                                                                                                    • Ratios AUC from 0-24h free linezolid in tissues to MIC50-100 for pathogens
                                                                                                                                                                                                      with MIC 2-4 mg/l

                        Pharmacokinetics and tissue                    Gee T, Ellis R,               6 healthy volunteers               Single-centre,                 Oral linezolid 600mg q12h    Results
                        penetration of linezolid following             Marshall G et al.                                                pharmacokinetic study                                       • After 5th oral dose mean plasma Cmax linezolid 18.3μg/ml Tmax 0.7h
                                                                       Antimicrob Agents
                        multiple oral doses.                           Chemother
                                                                                                                                                                                                    • Mean linezolid inflammatory fluid penetration 3h
                                                                       2001; 45(6): 1843 –6.                                                                                                        • Mean t1/2 from plasma 4.9h
                                                                                                                                                                                                    • Mean t1/2 from inflammatory fluid 5.7h
                                                                                                                                                                                                    • AUClast 107.5 μg.h/ml
                                                                                                                                                                                                    • AUC0-infinity140.3 μg.h/ml
                                                                                                                                                                                                    • Penetration into inflammatory fluid 104%
                                                                                                                                                                                                    • Inflammatory fluid mean peak concentration 16.4 μg/ml 3h after final dose

                                                                                                                                                                                            ZYVOXID ® MRSA susceptibility
                                    PUBLICATION                                                             NUMBER OF                          DESIGN                     TREATMENT                                                  MAIN RESULTS

                        Oxazolidinone susceptibility patterns          Ross JE, Fritsche TR,         24 363 Gram-positive               In vitro microbiology                                       Results
                                                                       Sader HS et al.                                                  study; susceptibility                                       • No trend towards linezolid resistance noted
                        for 2005: International report from
                                                                       Int J Antimicrob Agents
                                                                                                     strains isolated over the four     testing against a range
                        the ZYVOX® Annual Appraisal of                                               years of the ZAAPS Program                                                                     • The modal MIC for SA (1mg/l) <2005 vs 2002-2004
                                                                       2007; 29: 295 –301.                                              of antimicrobial agents                                     • Linezolid continued good activity against Enterococci
                        Potency and Spectrum Study.                                                                                     active against GP bacteria

                        Activity of linezolid against 3251 strains     Jones RN, Stilwell            3 251 strains Gram-positive        In vitro microbiology                                       Results
                        of uncommonly isolated Gram-positive           MG, Hogan PA et al.                                              study; testing of activity                                  • All but one species or serogroups tested were completely (100%) linezolid
                                                                       Antimicrob Agents
                                                                                                     organisms                          by reference MIC
                        organisms: report from the SENTRY                                            (32 different species)                                                                           susceptible
                                                                       Chemother                                                        methodology                                                 • MIC50: 0.5 to 1.0 μg/ml
                        antimicrobial surveillance program.            2007; 51: 1491–93.                                                                                                           • MIC90: 1 to 2 μg/ml
                                                                                                                                                                                                    • Only one strain of Streptococcus oralis linezolid resistant

                        Contemporary causes of skin and                Moet GJ, Jones RN,            12 920 isolates causing            A multicentre, longitudinal                                 Results
                        soft-tissue infections in North America,       Biedenbach DJ et al.                                             tracking system that                                        • SA most frequently isolated pathogen in all geographical areas
                                                                       Diagn Microbiol Infect Dis
                                                                                                     pyogenic wound infections          since 1997 has globally
                        Latin America, and Europe: Report from                                                                                                                                      • % of MRSA: NA 35.9%, LA 29.4%, EU 22.8%
                                                                       2007; 57: 7–13.                                                  monitored antimicrobial                                     • Increases during 7-year period NA and LA, relatively unchanged EU;
                        the SENTRY antimicrobial surveillance                                                                           resistance patterns                                           (24.3% 1998 vs 22.4% 2004)
                        program (1998-2004).                                                                                                                                                        • Linezolid and vanco. remain highly effective in vitro in all regions for
                                                                                                                                                                                                      SA from SSTIs

