TAZOCIN 2.25 G.

Israel - English - Ministry of Health

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Active ingredient:
PIPERACILLIN AS SODIUM 2 G/VIAL; TAZOBACTAM SODIUM 0.25 G/VIAL
Available from:
NEOPHARM LTD
ATC code:
J01CR05
Pharmaceutical form:
POWDER FOR SOLUTION FOR INJECTION
Administration route:
I.V
Manufactured by:
WYETH PIPER. DIV.OF WYETH HOLDINGS CORP.
Therapeutic group:
PIPERACILLIN AND ENZYME INHIBITOR
Therapeutic indications:
Antibiotic for the treatment of systemic and/or local bacterial infections caused by susceptible organisms. Tazocin in combination with an aminoglycoside, is indicated for suspected bacterial infections in neutropenic adults or children above 2 years. Appendicitis complicated by rupture with peritonitis and/or abscess formation in children aged 2-12 years.
Authorization number:
066072750201
Authorization date:
2010-06-01

TAZOCIN ®

(PiperacillinandTazobactamfor Injection)

Toreducethe developmentof drug-resistantbacteria andmaintainthe effectivenessof Tazocin

(piperacillinandtazobactam) injectionandother antibacterialdrugs,Tazocin(piperacillinand

tazobactam) shouldbe usedonlytotreatorpreventinfectionsthatareprovenor strongly

suspectedtobe causedbybacteria.

Description

Tazocin(Piperacillin/Tazobactamfor Injection) isaninjectableantibacterialcombination

productconsistingofthesemisynthetic antibioticpiperacillinsodiumandthebeta-lactamase

inhibitortazobactamsodiumfor intravenousadministration.

PiperacillinsodiumisderivedfromD(-)-α-aminobenzyl-penicillin.The chemicalname of

piperacillinsodiumissodium(2S,5R,6R)-6-[(R)-2-(4-ethyl-2,3-dioxo-1-

piperazinecarboxamido)-2-phenylacetamido]-3,3-dimethyl-7-oxo-4-thia-1-

azabicyclo[3.2.0]heptane-2-carboxylate.The chemicalformulaisC

S andthe

molecular weightis539.5.The chemicalstructure ofpiperacillinsodiumis:

Tazobactamsodium,a derivative ofthepenicillinnucleus,isapenicillanic acidsulfone.Its

chemicalname issodium(2S,3S,5R)-3-methyl-7-oxo-3-(1H-1,2,3-triazol-1-methyl)-4-thia-1-

azabicyclo[3.2.0]heptane-2-carboxylic acid4,4-dioxide.The chemicalformula is

S andthe molecular weightis322.3.

The chemicalstructure of tazobactamsodiumis:

PHARMACEUTICALFORMANDCOMPOSITION

TAZOCIN,piperacillin/tazobactamparenteralcombination,isa white tooff-white sterile,

cryodesiccatedpowder consistingof piperacillinandtazobactamas their sodiumsaltspackaged

inglassvials.

The formulationalsocontainsedetate disodiumdihydrate (EDTA) andcitric acid

monohydrate. 1

EachTAZOCIN2.25gsingledosevialcontainsanamountofdrugsufficientfor withdrawal

of piperacillinsodiumequivalentto2gramsof piperacillinandtazobactamsodiumequivalent

to0.25gramof tazobactam.The productalsocontains0.5 mgofEDTAper vial.

EachTAZOCIN4.5 gsingle dose vialcontainsan amountof drugsufficientfor withdrawalof

piperacillinsodiumequivalentto4gramsof piperacillinandtazobactamsodiumequivalentto

0.5gramof tazobactam.

The productalsocontains1mgof EDTAper vial.

Tazocin(piperacillinandtazobactamfor injection) containsatotalof2.79mEq(64mg) of

sodium(Na+) per gramof piperacillininthe combinationproduct.

CLINICAL PHARMACOLOGY

ADULTS

Peakplasma concentrationsof piperacillinandtazobactamareattainedimmediatelyafter

completionof anintravenousinfusionofTazocin.Piperacillinplasma concentrations,following

a 30-minuteinfusionofTazocin,were similar tothose attainedwhenequivalentdosesof

piperacillinwere administeredalone,withmeanpeakplasma concentrationsof approximately

134,242and298

g/mLfor the2.25g,3.375gand4.5gTazocin(piperacillin/tazobactam)

doses,respectively.The correspondingmeanpeakplasma concentrationsoftazobactamwere

15,24and34

g/mL,respectively.

Followinga30-minute I.V.infusionof 3.375gTazocinevery6 hours,steady-state plasma

concentrationsofpiperacillinandtazobactamwere similar tothoseattainedafterthefirstdose.

Inlike manner,steady-state plasma concentrationswere notdifferent fromthose attainedafter

the firstdose when2.25gor4.5gdosesofTazocinwere administeredvia 30-minute infusions

every6 hours.Steady-stateplasma concentrationsafter 30-minute infusionsevery6 hoursare

providedinTable 1.

FollowingsingleormultipleTazocindosestohealthysubjects,theplasma half-life of

piperacillinandof tazobactamrangedfrom0.7to1.2hoursandwasunaffectedbydose or

durationof infusion.

Piperacillinismetabolizedtoaminor microbiologicallyactive desethylmetabolite.Tazobactam

ismetabolizedtoasingle metabolitethatlackspharmacologicalandantibacterialactivities.

Bothpiperacillinandtazobactamare eliminatedvia the kidneybyglomerular filtrationand

tubular secretion.Piperacillinisexcretedrapidlyas unchangeddrugwith68%ofthe

administereddose excretedintheurine.Tazobactamanditsmetabolite areeliminatedprimarily

byrenalexcretionwith80%ofthe administereddose excretedasunchangeddrugandthe

remainder asthe single metabolite.Piperacillin,tazobactamanddesethylpiperacillinare also

secretedintothebile.

Bothpiperacillinandtazobactamareapproximately30%boundtoplasma proteins.The protein

bindingof eitherpiperacillinortazobactamisunaffectedbythepresence of the other

compound.Proteinbindingof thetazobactammetabolite isnegligible.

Piperacillinandtazobactamarewidelydistributedintotissuesandbodyfluidsincluding

intestinalmucosa,gallbladder,lung,female reproductivetissues(uterus,ovary,andfallopian

tube),interstitialfluid,andbile.Meantissue concentrationsaregenerally50%to100%of those

inplasma.Distributionofpiperacillinandtazobactamintocerebrospinalfluidislowinsubjects

withnon-inflamedmeninges,aswithotherpenicillins.

After the administrationof singledosesofpiperacillin/tazobactamtosubjectswithrenal

impairment,thehalf-life of piperacillinandof tazobactamincreaseswithdecreasingcreatinine

clearance.Atcreatinine clearancebelow20mL/min,the increase inhalf-life istwofoldfor

piperacillinandfourfoldfor tazobactamcomparedtosubjectswithnormalrenalfunction.

Dosage adjustmentsforTazocinare recommendedwhencreatinineclearance isbelow

40mL/mininpatientsreceivingthe usualrecommendeddailydoseofTazocin(piperacillinand

tazobactamfor injection).(SeeDOSAGEANDADMINISTRATIONsectionfor specific

recommendationsforthetreatmentofpatientswithrenalinsufficiency.)

Hemodialysisremoves30%to40%of apiperacillin/tazobactamdose withanadditional5%of

thetazobactamdose removedasthe tazobactammetabolite.Peritonealdialysisremoves

approximately6%and21%ofthe piperacillinandtazobactamdoses,respectively,withupto

16%of the tazobactamdose removedasthe tazobactammetabolite.For dosage

recommendationsforpatientsundergoinghemodialysis,seeDOSAGE AND

ADMINISTRATIONsection.

The half-life ofpiperacillinandoftazobactamincreasesbyapproximately25%and18%,

respectively,inpatientswithhepatic cirrhosiscomparedtohealthysubjects.However,this

differencedoesnotwarrant dosage adjustmentofTazocinduetohepatic cirrhosis.

