oxaliplatin

DrugMonograph
DrugName|MechanismofActionandPharmacokinetics|IndicationsandStatus|AdverseEffects|Dosing|Administration Guidelines|SpecialPrecautions|Interactions|RecommendedClinicalMonitoring|References

ADrugName

oxaliplatin
SYNONYM(S): 1OHPLOHPoxalatoplatinoxaliplatinum COMMONTRADENAME(S): Eloxatin(SanofiAventis) backtotop BMechanismofActionandPharmacokinetics Oxaliplatinisanalkylatingagent,belongingtoanewclassofplatinumagent,consistingofplatinum complexedtooxalateanddiaminocyclohexane(DACH)complex.Platinumcomplexesareformed intracellularlyandinhibitDNAsynthesisthroughcovalentbindingofDNAmoleculestoform intrastrandandinterstrandDNAcrosslinks.Oxaliplatindiffersmolecularly,fromotherplatinums (cisplatinandcarboplatin),byitsbulkyDACHcarrierligandthatmostlikelyaccountsforbothits efficacyandlackofcrossresistancewithotherplatinumcompounds.Cytotoxicityiscellcycle nonspecific.Oxaliplatinisaradiationsensitizingagent. Absorption Distribution Oral:no Approximately15%oftheadministeredplatinumispresentinthe systemiccirculation.Theremaining85%israpidlydistributedintotissues oreliminatedintheurine. Crossbloodbrainbarrier? PPB Metabolism noinformationfound >90%

Rapidandextensivenonenzymatic(nocytochromeP450mediated metabolism)biotransformationtoreactiveplatinumcomplexes. Activemetabolites Inactivemetabolites Diaminocyclohexane(DACH) platinumcomplexes. Yes,severalconjugates,including onewhichisassociatedwith

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oxaliplatin
neurotoxicity. Elimination Themajoreliminationrouteofplatinumanditsmetabolitesisrenal excretion.Renalclearanceofultrafilterableplatinumissignificantly relatedtoGFR. Halflife Urine backtotop CIndicationsandStatus HealthCanadaApprovals:
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(Eliminationhalflife):391hours (renal):54%within5days

Useincombinationwithinfusional5fluorouracil(5FU)/leucovorin(LV)intreatmentfor patientswithmetastaticcolorectalcancer. Useincombinationwithinfusional5fluorouracilandleucovorinasadjuvanttreatmentof patientswithstageIII(Duke'sC)coloncanceraftercompleteresectionofprimarytumor.

OtherUses:
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Adjuvanttherapy(FOLFOX)instageIIorIIIrectalcancer

backtotop DAdverseEffects

Emetogenicpotential: Moderate ExtravasationPotential: Irritant Thefollowingtablecontainsadverseeffectsreportedmainlyincombinationasadjuvanttherapy. Somesideeffects(markedwith*)werereportedonlyinmetastatictrialsorpostmarketing. ORGANSITE Auditory Cardiovascular SIDEEFFECT*(%) Hearingimpaired(deafnessrare)* Vertigo(<5%)* Chestpain(<5%) Hypertension(<5%) Hypotension(<5%) I I ONSET** E E I E

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oxaliplatin
Thromboembolism(6%)* Dermatological Alopecia(30%) Naildisorder(5%)* Handfootsyndrome(7%)* Rash(14%) Gastrointestinal Abdominalpain(18%) Anorexia(13%) Ascites(<5%)* Constipation(22%) Dehydration(9%) Diarrhea(56%) Drymouth(<5%)* Dyspepsia(8%) Dysphagia* Flatulence* GIhemorrhage(<5%) GIobstruction(5%) Ileus(rare)* Mucositis(42%) Nausea(74%) Rectalpain(<5%) Vomiting(47%) Weightchanges(10%) General Edema(15%) Fatigue(44%) Fever(27%) Pain(5%) Rigors Hematological Anemia(1%)(severe) Febrileneutropenia(1%) Hemolysis(immunehemolyticanemiarare)* Hemolyticuremicsyndrome(rare)* Hemorrhage INR/prothrombintimeincreased(<5%) Idiopathicthrombocytopenicpurpura(rare)* Neutropenia(41%)(grade3/4) Thrombocytopenia(2%)(grade3/4) Hepatobiliary Hepaticfailure(rare)* E I E E E E E E E D E E E E E E E E E E E E E E E E E I E E I E E E E E E E D E D