    C Zyvoxid Pfizer
           Antibakterielt middel.
           ATC-nr.: J01X X08

           TABLETTER, filmdrasjerte 600 mg: Hver tablett inneh.: Linezolid 600 mg, hjelpestoffer. Fargestoff: Rødt jernoksid (E 172).              Egnede tiltak bør institueres. Bruk av antibiotika kan noen ganger gi overvekst av ikke-følsomme organismer, f.eks. candidia-
           INFUSJONSVÆSKE, oppløsning 2 mg/ml: 1 ml inneh.: Linezolid 2 mg, glukosemonohydrat tilsv. 45,7 mg glukose, natrium-                    sis. Dersom superinfeksjon oppstår under behandling, må forhåndsregler tas. Sikkerhet og effekt av linezolid administrert i
           sitrat, sitronsyre, saltsyre, natriumhydroksid, vann til injeksjon. Indikasjoner: Behandling av nosokomial pneumoni og pneu-           perioder lengre enn 28 dager er ikke tilstrekkelig undersøkt. Pasienter bør informeres om risikoen for svimmelhet under
           moni oppstått utenfor sykehus, når en vet eller mistenker at de er forårsaket av grampositive bakterier følsomme for linezolid.        behandlingen, og rådes til ikke å kjøre bil eller betjene maskiner dersom de påvirkes. Kramper er rapportert under behandling.
           Hvorvidt preparatet er egnet behandling, bør bedømmes ut fra mikrobiologiske prøver eller informasjon om prevalens av                  I de fleste tilfellene er det rapportert om kramper eller risiko for kramper i anamnesen. Pasienter bør rådes til å informere legen
           resistens blant grampositive bakterier. Linezolid er ikke aktivt mot infeksjoner forårsaket av gramnegative patogener. Spesi-          dersom de har hatt kramper tidligere. Interaksjoner: Økning i blodtrykk forårsaket av pseudoefedrin og fenylpropanolamin
           fikk behandling mot gramnegative organismer må initieres hvis gramnegative patogener påvises eller mistenkes. Indisert for              kan forsterkes av linezolid. Samtidig administrering med enten pseudoefedrin eller fenylpropanolamin resulterte i gjennom-
           kompliserte hud- og bløtdelsinfeksjoner bare når det er påvist ved mikrobiologiske tester at infeksjonen er forårsaket av              snittlig økning i systolisk blodtrykk i størrelsesorden 30-40 mm Hg. Når linezolid gis samtidig med legemidler med karkon-
           følsomme grampositive bakterier. Linezolid er ikke aktivt mot infeksjoner forårsaket av gramnegative patogener. Ved hud- og            traherende effekt, inkl. dopaminerge midler, bør dosen titreres nøye. Kan tas sammen med dekstrometorfan. Overdrevet in-
           bløtdelsinfeksjoner en vet eller mistenker kan være forårsaket av kombinert infeksjon med gramnegative og grampositive                 ntak av mat og drikke med et høyt tyramininnhold bør unngås. Tilleggsbehandling med warfarin gir 10% reduksjon i
           patogener skal linezolid kun brukes dersom det ikke finnes andre behandlingsalternativ tilgjengelig. Behandling mot gram-               gjennomsnittlig maks. INR. Graviditet/Amming: Overgang i placenta: Ukjent. Skal ikke brukes under graviditet. Overgang i
           negative organismer må da initieres samtidig. Linezolidbehandling bør kun initieres i sykehus under veiledning av relevante            morsmelk: Kan gå over. Amming frarådes under behandling. Bivirkninger: Vanlige (≥1/100 til <1/10): Gastrointestinale:
           spesialister, som spesialist i infeksjonssykdommer eller mikrobiolog. Dosering: Behandling kan startes opp med infusjons-              Diaré, kvalme, oppkast. Infeksiøse: Candidainfeksjon (særlig oral og vaginal candidiasis) eller annen soppinfeksjon. Lever/
           væske eller tabletter. Det er ikke nødvendig med dosejustering ved overgang fra injeksjonsvæske til tabletter. Behandlings-            galle: Unormale leverfunksjonstester. Nevrologiske: Hodepine, smaksforstyrrelser (metallisk smak). Undersøkelser: Forhøyet
           varighet avhenger av patogenet, infeksjonssted og alvorlighet, samt pasientens kliniske respons. Maks. behandlingsvarighet             ASAT, ALAT, LDH, alkalisk fosfatase, BUN, kreatinkinase, lipase, amylase og ikke-fastende glukose. Reduksjon i total
           er 28 dager. Det er ikke nødvendig med økning i anbefalt dose eller varighet av behandlingen for infeksjoner med samtidig              protein, albumin, natrium eller kalsium. Forhøyet eller redusert kalium eller bikarbonat. Nøytrofili eller eosinofili. Reduksjon
           bakteriemi. Doseanbefalinger: Nosokomial pneumoni og pneumoni oppstått utenfor sykehus: 600 mg 2 ganger daglig i 10-14                 i hemoglobin, hematokrit, eller antall røde blodceller. Redusert eller forhøyet platetall eller antall hvite blodceller. Mindre
           dager. Kompliserte hud- og bløtdelsinfeksjoner: 600 mg 2 ganger daglig i 10-14 dager. Anbefales ikke til barn og ungdom <18            vanlige (≥1/1000 til <1/100): Blod/lymfe: Eosinofili, leukopeni, nøytropeni, trombocytopeni. Gastrointestinale: Lokaliserte
           år. Ingen dosejustering nødvendig for eldre pasienter, pasienter med nyre- eller leversvikt. Linezolid bør gis etter dialysen til      eller generaliserte magesmerter, forstoppelse, munntørrhet, dyspepsi, gastritt, glossitt, løs avføring, pankreatitt, stomatitt,
           pasienter som får hemodialyse. Infusjonsvæsken bør administreres over en periode på 30-120 minutter. Tablettene kan tas til            misfarging eller funksjonsforstyrrelse av tungen. Hjerte/kar: Hypertensjon, flebitt/tromboflebitt. Hud: Dermatitt, uttalt svette,
           eller utenom måltid. Kontraindikasjoner: Overfølsomhet for noen av innholdsstoffene. Bør ikke gis ved samtidig bruk av                 kløe, utslett, urticaria. Infeksiøse: Vaginitt. Kjønnsorganer/bryst: Vulvovaginale lidelser. Nevrologiske: Svimmelhet, hypes-
           monoaminoksidase A- eller B-hemmere (f.eks. selegilin, moklobemid, fenelzin, isokarboxacid) eller innen 2 uker etter at                tesi, parestesi. Nyre/urinveier: Polyuri. Psykiske: Søvnløshet. Undersøkelser: Økt total bilirubin, kreatinin, natrium eller
           slike legemidler er blitt brukt. Hvis det ikke finnes muligheter for grundig overvåkning av pasienten og blodtrykksmonitore-            kalsium. Reduksjon av ikke-fastende glukose. Forhøyet eller senket klorid. Forhøyet retikulocyttelling. Reduksjon i nøytro-
           ring, bør linezolid ikke gis ved følgende kliniske tilstander eller følgende typer samtidig medisinering: Ukontrollert hyperten-       filer. Øre: Tinnitus. Øye: Tåkesyn. Øvrige: Frysninger, slapphet, feber, smerte på injeksjonsstedet, økt tørste, lokalisert