TABLE1STEADYSTATE MEANPLASMACONCENTRATIONS INADULTS

AFTER30-MINUTE INTRAVENOUS INFUSIONOF

PIPERACILLIN/TAZOBACTAMEVERY6 HOURS

Plasma Concentrations**(

g/mL) AUC**

ghr/m

L)

PIPERA

CILLIN

TAZOB

ACTAM

Plasma Concentrations**(

g/mL) AUC**

ghr/m

L)

Piperacilli

n/

Tazobacta

m

Dose a

No.of

Evaluabl

e

Subjects30min 1hr 2hr 3hr 4hr 6hr AUC

2.25g 8 14.8(14)7.2(22)2.6

(30) 1.1

(35) 0.7(6) c

0.5 16.0(21)

3.375g 6 24.2(14)10.7(7)4.0

(18) 1.4

(21) 0.7

(16) b

0.5 25.0(8)

4.5g 8 33.8(15)17.3

(16) 6.8

(24) 2.8

(25) 1.3(30)

0.5 39.8(15)

**Numbersinparenthesesare coefficientsofvariation(CV%).

Piperacillinandtazobactamwere givenincombination.

N=4

N= 3

Pediatrics

Piperacillinandtazobactampharmacokineticswere studiedinpediatric patients2 monthsofage

andolder.The clearanceof bothcompoundsisslower inthe youngerpatientscomparedtoolder

Piperacilli

n/

Tazobacta

m

Dose a

No.of

Evaluabl

e

Subjects30min 1hr 2hr 3hr 4hr 6hr AUC

2.25g 8 134(14)57(14)17.1

(23) 5.2(32)2.5(35)0.9

(14) b

131(14)

3.375g 6 242(12)106(8)34.6

(20) 11.5

(19) 5.1(22)1.0(10)242(10)

4.5g 8 298(14)141

(19) 46.6

(28) 16.4

(29) 6.9(29)1.4(30)322(16)

InapopulationPKanalysis,estimatedclearance for9month-oldto12year-oldpatientswas

comparable toadults,withapopulationmean(SE) value of 5.64(0.34) mL/min/kg.The

piperacillinclearanceestimate is80%of thisvalue forpediatricpatients2-9monthsold.In

patientsyounger than2 monthsof age,clearance ofpiperacillinisslower comparedtoolder

children;however,itisnotadequatelycharacterizedfor dosingrecommendations.The

populationmean(SE) forpiperacillindistributionvolume is0.243(0.011) L/kgandis

independentof age.

Microbiology

Piperacillinsodiumexertsbactericidalactivitybyinhibitingseptumformationandcellwall

synthesisof susceptible bacteria.Invitro,piperacillinisactive againstavarietyof gram-

positive andgram-negative aerobic andanaerobic bacteria.Tazobactamsodiumhaslittle

clinicallyrelevantinvitroactivityagainstbacteria duetoitsreducedaffinitytopenicillin-

bindingproteins.Itis,however,a 

-lactamase inhibitor of the Richmond-SykesclassIII (Bush

class2b&2b') penicillinasesandcephalosporinases.Itvariesinits abilitytoinhibitclassIIand

IV(2a & 4)penicillinases.Tazobactamdoesnotinduce chromosomally-mediated 

-lactamases

attazobactamconcentrationsachievedwiththe recommendeddosage regimen.

Piperacillin/tazobactamhasbeenshowntobe active againstmoststrainsofthe following

microorganismsbothinvitroandinclinicalinfectionsasdescribedintheINDICATIONS

ANDUSAGEsection.

Aerobic and facultativegram-positivemicroorganisms:

Staphylococcusaureus(excludingmethicillinandoxacillin-resistantisolates)

Aerobic and facultativegram-negativemicroorganisms:

Acinetobacterbaumanii

Escherichiacoli

Haemophilusinfluenzae(excluding 

-lactamase negative,ampicillin-resistantisolates)

Klebsiellapneumoniae

Pseudomonasaeruginosa(givenincombinationwithanaminoglycoside towhichthe isolateis

susceptible)

Gram-negativeanaerobes:

Bacteroidesfragilisgroup(B.fragilis,B.ovatus,B.thetaiotaomicron,andB.vulgatus)

The followinginvitrodata are available,but theirclinicalsignificance isunknown.

Atleast90%of the followingmicroorganismsexhibitaninvitrominimuminhibitory

concentration(MIC)lessthanor equaltothe susceptiblebreakpointforpiperacillin/tazobactam.

However,the safetyandeffectivenessof piperacillin/tazobactamintreatingclinicalinfections

due tothese bacteriahave notbeenestablishedinadequateandwell-controlledclinicaltrials.

Aerobic and facultativegram-positivemicroorganisms:

Enterococcusfaecalis(ampicillinorpenicillin-susceptible isolatesonly)

Staphylococcusepidermidis(excludingmethicillinandoxacillinresistantisolates)

Streptococcusagalactiae

Streptococcuspneumoniae

(penicillin-susceptible isolatesonly)

Streptococcuspyogenes

Viridansgroupstreptococci †

Aerobic and facultativegram-negativemicroorganisms:

Citrobacterkoseri

Moraxellacatarrhalis

Morganellamorganii

Neisseriagonorrhoeae

Proteusmirabilis

Proteusvulgaris

Serratiamarcescens

Providenciastuartii

Providenciarettgeri

Salmonellaenterica

Gram-positive anaerobes:

Clostridiumperfringens

Gram-negativeanaerobes:

Bacteroidesdistasonis

Prevotellamelaninogenica

These arenot 

-lactamase producingbacteria and,therefore,aresusceptibletopiperacillin

alone.

SusceptibilityTestingMethods

Asisrecommendedwithallantimicrobials,the resultsof invitrosusceptibilitytests,when

available,shouldbeprovidedtothe physicianasperiodic reports,whichdescribe the

susceptibilityprofile of nosocomialandcommunity-acquiredpathogens.These reportsshould

aidthe physicianinselectingthe mosteffective antimicrobial.

DilutionTechniques:

Quantitative methodsareusedtodetermine antimicrobialminimuminhibitoryconcentrations

(MICs).These MICsprovide estimatesof the susceptibilityof bacteriatoantimicrobial

compounds.The MICsshouldbedeterminedusingastandardizedprocedure.Standardized

proceduresare basedonadilutionmethod(brothor agar) orequivalentwithstandardized

inoculumconcentrationsandstandardizedconcentrationsofpiperacillinandtazobactam

powders. 1,2

MICvaluesshouldbedeterminedusingserialdilutionsof piperacillincombined

withafixedconcentrationof4

g/mLtazobactam.The MICvaluesobtainedshouldbe

interpretedaccordingtocriteria providedinTable2.

DiffusionTechnique:

Quantitative methodsthatrequire measurementof zone diametersalsoprovide reproducible

estimatesofthe susceptibilityof bacteria toantimicrobialcompounds.One suchstandardized

procedure 1,3

requirestheuse ofstandardizedinoculumconcentrations.Thisprocedureuses

paper disksimpregnatedwith100

gof piperacillinand10

gof tazobactamtotestthe

susceptibilityofmicroorganismstopiperacillin/tazobactam.The diskdiffusioninterpreted

criteria areprovidedinTable2.

Anaerobic Techniques

For anaerobicbacteria,thesusceptibilitytopiperacillin/tazobactamcanbe determinedbythe

reference agardilutionmethod. 4

TABLE2SUSCEPTIBILITYINTERPRETIVE CRITERIAFOR

PIPERACILLIN/TAZOBACTAM

SusceptibilityTestResultInterpretive Criteria

MinimalInhibitory

Concentration DiskDiffusion

(MIC in

g/mL) (Zone Diameter inmm)

Pathogen S I R S I R

Enterobacteriaceaeand

Acinetobacterbaumanii

16 32-64

128

21 18-20

17

Haemophilusinfluenzae a

1 -

2

21 - -

Pseudomonas

aeruginosa

64 -

128

18 -

17

Staphylococcusaureus

8 -

16

18 -

17

Bacteroidesfragilis

group

32 64

128 - - -

These interpretive criteria forHaemophilusinfluenzaeare applicableonlytotestsperformed

usingHaemophilusTestMediuminoculatedwithadirectcolonysuspensionandincubatedat

C inambientair for 20to24hours.