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oxaliplatin
LFTs(57%) Pancreatitis(rare)* Venoocclusivedisease(rare)* Hypersensitivity Infection Injectionsite Metabolic/Endocrine Musculoskeletal Anaphylaxis(10%)(3%grade34) Infection(25%) Other(clostridiumdifficilerare)* Injectionsitereaction(11%) AbnormalElectrolyte(s)* Hyperglycemia(14%)* Arthralgia* Myalgia* Rhabdomyolysis(rare)* NervousSystem Anxiety* Ataxia(<5%)* Cranialneuropathy Depression* Dizziness(<5%) Dysgeusia(12%) Dysphasia GuillainBarresyndrome(rare)* Headache(7%) Insomnia(<5%) RPLS(rare) Seizure(rare)* Sensoryneuropathy(92%) Syncope* Ophthalmic Conjunctivitis(9%) Opticnervedisorder(rare)* Other(5%)(visionloss) Wateringeyes(<5%) Renal Respiratory Nephritis(interstitialrare)* Nephrotoxicity(<5%severe<1%,includesHUS)* Cough(<5%) Dyspnea(5%) Hiccups(5%)* Laryngopharyngealdysesthesia(38%) Pneumonitis(<5%)* I D I E E E E E I E E E I E I E E E E I E E E E E E I E E E E E E I E E D E E D

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oxaliplatin
Pulmonaryfibrosis(<1%) Rhinitis(6%) Urinary Dysuria(6%)* Urinaryfrequency(5%)* Urinarytractinfection(5%)* D E E E E

*"Incidence"mayrefertoanabsolutevalueorthehighervaluefromareportedrange. "Rare"mayrefertoeventswith<1%incidence,reportedinpostmarketing,phase1studies, isolateddataoranecdotalreports. Doselimitingsideeffectsareunderlined. **I=immediate(onsetinhourstodays)E=early(daystoweeks) D=delayed(weekstomonths)L=late(monthstoyears)

Adverseeffectsnotedabovearefromcontrolledclinicaltrialsofthecombinationintheadjuvant setting.Themostcommonadversereactionsassociatedwiththecombinationoxaliplatin/5FU/LV wereperipheralsensoryneuropathies,fatigue,myelosuppression,GItoxicityand increasedtransaminases. Theacute,reversible,primarilyperipheral,sensoryneuropathyassociatedwithoxaliplatinisof earlyonset,andcanoccurwithinhoursoronetotwodaysofdosing.Itusuallyresolveswithin14 days,andfrequentlyrecurswithfurtherdosing.Symptomsincludesensoryataxiaanddysesthesia ofthelimbs,mouth,throatandlarynx.Jawspasm,abnormaltonguesensation,dysarthria,eye pain,andafeelingofchestpressurehavealsobeenobserved.Symptomsmaybeexacerbated byexposuretocold(e.g.,touchingcoldsurface,drinkingcoldliquid).Ice(mucositisprophylaxis) shouldbeavoided.Theacute,reversiblepatternofsensoryneuropathywasobservedinabout 58%ofstudypatientswhoreceivedOxaliplatinwith5FU/LV.Pharyngolaryngealdysesthesia iscommon,withseveresymptomsin12%ofpatientsshortlyafterdruginfusion.Symptoms usuallyresolvewithinhoursofonsetbutthefeelingofdifficultyinbreathingorswallowingmaybe distressingtothepatient.Treatmentisusuallynotneeded,althoughantihistaminesand bronchodilatorshavebeenused.Topreventrecurrence,infusiontimeshouldbeextendedto6 hourswithsubsequenttreatments. Thepersistent(>14days),primarilyperipheral,sensoryneuropathyisusuallycharacterizedby paresthesias,dysesthesias,hypoesthesiasandalteredproprioception.Itcaninterferewithdaily activities(e.g,buttoningclothing,holdingobjects,writing)andoccursinmostpatientsreceiving oxaliplatinwith5FU/LV.Lhermittessignandurinaryretentionareseenrarely.Persistent neuropathycanoccurwithoutprioracuteneuropathyevent.Symptomsmayimproveinsome patientsupondiscontinuationofoxaliplatin.Smallstudiessuggestthatcalciumgluconate1gand magnesiumsulphate1ginfusionspreandpostoxaliplatinameliorateneurotoxicityandmaynot compromiseefficacy.Thisisnotrecommendedinpatientswithhypercalcemia,oronconcomitant thiazidediureticsordigoxin.Calciummaycausearrhythmiasinpatientstakingdigoxin,or precipitatehypercalcemiawithconcomitantuseofthiazidediuretics.Gabapentinseemsto reducesymptomsifadministeredattheonsetofneurotoxicity.Amifostineandcarbamezepine havebeenusedforneurotoxicitybuthavesignificanttoxicity.Theeffectofanyofthesemeasures onefficacyisasyetunknown. Anaphylaxishasbeenreported,includingsevere,in23%ofpatients.Patientsshouldnotbere challenged.
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oxaliplatin
Pulmonaryfibrosishasbeenreportedrarely,andpresentswithcough,dyspnea,cracklesand pulmonaryinfiltratesoxaliplatinshouldbediscontinuedpendinginvestigation. Elderlypatientsover65maybeathigherriskofsevere(grades34)diarrhea.Womenmaybe athigherriskofsevere(grades34)neutropenia.Incidencesofadverseeventsaregenerally similarbetweenoxaliplatinusedassingleagentorwithfluorouracilandleucovorin,although severe(grades34)diarrhea,nauseaandvomiting,andneurotoxicityaremorecommonwith combinationtherapy. backtotop EDosing Refertoprotocolbywhichpatientisbeingtreated.Prolongingtheinfusionto6hoursmayreduce neurotoxicity.Foradjuvantuse,treatmentisrecommendedforatotalof12cycles. Adults: AsSingleAgent:130mg/m2IVinfusionover2hoursevery3weeks(notHealthCanada approved) InCombinationwith5FluorouracilandLeucovorin:85mg/m2IVinfusionover2hoursevery2 weeks* 2 *somecombinationssuchasFOLFOX6recommendadoseofoxaliplatin100mg/m