           sjon, feokromocytom, karsinoid, tyreotoksikose, bipolar depresjon, schizoaffektiv lidelse, akutte forvirringstilstander.               smerte. Følgende bivirkninger er ansett som alvorlige i isolerte tilfeller: Lokalisert magesmerte, forbigående iskemiske anfall
           Pasienter som tar noen av følgende medikamenter: Serotoninreopptakshemmere, trisykliske antidepressiva, serotonin-5-HT1-               (TIA), hypertensjon, pankreatitt og nyresvikt. Et enkelttilfelle av arytmi (takykardi) er rapportert i kliniske studier. Etter
           reseptoragonister (triptaner), direkte og indirekte virkende sympatomimetika (inkl. adrenerge bronkodilatatorer, pseudoefed-           markedsføring: Blod/lymfe: Anemi (se Forsiktighetsregler), leukopeni, nøytropeni, trombocytopeni, pancytopeni og myelo-
           rin og fenylpropanolamin), karkontraherende midler (f.eks. adrenalin, noradrenalin), dopaminerge stoffer (f.eks. dopamin,              suppresjon. Hud: Angioødem, bulløse hudsykdommer, slik som beskrevet ved Stevens-Johnsons syndrom. Immunsystemet:
           dobutamin), petidin eller buspiron. Forsiktighetsregler: Linezolid er en reversibel, ikke-selektiv hemmer av monoaminoksi-             Anafylaksi. Nevrologiske: Perifer nevropati (hovedsakelig ved behandling utover 28 dager), kramper (primært ved kramper
           dase (MAO). Linezolid har ingen antidepressiv effekt ved doser brukt i antibakteriell behandling. Anbefales ikke brukt til             eller risiko for kramper i anamnesen), serotoninergt syndrom. Stoffskifte/ernæring: Melkesyreacidose, se Forsiktighetsregler.
           pasienter med underliggende tilstander og/eller samtidig behandling med medisiner som gir risiko for MAO-hemming, hvis                 Øye: Optisk nevropati (primært ved behandling utover 28 dager). Overdosering/Forgiftning: Ingen rapporterte tilfeller.
           ikke grundig overvåkning og monitorering av pasienten er mulig. Pasienter bør rådes til å unngå å spise store mengder mat              Behandling: Intet spesifikt antidot. Støttende behandling anbefales sammen med vedlikehold av den glomerulære filtrasjonen.
           med høyt innhold av tyramin (f.eks. modne oster, gjærekstrakter, udestillerte alkoholdrikker og fermenterte soyabønne-                 Ca. 30% av en dose fjernes under 3 timers hemodialyse. De to primære metabolittene fjernes i noen grad ved hemodialyse.
           produkter f.eks. soyasaus). Myelosuppresjon (inkl. anemi, leukopeni, pancytopeni og trombocytopeni) er rapportert. Risikoen            Se Giftinformasjonens anbefalinger J01X X08. Egenskaper: Klassifisering: Antibakterielt, syntetisk middel som tilhører
           ser ut til å ha sammenheng med behandlingsvarighet. Trombocytopeni kan oppstå oftere hos pasienter med alvorlig nyresvikt,             klassen oxazolidinoner. Virker mot aerobe grampositive bakterier (Enterococcus faecalis, Enterococcus faecium, Staphyloco-
           uavhengig av om de får dialyse eller ikke. Hematologisk status (hemoglobin, trombocytter, leukocytter total- og differen-              ccus aureus, koagulasenegative stafylokokker, Streptococcus agalactiae, Streptococcus pneumoniae, Streptococcus pyogenes,