Areportof S(―Susceptible‖) indicatesthatthepathogenislikelytobeinhibitedif the

antimicrobialcompoundinthebloodreachesthe concentrationusuallyachievable.Areportof

I(―Intermediate‖)indicatesthatthe resultsshouldbe consideredequivocal,andifthe

microorganismisnotfullysusceptible toalternative,clinicallyfeasible drugs,the testshouldbe

repeated.Thiscategoryimpliespossibleclinicalapplicabilityinbodysiteswhere thedrugis

physiologicallyconcentratedor insituationswherehighdosage of drugcanbeused.This

categoryalsoprovidesabuffer zone,whichpreventssmall,uncontrolledtechnicalfactorsfrom

causingmajor discrepanciesininterpretation.Areportof R(―Resistant‖)indicatesthatthe

pathogenisnotlikelytobe inhibitedifthe antimicrobialcompoundinthebloodreachesthe

concentrationusuallyachievable;other therapyshouldbe considered.

QualityControl

Standardizedsusceptibilitytest proceduresrequire the useof qualitycontrolmicroorganismsto

controlthe technicalaspectsof the testprocedures 1,2,3,4

.Standardpiperacillin/tazobactam

powdershouldprovide the followingrangesofvaluesnotedinTable3.Qualitycontrol

microorganismsarespecific strainsof microorganismswithintrinsicbiologicalproperties

relatingtoresistance mechanismsandtheirgenetic expressionwithin the microorganism;the

specificstrainsusedfor microbiologicalqualitycontrol arenotclinicallysignificant.

TABLE3ACCEPTABLEQUALITYCONTROL RANGESFORPIPERACILLIN/

TAZOBACTAMTO BEUSEDINVALIDATIONOFSUSCEPTIBILITYTEST

RESULTS

Acceptable QualityControlRanges

MinimumInhibitory

Concentration DiskDiffusion

QC Strain Range (MICin

g/mL) Zone Diameter Rangesinmm

Escherichiacoli

ATCC 25922 1-4 24-30

Escherichiacoli

ATCC 35218 0.5-2 24-30

Pseudomonas

aeruginosa

ATCC 27853 1-8 25-33

Haemophilus

influenzae a

ATCC 49247 0.06-0.5 33-38

Staphylococcus

aureus

ATCC 29213 0.25-2 -

Staphylococcus

aureus

ATCC 25923 - 27–36

Bacteroides

fragilis b

ATCC 25285 0.12-0.5 -

Acceptable QualityControlRanges

MinimumInhibitory

Concentration DiskDiffusion

QC Strain Range (MICin

g/mL) Zone Diameter Rangesinmm

Bacteroides

thetaiotaomicron b

ATCC 29741 4-16 -

Thisqualitycontrolrange forHaemophilusinfluenzaeisapplicable onlytotestsperformed

usingHaemophilusTestMediuminoculatedwithadirectcolonysuspensionandincubatedat

C inambientair for 20to24hours.

b

ThequalitycontrolrangesforBacteroidesfragilisandBacteroidesthetaiotaomicronare

applicable onlytotestsperformedusingthe agardilutionmethod.

INDICATIONSANDUSAGE

Tazocin(Piperacillinandtazobactamfor injection,USP) 2

isindicatedforthetreatmentof

infectionscausedbysusceptible organisms.

Piperacillin/tazobactamincombinationwithan aminoglycosideisindicatedforthetreatmentof

suspectedbacterialinfectionsinneutropenic adultsand childrenabove2years.

Appendicitiscomplicatedbyrupturewithperitonitisand/or abscessformationinchildrenaged

2-12years.

Appropriate culture andsusceptibilitytestsshouldbeperformedbefore treatmentinorderto

identifyorganismscausinginfectionsandtodetermine their susceptibilitiesto

piperacillin/tazobactam.Becauseof itsbroadspectrumof activityagainstGram-positive and

Gram-negative aerobic andanaerobic organismsas listedabove,piperacillin/tazobactamis

particularlyusefulinthetreatmentof mixedinfectionsandinpresumptivetherapyprior tothe

availabilityof the resultsof sensitivitytests.

Therapywithpiperacillin/tazobactammay,however,be initiatedbefore resultsof suchtestare

known.Modificationof thetreatmentmaybe requiredonce these resultsbecome availableor if

there isnoclinicalresponse.

Inseriousinfectionspresumptivetherapywithpiperacillin/tazobactammaybe initiatedbefore

susceptibilitytest resultsare available.

Piperacillin/tazobactamactssynergisticallywithaminoglycosidesagainstcertainstrainsof

Pseudomonasaeruginosa.Combinedtherapyhasbeensuccessful,especiallyinpatientswith

impairedhostdefenses.Bothdrugsshouldbe usedinfulltherapeuticdoses.Assoonasresults

of culture andsusceptibilitytestbecome available,antimicrobialtherapyshouldbe adjusted.

Toreduce thedevelopment of drug-resistant bacteriaandmaintain theeffectivenessof

Tazocin(piperacillin and tazobactam) injectionandotherantibacterialdrugs,Tazocin

(piperacillin and tazobactam)should be usedonlytotreat orprevent infectionsthat are

proven or stronglysuspected to be caused bysusceptible bacteria.When culture and

susceptibilityinformation are available,theyshould be considered in selectingor

modifyingantibacterialtherapy.In the absenceof such data,localepidemiologyand

susceptibilitypatternsmaycontribute totheempiric selection of therapy.

CONTRAINDICATIONS

Tazociniscontraindicatedinpatientswithahistoryof allergic reactionstoanyof thepenicillins

and/or cephalosporinsorß-lactamase inhibitors.

WARNINGS

SERIOUS ANDOCCASIONALLYFATALHYPERSENSITIVITY

(ANAPHYLACTIC/ANAPHYLACTOID) REACTIONS (INCLUDINGSHOCK)HAVE

BEENREPORTEDINPATIENTS RECEIVINGTHERAPYWITHPENICILLINS

INCLUDINGTAZOCIN.THESEREACTIONS AREMORELIKELYTOOCCUR IN

INDIVIDUALSWITHAHISTORYOF PENICILLINHYPERSENSITIVITYORA

HISTORYOF SENSITIVITYTOMULTIPLEALLERGENS.

THEREHAVEBEENREPORTS OF INDIVIDUALSWITHAHISTORYOFPENICILLIN

HYPERSENSITIVITYWHOHAVEEXPERIENCEDSEVEREHYPERSENSITIVITY

REACTIONSWHENTREATEDWITHACEPHALOSPORIN.BEFOREINITIATING

THERAPYWITHPIPERACILLIN/TAZOBACTAM,CAREFULINQUIRYSHOULDBE

MADECONCERNINGPREVIOUSHYPERSENSITIVITYREACTIONS TOPENICILLINS,

CEPHALOSPORINS,ANDOTHERALLERGENS.IF ANALLERGIC REACTION

OCCURS DURINGTHERAPYWITHPIPERACILLIN/TAZOBACTAM,TAZOCIN

SHOULDBE DISCONTINUEDANDAPPROPRIATETHERAPYINSTITUTED.SERIOUS

ANAPHYLACTIC/ANAPHYLACTOIDREACTIONS (INCLUDING SHOCK)

REQUIRE IMMEDIATE EMERGENCYTREATMENT WITH EPINEPHRINE.

OXYGEN,INTRAVENOUS,STEROIDS,ANDAIRWAYMANAGEMENT,

INCLUDING INTUBATION,SHOULDALSOBE ADMINISTRATEDAS INDICATED.

Clostridiumdifficileassociateddiarrhea (CDAD) hasbeenreportedwithuse of nearlyall

antibacterialagents,includingTazocin,andmayrangeinseverityfrommilddiarrheatofatal

colitis.Treatmentwithantibacterialagentsaltersthe normalflora of the colonleadingto

overgrowthofC.difficile.

C.difficileproducestoxinsAandBwhichcontribute tothedevelopmentof CDAD.Hypertoxin

producingstrainsofC.difficilecauseincreasedmorbidityandmortality,asthese infectionscan

be refractorytoantimicrobialtherapyandmayrequire colectomy.CDADmustbe consideredin

allpatientswhopresentwithdiarrhea followingantibiotic use.Carefulmedicalhistoryis

necessarysince CDADhasbeenreportedtooccurover twomonthsafter the administrationof

antibacterialagents.