DosagewithToxicity: DonotretreatuntiltheANCis1.5x109/Landtheplateletcountis75x109/L.Considerdose reductioninsubsequentcyclesafterrecoveryfromGrade3or4hematologicaltoxicities.Modify accordingtoprotocolbywhichpatientisbeingtreated.

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oxaliplatin
GradeToxicity Persistent*Grade2 Neurotoxicity Transient*Grade3 Neurotoxicity Persistent*Grade3 Neurotoxicity SingleAgent 20% 20% Discontinue Combinations Adjuvant** from8575 mg/m2 to75mg/m2 Discontinue from8575 mg/m2 Reduce5FUby 20% Combinations Palliative** from8565 mg/m2 to65mg/m2 Discontinue from8565 mg/m2 Reduce5FUby 20%

Grade3GItoxicity(after prophylaxis)OR 20% Grade3or4PlateletsOR Grade3or4Neutropenia Othergrade3toxicity*** Pharyngolaryngeal Pneumonitis RPLS

Consider Considerdose Considerdose dose Holdthenincreasedurationofinfusionto6hours Hold,investigatediscontinuepermanentlyifconfirmed. Discontinuepermanently

*transient=7days<1cyclepersistent=1cycle
**someregimensuseastartingdoseofoxaliplatin100mg/m2ingeneralthedosereductionshouldthenbeto 75mg/m2 ***forskintoxicity,reduce5FUdoseonly

DosagewithHepaticImpairment: Noadjustmentrequiredformildtomoderateliverdysfunctionnoinformationfoundregarding severehepaticinsufficiency. DosagewithRenalImpairment: Oxaliplatinshouldbeusedwithcautioninpatientswithmoderaterenalimpairmentastheclearance ofultrafilterableplatinumisdecreasedinpatientswithrenalimpairment.Oxaliplatinshouldnotbe usedinpatientswithsevererenalimpairment(creatinineclearance<30mL/min). Dosageintheelderly: Patients65yearshaveahigherincidenceofGItoxicity,myelosuppressionandfatigue.Caution shouldbeexercised.

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oxaliplatin

Children: Safetyandefficacynotestablished.

backtotop FAdministrationGuidelines Oxaliplatinshouldalwaysbeadministeredbefore5FU. Maybemixedin250500mLbag(D5WonlynotNSoralkalinesolutions,andshouldnotbe mixedwithfluorouracil)andgivenbyslowinfusion.Concentrationmustbebetween0.2to0.7 mg/mL Infuseover120minutes.Increasinginfusiontimeto6hoursmaydecreaseacutetoxicitysuch aspharyngolaryngealdysesthesia. InfusionmaybegivenatthesametimeasLeucovorininseparatebagsusingaYsite(notin thesamebag)providingtrometamolisnotusedasanexcipient.Maynotbeadministered withfluorouracil. Donotusewithinjectionequipmentcontainingaluminum.