           sialtelling) bør derfor monitoreres ved preeksisterende anemi, granulocytopeni eller trombocytopeni, samtidig behandling               gruppe C streptokokker, gruppe G streptokokker), og anaerobe mikroorganismer (Clostridium perfringens, Peptostreptococ-
           som kan senke hemoglobinnivået, redusere leukocyttnivået eller påvirke platetallet eller -funksjonen negativt, samt ved alvor-         cus anaerobius, Peptostreptococcusarter). Følgende påvirkes ikke: Haemophilus influenzae, Moraxella catarrhalis, Neisseri-
           lig nyresvikt, eller linezolidbehandling i mer enn 10-14 dager. Det anbefales at linezolid administreres til slike pasienter kun       aarter, Enterobacteriaceae, Pseudomonasarter. Virkningsmekanisme: Selektiv hemming av bakteriell proteinsyntese. Bindes
           når hematologisk status kan monitoreres nøye. Dersom betydelig myelosuppresjon oppstår under linezolidbehandling, bør                  spesifikt til det bakterielle ribosom (23S på 50S-subenheten) og hindrer dannelse av et funksjonelt 70S initieringskompleks.
           behandlingen avsluttes med mindre det anses som absolutt nødvendig å fortsette. I slike tilfeller må intensiv monitorering av          Linezolid er vanligvis aktivt mot organismer som er resistente mot en eller flere andre antibiotikaklasser. Absorpsjon: Raskt
           hematologisk status og egnede strategier for å håndtere problemet implementeres. I tillegg anbefales det at fullstendig blodtel-       og fullstendig etter peroral administrering. Biotilgjengeligheten er ca. 100%. Maks. plasmakonsentrasjon nås innen 2 timer.
           ling (inkl. hemoglobinnivåer, blodplater, totalt antall leukocytter og differensialtelling) bør utføres ukentlig, uavhengig av         Absorpsjonen påvirkes ubetydelig av mat. Proteinbinding: Ca. 31%, ikke konsentrasjonsavhengig. Fordeling: Distribusjons-
           verdiene før behandlingsstart. Tilfeller av anemi som krever blodoverføring er rapportert, dette forekommer hyppigere ved              volum ved «steady state» er ca. 40-50 liter. Halveringstid: Ca. 5-7 timer. Metabolisme: Primært ved ikke-enzymatisk oksidas-
           behandling >28 dager. Melkesyreacidose er rapportert. Pasienter som får symptomer på metabolsk acidose inkl. stadig                    jon. Utskillelse: Hovedsakelig i urinen, hvorav 30% uomdannet, ca. 3-6% i feces. Oppbevaring og holdbarhet: Injeksjons-
           tilbakevendende kvalme eller oppkast, buksmerter, lavt bikarbonatnivå eller hyperventilering, bør straks få medisinsk behan-           posene skal oppbevares i originalpakningen (forsegling og kartong) til de er klare til bruk. Utlevering: Til bruk på menneske
           dling. Ved alvorlig nyre- eller leversvikt bør preparatet brukes kun når den forventede fordelen antas å oppveie risikoen.             etter resept/rekvisisjon fra lege. Pakninger og priser: Tabletter: 10 stk. (blister) kr 5838,20. 30 stk. (blister) kr 17444,70.
           Pseudomembranøs kolitt er rapportert. Det er derfor viktig å tenke på denne diagnosen hos pasienter som får diaré etter                Infusjonsvæske: 10 × 300 ml (plastpose) kr 5961,70. Refusjon: Se Refusjonslisten, J01X X08.
           administrering. I tilfelle mistenkt eller fastslått antibiotikaassosiert kolitt, kan det være berettiget å avslutte behandlingen.      Sist endret: 02.02.2009