If CDADissuspectedor confirmed,ongoingantibioticuse notdirectedagainstC.difficilemay

needtobediscontinued.Appropriate fluidandelectrolytemanagement,protein

supplementation,antibiotictreatmentofC.difficile,andsurgicalevaluationshouldbeinstituted

asclinicallyindicated.

Seriousskinreactions,suchasStevens-Johnsonsyndrome andtoxic epidermalnecrolysis,have

beenreportedinpatientsreceivingZOSYN(seeADVERSEREACTIONS).If patientsdevelop

a skinrashtheyshouldbe monitoredcloselyandZOSYNdiscontinuedif lesionsprogress.

PRECAUTIONS

General

Bleedingmanifestationshaveoccurredinsome patientsreceivingß-lactamantibiotics ,

includingpiperacillin. These reactionshave sometimesbeenassociatedwithabnormalitiesof

coagulationtestssuchas clottingtime,plateletaggregationandprothrombintime,andaremore

likelytooccurinpatientswithrenalfailure.If bleedingmanifestationsoccur, Tazocinshouldbe

discontinuedandappropriatetherapyinstituted.

The possibilityof theemergence of resistantorganisms that mightcause superinfectionsshould

be keptinmind.If thisoccurs,appropriatemeasuresshouldbetaken.

Aswithother penicillins,patientsmayexperienceneuromuscular excitabilityor convulsionsif

higher thanrecommendeddosesaregivenintravenously.(particularlyinthepresenceof renal

failure).

Tazocincontainsatotalof2.79mEq(64mg) of Na +

per gramof piperacillininthe combination

product.

Thisshouldbe consideredwhentreatingpatientsrequiringrestrictedsaltintake.Periodic

electrolyte determinationsshouldbe made inpatientswithlowpotassiumreserves,andthe

possibilityof hypokalemia shouldbe keptinmindwithpatientswhohave potentiallylow

potassiumreservesandwhoare receivingcytotoxic therapyor diuretics.

Aswithother semisynthetic penicillins,piperacillintherapyhasbeenassociatedwithan

increasedincidenceof fever andrashincystic fibrosispatients.

Inpatientswithcreatinine clearance

40mL/minanddialysispatients(hemodialysisand

CAPD),the intravenousdoseshouldbe adjustedtothedegreeofrenalfunctionimpairment.

(SeeDOSAGE ANDADMINISTRATION.)

PrescribingTazocin(piperacillinandtazobactam) inthe absenceof a provenorstrongly

suspectedbacterialinfectionor aprophylactic indicationisunlikelytoprovide benefittothe

patientandincreasesthe riskof developmentof drug-resistantbacteria.

Information for Patients

Patientsshouldbe counseledthatantibacterialdrugsincludingTazocinshouldonlybe usedto

treatbacterialinfections.Theydonottreatviralinfections(e.g.,the commoncold).When

Tazocinisprescribedtotreatabacterialinfection,patientsshouldbe toldthatalthoughitis

commontofeelbetter earlyinthe courseof therapy,the medicationshouldbetakenexactlyas

directed.Skippingdosesornotcompletingthe fullcourseof therapymay(1) decrease the

effectivenessof the immediate treatmentand(2)increase the likelihoodthatbacteria will

developresistance andwillnotbetreatablebyTazocinor otherantibacterialdrugsinthe future.

Diarrheaisacommon problemcausedbyantibioticswhichusuallyendswhen the

antibiotic isdiscontinued.Sometimesafter startingtreatmentwith antibiotics,patients

can developwateryandbloodystools(with orwithout stomachcrampsand fever) evenas

late astwoor more monthsafter havingtaken thelast dose of theantibiotic.If thisoccurs,

patientsshould contact their physician assoonaspossible.

LaboratoryTests

Periodic assessmentof hematopoietic functionshouldbeperformed,especiallywithprolonged

therapy,i.e.,≥21days.(See ADVERSEREACTIONS-Adverse laboratoryevents.)

DrugInteractions

Aminoglycosides

The mixingofbeta-lactamantibioticswithaminoglycosidesinvitrocanresultinsubstantial

inactivationof the aminoglycoside.However,amikacinandgentamicinhavebeenshowntobe

compatible invitrowithreformulatedTazocincontainingEDTAsuppliedinvialsor bulk

pharmacycontainersincertaindiluentsatspecific concentrationsfor asimultaneousY-site

infusion.(SeeDOSAGE ANDADMINISTRATION.)ReformulatedTazocincontaining

EDTAisnot compatible withtobramycinfor simultaneouscoadministrationvia Y-site infusion.

The inactivationof aminoglycosidesinthe presence of penicillin-classdrugshasbeen

recognized.Ithasbeenpostulatedthatpenicillin-aminoglycosidecomplexesform;these

complexesaremicrobiologicallyinactiveandofunknowntoxicity.Sequentialadministrationof

Tazocinwithtobramycintopatientswithnormalrenalfunctionandmildtomoderate renal

impairmenthasbeenshowntomodestlydecrease serumconcentrationsof tobramycinbut does

notsignificantlyaffecttobramycinpharmacokinetics.Whenaminoglycosidesareadministered

incombinationwithpiperacillintopatientswithend-stage renaldisease requiringhemodialysis,

theconcentrationsof theaminoglycosides(especiallytobramycin) maybe significantlyaltered

andshouldbe monitored.Sinceaminoglycosidesare notequallysusceptibletoinactivationby

piperacillin,considerationshouldbegiventothe choice ofthe aminoglycoside when

administeredincombinationwithpiperacillintothese patients.

Probenecid

ProbenecidadministeredconcomitantlywithTazocinprolongsthe half-lifeof piperacillinby

21%andthatof tazobactamby71%.

Vancomycin

Nopharmacokinetic interactionshave beennotedbetweenTazocinandvancomycin.

Heparin

Coagulationparametersshouldbetestedmore frequentlyandmonitoredregularlyduring

simultaneousadministrationofhighdosesof heparin,oralanticoagulants,orotherdrugsthat

mayaffectthe bloodcoagulationsystemor thethrombocyte function.

Vecuronium

Piperacillinwhenusedconcomitantlywithvecuroniumhasbeenimplicatedinthe prolongation

oftheneuromuscular blockade of vecuronium.Tazocin(piperacillin/tazobactam) couldproduce

thesame phenomenonifgivenalongwithvecuronium.Due totheir similarmechanismof

action,itisexpectedthatthe neuromuscular blockade producedbyanyof the non-depolarizing

muscle relaxantscouldbeprolongedinthepresence of piperacillin.(See packageinsertfor

vecuroniumbromide.)

Methotrexate

Limiteddatasuggeststhatco-administrationof methotrexate andpiperacillinmayreducethe

clearance of methotrexate due tocompetitionfor renalsecretion.The impactoftazobactamon

theeliminationof methotrexate hasnotbeenevaluated.If concurrenttherapyisnecessary,

serumconcentrationsof methotrexate aswellasthesignsandsymptomsof methotrexate

toxicityshouldbe frequentlymonitored.

Drug/LaboratoryTest Interactions

Aswithother penicillins,the administrationofpiperacillin/tazobactammayresultina false-

positive reactionforglucose inthe urineusingacopper-reductionmethod(CLINITEST ®

).Itis

recommendedthatglucosetestsbasedonenzymatic glucoseoxidase reactions(suchas

DIASTIX ®

or TES-TAPE) be used.

There have beenreportsof positivetestresultsusingthe Bio-RadLaboratoriesPlatelia

AspergillusEIAtestinpatientsreceivingpiperacillin/tazobactaminjectionwhowere

subsequentlyfoundtobe free of Aspergillusinfection.Cross-reactionswithnon-Aspergillus

polysaccharidesandpolyfuranoses withthe Bio-RadLaboratoriesPlatelia AspergillusEIAtest

have beenreported.

Therefore,positivetestresultsinpatientsreceivingpiperacillin/tazobactamshouldbe

interpretedcautiouslyandconfirmedbyotherdiagnostic methods.

Carcinogenesis,Mutagenesis,Impairment of Fertility

Long-termcarcinogenicitystudiesinanimalshave notbeenconductedwith

piperacillin/tazobactam,piperacillin,or tazobactam.

