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)[Link] intracellularlyandinhibitDNAsynthesisthroughcovalentbindingofDNAmoleculestoform [Link],fromotherplatinums (cisplatinandcarboplatin),byitsbulkyDACHcarrierligandthatmostlikelyaccountsforbothits [Link] [Link]. 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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neurotoxicity. Elimination Themajoreliminationrouteofplatinumanditsmetabolitesisrenal [Link] 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 [Link]/5FU/LV wereperipheralsensoryneuropathies,fatigue,myelosuppression,GItoxicityand increasedtransaminases. Theacute,reversible,primarilyperipheral,sensoryneuropathyassociatedwithoxaliplatinisof earlyonset,andcanoccurwithinhoursoronetotwodaysofdosing.Itusuallyresolveswithin14 days,[Link] ofthelimbs,mouth,[Link],abnormaltonguesensation,dysarthria,eye pain,[Link] byexposuretocold(e.g.,touchingcoldsurface,drinkingcoldliquid).Ice(mucositisprophylaxis) [Link],reversiblepatternofsensoryneuropathywasobservedinabout 58%ofstudypatientswhoreceivedOxaliplatinwith5FU/[Link] iscommon,withseveresymptomsin12%[Link] usuallyresolvewithinhoursofonsetbutthefeelingofdifficultyinbreathingorswallowingmaybe [Link],althoughantihistaminesand [Link],infusiontimeshouldbeextendedto6 hourswithsubsequenttreatments. Thepersistent(>14days),primarilyperipheral,sensoryneuropathyisusuallycharacterizedby paresthesias,dysesthesias,[Link] activities(e.g,buttoningclothing,holdingobjects,writing)andoccursinmostpatientsreceiving oxaliplatinwith5FU/[Link] [Link] patientsupondiscontinuationofoxaliplatin.Smallstudiessuggestthatcalciumgluconate1gand magnesiumsulphate1ginfusionspreandpostoxaliplatinameliorateneurotoxicityandmaynot [Link],oronconcomitant [Link],or [Link] [Link] [Link] onefficacyisasyetunknown. Anaphylaxishasbeenreported,includingsevere,in23%[Link] challenged.
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oxaliplatin
Pulmonaryfibrosishasbeenreportedrarely,andpresentswithcough,dyspnea,cracklesand pulmonaryinfiltratesoxaliplatinshouldbediscontinuedpendinginvestigation. Elderlypatientsover65maybeathigherriskofsevere(grades34)[Link] athigherriskofsevere(grades34)[Link] similarbetweenoxaliplatinusedassingleagentorwithfluorouracilandleucovorin,although severe(grades34)diarrhea,nauseaandvomiting,andneurotoxicityaremorecommonwith combinationtherapy. backtotop EDosing Refertoprotocolbywhichpatientisbeingtreated.Prolongingtheinfusionto6hoursmayreduce [Link],treatmentisrecommendedforatotalof12cycles. Adults: AsSingleAgent:130mg/m2IVinfusionover2hoursevery3weeks(notHealthCanada approved) InCombinationwith5FluorouracilandLeucovorin:85mg/m2IVinfusionover2hoursevery2 weeks* 2 *somecombinationssuchasFOLFOX6recommendadoseofoxaliplatin100mg/m
DosagewithToxicity: DonotretreatuntiltheANCis1.5x109/Landtheplateletcountis75x109/[Link] [Link] 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 [Link] usedinpatientswithsevererenalimpairment(creatinineclearance<30mL/min). Dosageintheelderly: Patients65yearshaveahigherincidenceofGItoxicity,[Link] 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)[Link] withfluorouracil. Donotusewithinjectionequipmentcontainingaluminum.
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backtotop GSpecialPrecautions Other: Oxaliplatiniscontraindicatedinpatientswithhypersensitivitytothedrugortootherplatinum agents([Link],carboplatin)[Link] warnedaboutcoldavoidancepriortotreatmentandiceprophylaxisshouldnotbeused. Oxaliplatinisfetotoxic,mutagenic,clastogenic,teratogenic,genotoxicandisprobably carcinogenic,[Link]. Adequatecontraceptionforbothsexesismandatorybefore,duringandfor6monthsafter [Link].
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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,[Link] metastaticcolorectalcancerpatients.JournalofClinicalOncology199816:273944. [Link]:[Link] Forum,200330(6):957966.
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[Link]:[Link].2005:39, 12835. [Link] infusions:ARetrospectiveStudyof161patientsReceivingOxaliplatinand5fluorouracilfor [Link].2004.10:405561. GrotheyA,HartLL,RowlandKM,[Link](oxali)administrationandtimeto treatmentfailure(TTF)inmetastaticcolorectalcancer(mCRC):FinalresultsofthephaseIII [Link](MeetingAbstracts)200826(15_suppl):4010. GrotheyA,[Link] [Link],2008. [Link]:PrescriptionProductforHumanUse.January1 December31,2007 HochsterHS,GrotheyA,[Link] Relatedneurotoxicity.JCO25(25):Sept2007(Earlypublication) HochsterHS,GrotheyA,ShpilskyA,[Link](IV)calciumandmagnesium (Ca/Mg)versusplaceboonresponsetoFOLFOX+bevacizumab(BEV)[Link] AmSocClinOncolGastrointestinalCancersSymposium2008:(abstract280). KueblerJP,WieandS,[Link] andLeucovorinAsSurgicalAdjuvantChemotherapyforStageIIandIIIColonCancer:Results FromNSABPC07.JCO25(16)June2007:21982204. NationalPBMDrugMonograph:Oxaliplatin(Eloxatin).VHAPharmacyBenefitsManagement StrategicHealthcareGroupAndtheMedicalAdvisoryPanel.March2003. NikcevichDA,GrotheyA,SloanJA,[Link](IVCaMg) onoxaliplatininducedsensoryneurotoxicity(sNT)inadjuvantcoloncancer:ResultsofthephaseIII placebocontrolled,[Link](MeetingAbstracts)200826 (15_suppl):4009. [Link].USA2006. Eloxatin(oxaliplatin)ProductMonograph,Quebec,Canada:SanofiAventis,8June,2011. RevisedJune2011
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