40901_ClinicalTrialList_NY.indd 1                                                                                                                                                                                                                                                          17.08.09 10.50
                                                                                                                                                                                                                                              ZYVOX ® Safety

                                     PUBLICATION                                                            NUMBER OF                            DESIGN                    TREATMENT                                               MAIN RESULTS

                       Worldwide assessment of linezolid’s          Rubinstein E, Isturiz R,         2 046 linezolid-treated adult        Seven multicentre,            600 mg 2qd linezolid:        Safety results
                       clinical safety and tolerability:            Standiford HC et al.                                                  multinational, comparator
                                                                    Antimicrob Agents
                                                                                                     pts, 44% with pneumonia,             drug-controlled, phase III
                       comparator-controlled Phase III              Chemother 2003; 47(6):           53% SSTI                             clinical trials                                               Es resulting in study drug discontinuation, S Es and deaths comparable
                       studies.                                     1824–31.                                                                                                                          linezolid and comparator groups
                                                                                                                                                                                                                          C. difficile-related complications with linezolid
                                                                                                                                                                                                      Haematological events mild-to-moderate transient, related to Tt duration
                                                                                                                                                                                                      and reversible

                       Haematologic effects of linezolid:                                            2 046 linezolid-treated              Prospective analysis of         inezolid at 400 mg q12h    Safety results
                       summary of clinical experience.              Bruss JB et al.                                                       data from 7 controlled,        (2 studies)                  Downward shifts in haemoglobin, P TC and           C with linezolid
                                                                    Antimicrob Agents
                                                                                                     adult pts                            clinical trials                 inezolid at 600 mg q12h
                                                                    Chemother 2002; 46(8):           2001 adult pts treated with                                         (5 studies)                    ost mild (grade 1 or 2) S differences in severe shifts (grade 3 or 4)
                                                                    2723–6.                          comparator antibiotics                                                                           and most in pts treated ≥2 weeks
                                                                                                                                                                                                        ean RI in linezolid (600mg dose only) were significantly decreased
                                                                                                                                                                                                      vs comparator at EOT p<0.01 but not different at follow-up
                                                                                                                                                                                                      Thrombocytopenia and anaemia occurred in some linezolid treated pts
                                                                                                                                                                                                      treated ≥2 weeks

                                                                                                                                                                                                      Pts with underlying haematological abnormalities more likely to have Es
                                                                                                                                                                                                      regardless of antibiotic therapy

                                                                                                                                                                                                            ZYVOX ® Healthcare value
                                                                                                                                                                                                            ZYVOX ® Healthcare value
                                     PUBLICATION                                                              NUMBER OF                          DESIGN                     TREATMENT                                                  MAIN RESULTS

                       Cost-effectiveness of linezolid versus       Schürmann D,                                                          Decision-analytical model                                  Average cost per episode:
                       vancomycin for hospitalised patients         Sorensen S , De Cock E
                                                                    et al. Eur J Health Econ
                       with complicated skin and soft-tissue
                       infections in Germany.

                       Pharmacoeconomics of linezolid.              Grau S, Rubio-Terres C.                                               Systematic review of                                       Health care resource use
                                                                    Expert Opin                                                           pharmacoeconomic
                                                                    Pharmacother                                                          analyses to summarise                                      compared to vancomycin and teicoplanin
                                                                      7–1000.                                                             all the available                                          This results in shorter hospital stays and earlier hospital discharge
                                                                                                                                          evidence regarding the                                     Costs:
                                                                                                                                          pharmacoeconomics of

                                                                                                                                          41 references                                              1125 euros
                                                                                                                                          corresponding to 31                                         In a comparison with teicoplanin, savings with linezolid ranged between $335
                                                                                                                                          studies, 16 of which                                        and $1286
                                                                                                                                          were studies of resource
                                                                                                                                          utilisation, costs and/
                                                                                                                                          or cost minimisation
                                                                                                                                          analyses and 15 of which
                                                                                                                                          were cost-effectiveness

                         comparison of costs and hospital length                                     163 elderly (≥65 years old)          Sub-group analysis from a       inezolid 600mg I /oral     Results
                       of stay associated with intravenous/oral     Sorensen S ,                                                          multinational, randomised,     q12h                         Both mean hospitalisation and total costs lower with linezolid (hospitalisation:
                                                                                                     pts hospitalised for cSSTI           open-label, prospective
                       linezolid or intravenous vancomycin                                                                                                                                            US $4510 vs                                          vs
                                                                    Clin Ther
                       treatment of complicated skin and                            –77.                                                                                                                                                 vs vancomycin p<0.001
                       soft-tissue infections caused by                                                                                                                                                inezolid .5 day reduction in duration I therapy vs vancomycin ITT group
                       suspected or confirmed methicillin-                                                                                                                                             p<0.001
                       resistant Staphylococcus aureus in
                       elderly US patients.