Piperacillin/Tazobactam

Piperacillin/tazobactamwasnegativeinmicrobialmutagenicityassaysat concentrationsupto

14.84/1.86

g/plate.Piperacillin/tazobactamwasnegativeintheunscheduledDNAsynthesis

(UDS) test atconcentrationsupto5689/711

g/mL.Piperacillin/tazobactamwasnegativeina

mammalianpointmutation(Chinesehamster ovarycellHPRT)assayat concentrationsupto

8000/1000

g/mL.Piperacillin/tazobactamwasnegative inamammaliancell(BALB/c-3T3)

transformationassayatconcentrationsupto8/1

g/mL.Invivo,piperacillin/tazobactamdid

notinduce chromosomalaberrationsinratsdosedI.V.with1500/187.5mg/kg;thisdoseis

similar tothe maximumrecommendedhumandailydose onabody-surface-areabasis(mg/m 2

).

Piperacillin

Piperacillinwasnegative inmicrobialmutagenicityassaysat concentrationsupto50

g/plate.

There wasnoDNAdamage inbacteria (Rec assay) exposedtopiperacillinatconcentrationsup

to200

g/disk.Piperacillinwasnegativeinthe UDS testatconcentrationsupto10,000

g/mL.

Inamammalianpointmutation(mouse lymphoma cells) assay,piperacillinwaspositive at

concentrations

2500

g/mL.Piperacillinwasnegativeinacell(BALB/c-3T3) transformation

assayat concentrationsupto3000

g/mL.In vivo,piperacillindidnotinducechromosomal

aberrationsinmice atI.V.dosesupto2000mg/kg/dayor ratsatI.V.dosesupto

1500mg/kg/day.These dosesare half (mice) or similar (rats)tothe maximumrecommended

humandailydose basedonbody-surface area (mg/m 2

).Inanother invivotest,there wasno

dominantlethaleffectwhenpiperacillinwasadministeredtoratsat I.V.dosesupto

2000mg/kg/day,whichissimilar tothe maximumrecommendedhumandailydosebasedon

body-surface area (mg/m 2

).Whenmice were administeredpiperacillinatI.V.dosesupto

2000mg/kg/day,whichishalfthe maximumrecommendedhumandailydosebasedon

body-surface area (mg/m 2

),urine fromthese animalswasnotmutagenic whentestedina

microbialmutagenicityassay.Bacteriainjectedintothe peritonealcavityofmice administered

piperacillinat I.V.dosesupto2000mg/kg/daydid notshowincreasedmutationfrequencies.

Tazobactam

Tazobactamwasnegativeinmicrobialmutagenicityassaysat concentrationsupto

333

g/plate.Tazobactamwasnegativeinthe UDS testat concentrationsupto2000

g/mL.

Tazobactamwasnegativeinamammalianpoint mutation(Chinesehamster ovarycellHPRT)

assayat concentrationsupto5000

g/mL.In another mammalianpointmutation(mouse

lymphoma cells) assay,tazobactamwaspositive atconcentrations

3000

g/mL.Tazobactam

wasnegativeinacell(BALB/c-3T3) transformationassayat concentrationsupto900

g/mL.

Inaninvitrocytogenetics(Chinesehamster lungcells) assay,tazobactamwasnegative at

concentrationsupto3000

g/mL.Invivo,tazobactamdidnotinduce chromosomalaberrations

inratsat I.V.dosesupto5000mg/kg,whichis23timesthe maximumrecommendedhuman

dailydose basedonbody-surface area (mg/m 2

).

Pregnancy

Teratogenic effects—Pregnancy CategoryB

Piperacillin/tazobactam

Reproductionstudieshave beenperformedinratsandhave revealednoevidence of impaired

fertilityduetopiperacillin/tazobactamadministereduptoadose whichissimilar tothe

maximumrecommendedhumandailydosebasedonbody-surface area (mg/m 2

).

Teratologystudieshave beenperformedinmice andratsandhave revealednoevidence of

harmtothefetusduetopiperacillin/tazobactamadministereduptoadose whichis1to2times

and2to3timesthe humandose ofpiperacillinandtazobactam,respectively,basedonbody-

surface area (mg/m 2

).

Piperacillinandtazobactamcross the placentainhumans.

Piperacillin

Reproductionandteratologystudieshavebeenperformedinmice andratsandhave revealedno

evidenceof impairedfertilityor harmtothefetusdue topiperacillinadministereduptoadose

whichishalf (mice)or similar (rats)tothemaximumrecommendedhumandailydose basedon

body-surface area (mg/m 2

).

Tazobactam

Reproductionstudieshave beenperformedinratsandhave revealednoevidence of impaired

fertilityduetotazobactamadministeredatdosesupto3timesthemaximumrecommended

humandailydose basedonbody-surface area (mg/m 2

).

Teratologystudieshave beenperformedinmice andratsandhave revealednoevidence of

harmtothefetusduetotazobactamadministeredatdosesupto6and14times,respectively,

thehumandose basedonbody-surface area (mg/m 2

).Inrats,tazobactamcrossesthe placenta.

Concentrationsinthefetus arelessthanorequalto10%of thosefoundinmaternalplasma.

There are,however,noadequate andwell-controlledstudieswiththepiperacillin/tazobactam

combinationor withpiperacillinortazobactamaloneinpregnantwomen.Because animal

reproductionstudiesarenotalwayspredictiveof the humanresponse,thisdrugshouldbe used

duringpregnancyonlyif clearlyneeded.

NursingMothers

Piperacillinisexcretedinlowconcentrationsinhumanmilk;tazobactamconcentrationsin

humanmilkhave notbeenstudied.Cautionshouldbe exercisedwhenTazocin(piperacillinand

tazobactamfor injection)isadministeredtoanursingwoman.

Geriatric Use

Patientsover65yearsarenotatanincreasedriskofdevelopingadverse effectssolelybecause

of age.However,dosageshouldbe adjustedinthepresence of renalinsufficiency.

(SeeDOSAGEANDADMINISTRATION.)

Ingeneral,doseselectionforanelderlypatient shouldbe cautious,usuallystartingatthelow

endofthedosingrange,reflectingthe greater frequencyof decreasedhepatic,renal,or cardiac

function,andof concomitantdiseaseorotherdrugtherapy.

Tazocincontains64mg(2.79mEq) of sodiumper gramof piperacillininthe combination

product.Atthe usualrecommendeddoses,patientswouldreceive between768and1024

mg/day(33.5 and44.6mEq) of sodium.The geriatricpopulationmayrespond withablunted

natriuresistosaltloading.Thismaybe clinicallyimportantwithregardtosuchdiseasesas

congestiveheartfailure.

Thisdrugisknowntobesubstantiallyexcretedbythekidney,andthe riskof toxic reactionsto

thisdrugmaybe greater inpatientswithimpairedrenalfunction.Because elderlypatientsare

more likelytohavedecreasedrenalfunction,care shouldbetakenindose selection,anditmay

be usefultomonitor renalfunction.

Adverse Reactions

Adverse EventsfromClinicalTrials

Duringthe initialclinicalinvestigations,2621patientsworldwide were treatedwithTAZOCIN

(piperacillinandtazobactamfor injection)phase3trials.InthekeyNorthAmericanclinical

trials(n=830patients),90%of the adverseeventsreportedweremildtomoderate inseverity

andtransientinnature.However,in3.2%of thepatientstreatedworldwide,TAZOCINwas

discontinuedbecauseof adverse eventsprimarilyinvolvingtheskin(1.3%),includingrashand

pruritus;the gastrointestinalsystem(0.9%),includingdiarrhea,nausea,andvomiting;and

allergic reactions(0.5%)

Adverselocalreactionsthatwere reported,irrespective of relationshiptotherapywith

TAZOCINwere phlebitis(1.3%),injectionsite reaction(0.5%),pain(0.2%),inflammation

(0.2%),thrombophlebitis(0.2%),andedema (0.1%).