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backtotop GSpecialPrecautions Other: Oxaliplatiniscontraindicatedinpatientswithhypersensitivitytothedrugortootherplatinum agents(e.g.cisplatin,carboplatin)andinpatientswithsevererenalimpairment.Patientsshouldbe warnedaboutcoldavoidancepriortotreatmentandiceprophylaxisshouldnotbeused. Oxaliplatinisfetotoxic,mutagenic,clastogenic,teratogenic,genotoxicandisprobably carcinogenic,causestesticulardamageandinfertility.Itiscontraindicatedinpregnancy. Adequatecontraceptionforbothsexesismandatorybefore,duringandfor6monthsafter treatment.Breastfeedingiscontraindicatedduetothepotentialsecretionintobreastmilk.

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oxaliplatin
backtotop HInteractions AGENT Warfarin Otherhighlyprotein bounddrugs Othernephrotoxicdrugs EFFECT incidenceof hemorrhage toxicity incidenceofrenal dysfunction MECHANISM ProlongINRand prothrombintime displacement renalclearance MANAGEMENT monitorINRclosely Caution monitorclosely

backtotop IRecommendedClinicalMonitoring RecommendedClinicalMonitoring

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INR,ifpatientonanticoagulants. Renalfunctiontestsbaselineandregular Electrolytes,includingMagnesiumbaselineandregular CBCbeforeeachcycle Clinicalgastrointestinalandneurotoxicityassessment GradetoxicityusingthecurrentNCICTCAE(CommonTerminologyCriteriaforAdverse Events)version

SuggestedClinicalMonitoring
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Liverfunctiontestsbaselineandregular

backtotop JReferences BecouarnY,YchouM,DucreuxM,etal.PhaseIItrialofoxaliplatinasfirstlinechemotherapyin metastaticcolorectalcancerpatients.JournalofClinicalOncology199816:273944. BergD.Oxaliplatin:anovelplatinumanalogwithactivityincolorectalcancer.OncologyNursing Forum,200330(6):957966.

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oxaliplatin
Cersosimo.OxaliplatinAssociatedNeuropathy:AReview.AnnalsofPharmacotherapy.2005:39, 12835. Gamelinetal.PreventionofOxaliplatinRelatedNeurotoxicitybyCalciumandMagnesium infusions:ARetrospectiveStudyof161patientsReceivingOxaliplatinand5fluorouracilfor AdvancedColorectalCancer.ClinicalCancerResearch.2004.10:405561. GrotheyA,HartLL,RowlandKM,etal.Intermittentoxaliplatin(oxali)administrationandtimeto treatmentfailure(TTF)inmetastaticcolorectalcancer(mCRC):FinalresultsofthephaseIII CONcePTtrial.JClinOncol(MeetingAbstracts)200826(15_suppl):4010. GrotheyA,TurjaTH.OptimizingkTherapybyMinimizingToxicitiesintheTreatmentofColorectal Cancer.MedscapeCME,2008. HealthCanada.NoticesofCompliance:PrescriptionProductforHumanUse.January1 December31,2007 HochsterHS,GrotheyA,ChildsBH.UseofCalciumandMagnesiumSaltstoreduceOxaliplatin Relatedneurotoxicity.JCO25(25):Sept2007(Earlypublication) HochsterHS,GrotheyA,ShpilskyA,etal.Effectofintravenous(IV)calciumandmagnesium (Ca/Mg)versusplaceboonresponsetoFOLFOX+bevacizumab(BEV)intheCONcePTtrial.Proc AmSocClinOncolGastrointestinalCancersSymposium2008:(abstract280). KueblerJP,WieandS,OConnelMJetal.OxaliplatinCombinedWithWeeklyBolusFluorouracil andLeucovorinAsSurgicalAdjuvantChemotherapyforStageIIandIIIColonCancer:Results FromNSABPC07.JCO25(16)June2007:21982204. NationalPBMDrugMonograph:Oxaliplatin(Eloxatin).VHAPharmacyBenefitsManagement StrategicHealthcareGroupAndtheMedicalAdvisoryPanel.March2003. NikcevichDA,GrotheyA,SloanJA,etal.Effectofintravenouscalciumandmagnesium(IVCaMg) onoxaliplatininducedsensoryneurotoxicity(sNT)inadjuvantcoloncancer:ResultsofthephaseIII placebocontrolled,doubleblindNCCTGtrialN04C7.JClinOncol(MeetingAbstracts)200826 (15_suppl):4009. SanofiSynthelabo.Eloxatinproductmonograph.USA2006. Eloxatin(oxaliplatin)ProductMonograph,Quebec,Canada:SanofiAventis,8June,2011. RevisedJune2011

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