                       Cost-effectiveness of linezolid and                                                                                                              Three primary event          Results
                                                                                                                                          modelling approach using      pathways after diagnosis      Tt with oral linezolid both during hospitalisation and after discharge is the
                       vancomycin in the treatment of                                                                                     both internal and external
                       surgical site infections.                    Curr Med Res Opin 2007;                                               data sources                   Tt with I vancomycin
                                                                    23(1): 185–                                                                                          during hospitalisation
                                                                                                                                                                         and after discharge in a
                                                                                                                                                                         homecare situation
                                                                                                                                                                         I vancomycin during
                                                                                                                                                                         hospitalisation and oral
                                                                                                                                                                         linezolid after discharge
                                                                                                                                                                         Oral linezolid during
                                                                                                                                                                         hospitalisation and after

                       Impact of linezolid on economic                                               ITT pop, 717 adult pts with          Randomised open-label,         Oral or I linezolid         Results
                       outcomes and determinants of cost in         Sorensen S ,                                                                                         600mg q12h                  Duration of antibiotic therapy:
                                                                           et al.
                       a clinical trial evaluating patients with    Ann Pharmacother 2006;           cSSTI:
                                                                                                                                                                                                      Total duration of antibiotic therapy similar between the 2 groups
                                                                    40: 1017–23.
                       infections.                                                                                                                                                                   LOS:
                                                                                                     MRSA pop, 295 pts,                                                                                                                             vs
                                                                                                                                                                                                     Cost of Tt:

                       Clinical and economic outcomes of                                             60 adult pts with at least one       Single centre, open-label       ll pts received post-op    Results
                       oral linezolid versus intravenous            Polk HC.                                                              study                          cefazolin Tt and could
                                                                    Am J Surg                                                                                            have up to 48h of topical                                                            vs
                       vancomycin in the treatment of               425 –8.                          requiring surgery                                                   or systemic antibiotics
                         RS -complicated, lower-extremity                                                                                                                before randomisation
                       skin and soft-tissue infections caused                                                                                                            Oral linezolid 600mg q12h
                       by methicillin-resistant Staphylococcus

                       Linezolid reduces length of stay and                    , Weigelt J,          ITT pop, 1 180 adult pts with        Sub-group analysis from a      Oral or I linezolid         Results
                                                                          et al.                                                          multinational, multicentre,    600mg q12h                  All-cause mean total LOS significantly shorter linezolid all patient pops p<0.01
                       duration of intravenous treatment vs         Int J Antimicrob Agents
                                                                                                     cSSTI:                               randomised, open-label,
                       vancomycin for complicated skin and                                                                                                                                                       vs
                                                                    2005; 26: 442–8.                                                      comparator-controlled                                                     vs
                       soft-tissue infections due to suspected                                                                            clinical study                                                         vs
                       or proven methicillin-resistant                                               MITT pop, 664 pts, culture                                                                                   vs
                       Staphylococcus aureus                                                         confirmed GP:                                                                                                    vs 10.7 days

                                                                                                                                                                                                     Fewer IV Tt required linezolid than vancomycin for all patient pops p<0.0001
                                                                                                     CE pop, 898 pts, > 4 days of                                                                                    vs
                                                                                                     therapy and returned for TOC:                                                                                vs
                                                                                                                                                                                                                      vs 12.6 days

                                                                                                     ME pop, 640 pts, all CE with
                                                                                                     at least 1 GP organism:

                       Cost-effectiveness analysis of the           Grau S,                                                               Pharmacoeconomic                                           Results
                       treatment of ventilator-associated                         ,                                                       modelling of data from a                                                                                                             Y
                                                                                et al. J                                                  retrospective analysis,
                       pneumonia with linezolid or                  Chemother 2005; 17(2):                                                which pooled data from 2                                              r, linezolid is overall more cost-effective than vancomycin
                       vancomycin in Spain.                         203–11.                                                               double-blind, randomised,
                                                                                                                                          comparative trials

                       Linezolid for treatment of                                                    Hypothetical cohort of 1 000         Decision model analysis        I linezolid 600mg q12h      Results
                                                                                                                                                                         + aztreo 1-2g q8h            Cost per quality-ad usted life-year of linezolid vs vancomycin ranges from
                       ventilator-associated pneumonia:             Crit Care Med
                                                                                                     adult pts with                                                      I vancomycin 1g q12h
                       a cost-effective alternative to                                                                                                                                                $23637–$42785
                                                                    2004; 32: 137–43.                                                                                    + aztreo 1-2g q8h             inezolid is a cost-effective alternative to vancomycin for the treatment of
                       vancomycin.                                                                                                                                                                    ventilator-associated pneumonia