Basedonpatientsfromclinicaltrials(n=1063),the eventswiththehighestincidenceinpatients,

irrespective of relationshiptoTazocintherapy,werediarrhea (11.3%);headache (7.7%);

constipation(7.7%);nausea (6.9%);insomnia (6.6%);rash(4.2%),includingmaculopapular,

bullous,urticarial,andeczematoid;vomiting(3.3%);dyspepsia(3.3%);pruritus(3.1%) ; stool

changes(2.4%);fever (2.4%);agitation(2.1%);pain(1.7%);moniliasis(1.6%);hypertension

(1.6%);dizziness(1.4%); abdominalpain(1.3%);chestpain(1.3%); edema (1.2%);anxiety

(1.2%);rhinitis(1.2%);anddyspnea (1.1%).

Additionaladversesystemic clinicaleventsreportedin1.0%or lessof thepatientsinthe initial

NorthAmericantrialsare listedbelowwithineachbodysystem.

AutonomicNervousSystemhypotension,ileus,syncope

Bodyasawhole—rigors,backpain,malaise

Cardiovascular—tachycardia,includingsupraventricular andventricular;bradycardia;

arrhythmia,includingatrial fibrillation,ventricular fibrillation,cardiac arrest,cardiacfailure,

circulatoryfailure,myocardialinfarction

CentralNervousSystem—tremor,convulsions,vertigo

Gastrointestinal—melena,flatulence,hemorrhage,gastritis,hiccough,ulcerative stomatitis

Pseudomembranouscolitiswasreportedinone patientduringtheclinicaltrials.Theonsetof

pseudomembranouscolitissymptomsmayoccur duringor afterantibacterialtreatment.

(SeeWARNINGS.)

HearingandVestibularSystem—tinnitus

Hypersensitivity—anaphylaxis

Metabolic andNutritional—symptomatichypoglycemia,thirst

Musculoskeletal—myalgia,arthralgia

Platelets,Bleeding,Clotting—mesenteric embolism,purpura,epistaxis,pulmonaryembolism

(seePRECAUTIONS,General).

Psychiatric—confusion,hallucination,depression

Reproductive,Female—leukorrhea,vaginitis

Respiratory—pharyngitis,pulmonaryedema,bronchospasm,coughing

SkinandAppendages—genitalpruritus,diaphoresis

Specialsenses—tasteperversion

Urinary—retention,dysuria,oliguria,hematuria,incontinence

Vision—photophobia

Vascular(extracardiac)—flushing

NosocomialPneumoniaTrials

Inacompletedstudyof nosocomiallowerrespiratorytractinfections,222patientswere treated

withTazocininadosingregimenof4.5gevery6 hoursincombinationwithanaminoglycoside

and215patientsweretreatedwithimipenem/cilastatin(500mg/500mgq6h) incombination

withan aminoglycoside.Inthistrial,treatment-emergentadverse eventswere reportedby

402patients,204(91.9%) inthe piperacillin/tazobactamgroupand198(92.1%) inthe

imipenem/cilastatingroup.Twenty-five (11.0%)patientsinthepiperacillin/tazobactamgroup

and14(6.5%) intheimipenem/cilastatingroup(p 

0.05)discontinuedtreatmentdue toan

adverse event.

Inthisstudyof Tazocinincombinationwithan aminoglycoside,adverse eventsthatoccurredin

more than1%ofpatientsandwere consideredbythe investigator tobe drug-relatedwere:

diarrhea (17.6%),fever (2.7%),vomiting(2.7%),urinarytractinfection(2.7%),rash(2.3%),

abdominalpain(1.8%),generalizededema (1.8%),moniliasis(1.8%),nausea (1.8%),oral

moniliasis(1.8%),BUNincreased(1.8%),creatinine increased(1.8%),peripheraledema

(1.8%),abdomenenlarged(1.4%),headache (1.4%),constipation(1.4%),liver functiontests

abnormal(1.4%),thrombocythemia (1.4%),excoriations(1.4%),andsweating(1.4%).

Drug-relatedadverse eventsreportedin1%or lessofpatientsinthenosocomialpneumonia

studyof Tazocinwithan aminoglycoside were:acidosis,acute kidneyfailure,agitation,alkaline

phosphatase increased,anemia,asthenia,atrialfibrillation,chestpain, CNS depression,colitis,

confusion,convulsion,coughincreased,thrombocytopenia,dehydration,depression,diplopia,

drugleveldecreased,drymouth,dyspepsia,dysphagia,dyspnea,dysuria,eosinophilia,fungal

dermatitis,gastritis,glossitis,grandmalconvulsion,hematuria,hyperglycemia,hypernatremia,

hypertension,hypertonia,hyperventilation,hypochromic anemia,hypoglycemia,hypokalemia,

hyponatremia,hypophosphatemia,hypoxia,ileus,injectionsiteedema,injectionsitepain,

injectionsite reaction,kidneyfunctionabnormal,leukocytosis,leukopenia,localreactionto

procedure,melena,pain,prothrombindecreased,pruritus,respiratorydisorder,SGOT

increased,SGPTincreased,sinusbradycardia,somnolence,stomatitis,stupor,tremor,

tachycardia,ventricular extrasystoles,andventricular tachycardia.

Inapreviousnosocomialpneumonia studyconductedwithadosingregimenof 3.375ggiven

every4 hourswithanaminoglycoside,thefollowingadverse events,irrespective ofdrug

relationship,wereobserved:diarrhea (20%);constipation(8.4%);agitation(7.1%);nausea

(5.8%);headache (4.5%);insomnia (4.5%);oralthrush(3.9%);erythematousrash(3.9%);

anxiety(3.2%);fever(3.2%);pain(3.2%);pruritus(3.2%);hiccough(2.6%);vomiting(2.6%);

dyspepsia (1.9%);edema (1.9%);fluidoverload(1.9%);stoolchanges(1.9%);anorexia (1.3%);

cardiac arrest(1.3%);confusion(1.3%);diaphoresis(1.3%);duodenalulcer (1.3%);flatulence

(1.3%);hypertension(1.3%);hypotension(1.3%);inflammationatinjectionsite (1.3%);pleural

effusion(1.3%);pneumothorax(1.3%);rash,nototherwisespecified(1.3%);supraventricular

tachycardia (1.3%);thrombophlebitis(1.3%);andurinaryincontinence (1.3%).

Adverse eventsirrespectiveofdrugrelationshipobservedin1%or lessofpatientsintheabove

studywithTazocinandanaminoglycoside included:aggressive reaction(combative),angina,

asthenia,atelectasis,balanoposthitis,cerebrovascular accident,chestpain,conjunctivitis,

deafness,dyspnea,earache,ecchymosis,fecalincontinence,gastric ulcer,gout,hemoptysis,

hypoxia,pancreatitis,perinealirritation/pain,urinarytractinfectionwithtrichomonas,vitamin

deficiencyanemia,xerosis,andyeastinurine.

Pediatrics

StudiesofTazocininpediatric patientssuggestasimilar safetyprofiletothatseeninadults.In

a prospective,randomized,comparative,open-labelclinicaltrialofpediatricpatientswith

severe intra-abdominalinfections(includingappendicitisand/or peritonitis),273patientswere

treatedwithTazocin(112.5mg/kgevery8 hours) and269patientswere treatedwithcefotaxime

(50mg/kg)plusmetronidazole (7.5mg/kg) every8 hours.Inthistrial,treatment-emergent

adverse eventswere reportedby146patients,73(26.7%) intheTazocingroupand73(27.1%)

inthe cefotaxime/metronidazole group.Sixpatients(2.2%)intheTazocingroupand5patients

(1.9%)inthe cefotaxime/metronidazole groupdiscontinuedduetoanadverse event.

Inthisstudy,adverseeventsthatwere reportedinmore than1%of patients,irrespective of

relationshiptotherapywithTazocin,were:diarrhea (7.0%),fever (4.8%),vomiting(3.7%),

localreaction(3.3%),abscess(2.2%),sepsis(2.2%),abdominalpain(1.8%),infection(1.8%),

bloodydiarrhea (1.1%),pharyngitis(1.5%),constipation(1.1%),andSGOTincrease (1.1%).

Adverse eventsreportedin1%orlessof pediatricpatientsreceivingTazocinare consistentwith

adverse eventsreportedinadults.

Additionalcontrolledstudiesinpediatricpatientsshowedasimilar safetyprofile asthat

describedabove.

Post-MarketingExperience

Additionaladverseeventsreportedfromworldwidemarketingexperience withTazocin,

occurringunder circumstanceswhere causalrelationshiptoTazocinisuncertain:

Gastrointestinal—hepatitis,cholestatic jaundice

Hematologic—hemolytic anemia,anemia,thrombocytosis,agranulocytosis,pancytopenia

Immune—hypersensitivityreactions,anaphylactic/anaphylactoidreactions(includingshock)

Infections—candidalsuperinfections

Renal—interstitialnephritis,renalfailure

SkinandAppendages—erythemamultiforme,Stevens-Johnsonsyndrome,toxic epidermal

necrolysis

Post-marketingexperiencewithTazocinin pediatric patientssuggestsasimilar safety

profile to that seen in adults.

AdverseLaboratoryEvents: (seen duringClinicalTrials)

Of thestudiesreported,includingthatofnosocomiallower respiratorytractinfectionsinwhich

a higher dose of Tazocin(piperacillinandtazobactamfor injection) wasusedincombination

withan aminoglycoside,changesinlaboratoryparameters,withoutregardtodrugrelationship,

include:

Hematologic—Decreasesinhemoglobinandhematocritthrombocytopenia,increasesin

plateletcount,eosinophilia,leukopenia,neutropenia.The leukopenia/neutropenia associated

withTAZOCINadministrationappearstobe reversible andmostfrequentlyassociatedwith

prolongedadministration,ie. ≥

21daysof therapy.These patientswere withdrawnfromtherapy;

some hadaccompanyingsystemic symptoms(e.g.,fever,rigors,chills).

Coagulation—Positive directCoombs’test, prolongedprothrombintime,prolongedpartial

thromboplastintime

Hepatic—Transientelevationsof AST(SGOT),ALT(SGPT),alkaline phosphatase,bilirubin

Renal—Increasesinserumcreatinine,bloodureanitrogen

Urinalysis—Proteinuria,hematuria,pyuria

Additionallaboratoryeventsinclude abnormalitiesinelectrolytes(i.e.,increasesanddecreases

insodium,potassiumandcalcium),hyperglycemia,decreasesintotalproteinor albumin.,

bloodglucose decreased,gamma-glutamyltransferase increased,hypokalemia,andbleeding

time prolonged.

The followingadverse reactionhasalsobeenreportedfor PIPRACIL ®

(piperacillinfor

injection):

Skeletal—prolongedmuscle relaxation(SeePRECAUTIONS,DrugInteractions.)

Piperacillintherapyhasbeenassociatedwithanincreasedincidenceof fever andrashincystic

fibrosispatients.

OVERDOSAGE

There have beenpostmarketingreportsofoverdose withpiperacillin/tazobactam.Themajority

of those eventsexperienced,includingnausea,vomiting,anddiarrhea,have alsobeenreported

withthe usualrecommendeddosages.Patientsmayexperience neuromuscular excitabilityor

convulsionsifhigherthanrecommendeddosesaregivenintravenously(particularlyinthe

presence of renalfailure).

Treatmentshouldbesupportive andsymptomatic according to the patient’sclinical

presentation.Excessive serumconcentrationsof either piperacillinortazobactammaybe

reducedbyhemodialysis.Followingasingle3.375gdoseof piperacillin/tazobactam,the

percentage ofthe piperacillinandtazobactamdose removedbyhemodialysiswas

approximately31%and39%,respectively.(SeeCLINICAL PHARMACOLOGY.)

DOSAGE ANDADMINISTRATION

Tazocinshouldbe administeredbyintravenousinfusionover30minutes.

Neutropenicpatientswithsignsofinfection(e.g.fever) shouldreceiveimmediateempirical

antibiotictherapybefore laboratoryresultsareavailable.

Adultsandadolescents(over 12years)

The usualdosage foradultsandjuvenileswithnormalrenalfunctionis4.5g

piperacillin/tazobactamgiveneveryeighthours.

For nosocomialpneumonia andbacterialinfectionsinneutropenicpatients,the recommended

doseis4gpiperacillin/0.5tazobactamadministeredevery6 hours.Thisregimenmayalso be

applicable totreatpatientswithotherindicatedinfectionswhenparticularlysevere.

NosocomialPneumonia

Initialpresumptivetreatmentofpatientswithnosocomialpneumonia shouldstart

withTazocinatadosageof 4.5geverysixhoursplusanaminoglycoside,totaling

18.0g(16.0gpiperacillin/2.0gtazobactam).Treatmentwiththe aminoglycoside shouldbe

continuedinpatientsfromwhomPseudomonasaeruginosa isisolated.If Pseudomonas

aeruginosa isnotisolated,the aminoglycoside maybe discontinuedatthediscretionof the

treatingphysician.

Due tothe invitroinactivationof the aminoglycosidebybeta-lactamantibiotics,Tazocinand

theaminoglycosideare recommendedforseparate administration.Tazocinandthe

aminoglycosideshouldbe reconstituted,diluted,andadministeredseparatelywhenconcomitant

therapywithaminoglycosidesisindicated.(SeePRECAUTIONS,DrugInteractions.)

Incircumstanceswhere co-administrationvia Y-siteisnecessary,reformulatedTazocin

containingEDTAsuppliedinvialsor bulkpharmacycontainersiscompatible for simultaneous

coadministrationviaY-site infusiononlywiththe followingaminoglycosidesunder the

followingconditions:

The followingcompatibilityinformationdoesnotapplytothe Tazocin

(piperacillin/tazobactam) formulation not containingEDTA.

TABLE 4

Aminoglycoside Tazocin

Dose

(grams) Tazocin

Diluent

volume

(mL) Aminoglycoside

Concentration

Range*

(mg/mL) Acceptable

diluents

Amikacin 2.25,

3.375,4.5 50,100,150 1.75-7.5 0.9%Sodium

Chloride or5%

Dextrose

Gentamicin 2.25,

3.375,4.5 50,100,150 0.7-3.32 0.9%Sodium

Chlorideor5%

Dextrose 2

*The concentrationrangesinTable 4 are basedonadministrationof the aminoglycoside in

divideddoses(10-15mg/kg/dayintwodailydosesfor amikacinand3-5mg/kg/dayinthree

dailydosesforgentamicin).Administrationof amikacinorgentamicininasingle dailydoseor

indosesexceedingthosestatedaboveviaY-site withTazocincontainingEDTAhasnotbeen

evaluated.Seepackage insertfor eachaminoglycoside for complete Dosage andAdministration

instructions.

Tazocin isnot compatiblewith tobramycin for simultaneouscoadministration viaY-site

infusion.Compatibilityof Tazocinwithotheraminoglycosideshasnotbeen established.

Onlytheconcentrationanddiluentsforamikacin orgentamicinwith thedosagesof

Tazocin listed abovehave been established ascompatible forcoadministration viaY-site

infusion.Simultaneouscoadministration via Y-siteinfusionin anymanner other than

listedabove mayresult ininactivationoftheaminoglycosidebyTazocin.

RenalInsufficiency:Adults

Inpatientswithrenalinsufficiency(Creatinine Clearance

40mL/min),the intravenousdose

of Tazocin(piperacillinandtazobactamfor injection)shouldbeadjustedtothe degreeof actual

renalfunctionimpairment.Inpatientswithnosocomialpneumonia receivingconcomitant

aminoglycosidetherapy,the aminoglycoside dosage shouldbeadjustedaccordingtothe

recommendationsofthe manufacturer.Therecommendeddailydosesof Tazocinforpatients

withrenalinsufficiencyareasfollows:

Recommended Dosingof Tazocin in Patientswith NormalRenalFunctionandRenal

Insufficiency

(Astotalgramspiperacillin/tazobactam)

TABLE5

RenalFunction

(Creatinine Clearance,

mL/min) AllIndications(except nosocomial

pneumonia) Nosocomial

Pneumonia

40mL/min Nodose adjustmentnecessary 4.5q6h

20-40mL/min* Maximumdose suggested:4.5gq8h 3.375q6h

20mL/min* Maximumdose suggested:4.5gq12h 2.25q6h

Hemodialysis** 2.25q12h 2.25q8h

CAPD 2.25q12h 2.25q8h

*Creatinine clearance for patientsnotreceivinghemodialysis

**0.75gshouldbe administeredfollowingeachhemodialysissessiononhemodialysisdays

For patientsonhemodialysis,the maximumdoseis2.25geverytwelvehoursfor allindications

otherthannosocomialpneumonia and2.25geveryeighthoursfor nosocomialpneumonia.