                                                                                                     European cohort of 227                                               inezolid 600 mg q12h I     Results
                       cohort from a multinational trial of                    et al.                                                     randomised, open-label         with switch to oral         For the total sample
                                                                    Int J Antimicrob Agents
                                                                                                     hospitalised pts                     trial                          Teicoplanin I with an
                       linezolid versus teicoplanin in serious                                                                                                                                                                           vs
                                                                    2004; 23: 315–24.                                                                                                                                                         vs
                       Gram-positive bacterial infections:
                       the importance of treatment setting in                                                                                                                                         Baseline variables especially inpatient location at enrolment and presence
                       evaluating treatment effects.                                                                                                                                                  of OHP T have significant effect on total cost Tt

                       Effect of linezolid versus vancomycin                                         ITT pop, 230 adult patients          Phase 3 randomised,                                        ITT pop:
                       on length of hospital stay in patients       Rittenhouse BE et al.            with cSSTI                           open-label,                   followed by option to
                                                                    Surg Infect 2003; 4 (1):                                              comparator-controlled,        switch to oral of the same
                       with complicated skin and                    57–70.                                                                multicentre clinical trial    dose) vs. vancomycin         Clinically-evaluable pop:
                       soft-tissue infections caused by known                                                                             to compare efficacy and                                     the linezolid group compared with the vancomycin group (8 vs. 16 days,
                       or suspected methicillin-resistant                                                                                 safety of linezolid with                                   respectively; p<0.0025)
                       staphylococci: results from                                                                                        vancomycin
                       a randomised clinical trial

                       Effects of linezolid on hospital length                                       ITT pop, 460 adult patients          Open-label,
                       of stay compared with vancomycin                   et al. Int J Technol       with methicillin-resistant           comparator-controlled,        followed by option to
                                                                    Assess Health Care 2002;                                              multinational, ranomised      switch to oral of the same
                       in treatment of methicillin-resistant        18(3): 540–554.                  staphyococcal infections             phase 3 clinical trial to     dose) vs. vancomycin
                       Staphylococcus infections: an                                                                                      compare the effects of
                       application of multivariate survival                                                                               treatment with linezolid

                       Comparison of length of hospital                                              ITT pop, 460 pts hospitalised        Open-label,                    Oral or I linezolid         Results
                       stay for patients with known or                        et al.                                                      comparator-controlled,         600mg q12h                  LOS:
                                                                    Pharmacotherapy 2001;
                                                                                                     pts >13 yrs old suspected            multicentre, multinational,
                       suspected methicillin-resistant                                               Staphylococcal infection:                                                                                                    vs
                                                                    21(3): 263–74.                                                        randomised phase III trial                                                              vs
                       Staphylococcus species infections
                       treated with linezolid or vancomycin:                                                                                                                                         Mean duration of IV antibiotic Tt:
                       a randomised, multicentre trial.                                                                                                                                                                         vs 11.3 days vancomycin p<0.0001
                                                                                                     CE pop, 254 pts:                                                                                                          vs 13.8 days vancomycin p<0.0001

                                                                                                                                                                                                     Duration of antibiotic Tt:

                                                                                                                                    Staphylococcus aureus


                               Twice daily

                                    dence Interval
                                                             Tissue Infection


                                                                                                        Staphyloccocus aureus

                                                                                                                    Tissue Infection
                                                                                                 T      Teicoplanin
                                     Year Gained                                                    Treatment
                                     Year Saved                                                     Treatment failure
                                                                                                                                                                                                                                                                                              EU.ZY OX. 2008.028 Date of preparation: September 2008

                                                                                                 vs ersus
                                        ed Intent-to-Treat

                                                                                                     Pfizer AS - Postboks 3 - 1324 Lysaker - Tlf. 67 52 61 00 - www.pfizer.no

40901_ClinicalTrialList_NY.indd 2                                                                                                                                                                                                                                                        17.08.09 10.50

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