Since hemodialysisremoves30%to40%of the administereddose,anadditionaldoseof 0.75g

Tazocinshouldbe administeredfollowingeachdialysisperiodonhemodialysisdays.No

additionaldosageofTazocinisnecessaryfor CAPDpatients.

Durationof Therapy

The usualdurationofTazocintreatment formostindicationsisinthe rangeof5-14days.

However,the recommendeddurationof Tazocintreatmentofnosocomialpneumonia is7to14

days.Inallconditions,the durationoftherapyshouldbe guidedbythe severityof theinfection

andthe patient'sclinicalandbacteriologicalprogress.

Pediatric Patients(2-12yearsofage)

For childrenwithappendicitisolder than2yearsand/or peritonitis,weighingupto40kg,and

withnormalrenalfunction,the recommendedTazocindosage is100mgpiperacillin/12.5mg

tazobactamper kilogramofbodyweight,every8 hours.Pediatric patientsweighingover40kg

andwithnormalrenalfunctionshouldreceivethe adultdose.

The followingtable summarizesthetreatmentfrequencyandthedose per bodyweightfor

pediatric patients2-12yearsof agebyindicationor condition:

TABLE6

Doseper weightandtreatmentfrequencyIndication/ condition

80mgPiperacillin/10mgTazobactam

perkgbodyweight/every6 hours Neutropenic childrenwithfever suspectedto

be duetobacterialinfections*

100mgPiperacillin/12.5mg

Tazobactamper kgbodyweight/every8

hours Complicatedintra-abdominalinfections*

*Nottoexceedthemaximum4 g/ 0.5gperdose over 30minutes.

Renalimpairment

The intravenousdoseshouldbe adjustedtothedegreeofactualrenalimpairmentas follows

(eachpatientmustbemonitoredcloselyfor signsof substance toxicity;medicinalproductdose

andintervalshouldbe adjustedaccordingly):

For childrenonhaemodialysis,one additionaldoseof40mgpiperacillin/5mgtazobactam/ kg

shouldbe administeredfollowingeachdialysisperiod.

Directionsfor ReconstitutionandDilution for Use

IntravenousAdministration

For conventionalvials,reconstitute Tazocinper gramof piperacillinwith5mLof a compatible

reconstitutiondiluentsfromthe listprovidedbelow.

2.25g and4.5g Tazocinshouldbereconstitutedwith10mLand20mLrespectively.Swirl

untildissolved.

Compatible Reconstitution Diluents

0.9%SodiumChloride forInjection

Sterile Water for Injection †

Dextrose 5%

Bacteriostatic Saline/Parabens

Bacteriostatic Water/Parabens

Bacteriostatic Saline/BenzylAlcohol

Bacteriostatic Water/BenzylAlcohol

ReconstitutedTazocinsolutionshouldbe furtherdiluted(recommendedvolume per doseof50

mlto150 ml)ina compatible intravenoussolutionlistedbelow.Administer byinfusionover a

periodof atleast30minutes.Duringthe infusionitisdesirabletodiscontinue theprimary

infusionsolution.

Compatible Intravenous Solutions

0.9%SodiumChloride forInjection

Sterile Water for Injection †

Dextrose 5%

Dextran6%inSaline

LactatedRinger’sSolution(CompatibleonlywithreformulatedTazocincontainingEDTA-and

iscompatible forco-administrationvia aY-site). 2

Maximumrecommendedvolumeper doseof Sterile Water forInjectionis50ml.

Tazocinshouldnotbemixedwithother drugsinasyringeor infusionbottlesince compatibility

hasnotbeenestablished.

Tazocinisnotchemicallystable insolutionsthatcontainonlysodiumbicarbonateandsolutions

thatsignificantlyalter thepH.

Tazocinshouldnotbe addedtobloodproductsor albuminhydrolysates.

Tazocincanbe usedinambulatoryintravenousinfusionpumps.

Stability ofTazocinFollowingReconstitution

Tazocinisstable inglassandplastic containers(plastic syringes,I.V.bagsandtubing)when

usedwithcompatiblediluents.

Pharmacyvialsshouldbeusedimmediatelyafter reconstitution.Discardanyunusedportion

after24hoursif storedat atemperaturebelow25°C, or after 48hoursifstoredatrefrigerated

temperature (2°C to8°C).

Vialsshouldnotbe frozenafter reconstitution.

Unusedportionof thereconstitutedsolutionshouldbediscarded.

Stabilitystudiesinthe I.V.bagshavedemonstratedchemicalstability(potency,pHof

reconstitutedsolution,andclarityof solution) forupto24hoursat roomtemperatureandupto

one weekatrefrigeratedtemperature.Tazocincontainsnopreservatives.Appropriate

considerationof aseptictechnique shouldbe used.

Stabilityof Tazocininan ambulatoryintravenousinfusionpumphasbeendemonstratedfor a

periodof 12hoursatroomtemperature.Eachdose wasreconstitutedanddilutedtoavolume of

37.5mLor 25mL.One-daysuppliesof dosingsolutionwere asepticallytransferredintothe

medicationreservoir(I.V.bagsor cartridge).The reservoir wasfittedtoapreprogrammed

ambulatoryintravenousinfusionpumpper the manufacturer'sinstructions.Stabilityof Tazocin

isnotaffectedwhenadministeredusinganambulatoryintravenousinfusionpump.

Parenteraldrugproductsshouldbe inspectedvisuallyfor particulate matter anddiscoloration

priortoadministration,whenever solutionandcontainerpermit.

HOW SUPPLIED

Tazocin(piperacillinandtazobactamfor injection) issuppliedinthe followingsizes:

EachTazocin2.25gvialprovidespiperacillinsodiumequivalentto2gramsof piperacillinand

tazobactamsodiumequivalentto0.25goftazobactam.Eachvialcontains5.58mEq(128mg) of

sodium.

EachTazocin4.5gvialprovidespiperacillinsodiumequivalentto4gramsof piperacillinand

tazobactamsodiumequivalentto0.5gof tazobactam.Eachvialcontains11.17mEq(256mg)

of sodium.

Tazocinvialsshouldbe storedatatemperature below25°Cprior toreconstitution.

REFERENCES

1.ClinicalandLaboratoryStandardsInstitute (CLSI).Performance Standardsfor Antimicrobial

SusceptibilityTesting;21stInformationalSupplement.CLSI documentM100-S21.CLSI,940

WestValleyRd.,Suite 1400,Wayne,PA19087,2011.

2.CLSI.MethodsforDilutionAntimicrobialSusceptibilityTestfor BacteriathatGrow

Aerobically;ApprovedStandard–8thed.CLSI documentM07-A8,2009.

3.CLSI.Performance Standardsfor AntimicrobialDiskSusceptibilityTest;ApprovedStandard

–10thed.CLSI documentM02-A10,2009.

4.CLSI.MethodsforAntimicrobialSusceptibilityTestingof Anaerobic Bacteria;Approved

Standard–7thed.CLSI documentM11-A7,2007.

DIASTIX ®

isaregisteredtrademarkof Bayer Healthcare LLC.

CLINITEST ®

isaregisteredtrademarkSiemensHealthcare DiagnosticsInc.

REGISTRATIONNUMBER:

Tazocin4.5gvial:066-09-27500-01 (1)

,066-09-27500-02 (2)

Tazocin2.25gvial:066-07-27502-01 (2 )

MANUFACTURER:

1)WyethLederle S.P.A,Aprilia,Italy

2)WyethPiperacillinDivisionof WyethHoldingsCorporation,Carolina,PuertoRico,USA

REGISTRATIONHOLDER:

NeopharmLtd.P.O.Box7063PetachTiqva 49170

The formatof thisleaflethasbeendefinedbythe Ministryof Health;itscontenthasbeen

checkedandapprovedAugust2012.

The formatofthis leafletisbased onFDAUSPIfrom06/2012andUKSPCfrom9/2011.

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