Imatinib - Pediatric Drug Information PDF

11/12/2015
Imatinib:Pediatricdruginformation
OfficialreprintfromUpToDate
www.uptodate.com2015UpToDate
Copyright19782015Lexicomp,Inc.Allrightsreserved.
(Foradditionalinformationsee"Imatinib:Druginformation"andsee"Imatinib:Patientdruginformation")
ForabbreviationsandsymbolsthatmaybeusedinLexicomp(showtable)
BrandNames:US Gleevec
BrandNames:Canada ACTImatinibApoImatinibGleevecTevaImatinib
TherapeuticCategory AntineoplasticAgent,BCRABLTyrosineKinaseInhibitorAntineoplastic
Agent,TyrosineKinaseInhibitor
Dosing:Usual
(Foradditionalinformationsee"Imatinib:Druginformation")
Note:Treatmentmaybecontinueduntildiseaseprogressionorunacceptabletoxicity.Theoptimaldurationof
therapyforCMLincompleteremissionisnotyetdetermined.DiscontinuingCMLtreatmentisnot
recommendedunlesspartofaclinicaltrial(Baccarani,2009NCCNCMLguidelinesv.3.2013).
ChildrenandAdolescents:
Ph+ ALL (newly diagnosed): Oral: 340 mg/m2/day administered once daily in combination with
chemotherapymaximumdailydose:600mg/day
Ph+ CML (chronic phase, newly diagnosed):Oral:340mg/m2/day may administer once daily or in 2
divideddosesmaximumdailydose:600mg/day
Adults:Note:Doses600mgshouldbeadministeredoncedaily800mgdosesshouldbeadministeredas400
mg/dosetwiceaday
ASMwitheosinophilia:Oral:Initiateat100mgoncedailytitrateuptoamaximumof400mgoncedaily
(iftolerated)forinsufficientresponsetolowerdose
ASMwithoutD816VcKitmutationorcKitmutationstatusunknown:Oral:400mgoncedaily
GIST (adjuvant treatment following complete resection): Oral: 400 mg once daily recommended
treatmentduration:3years
GIST (unresectable and/or metastatic malignant): Oral: 400 mg/day may be increased up to 800
mg/day (400 mg/dose twice daily), if tolerated, for disease progression Note: Significant
improvement (progressionfree survival, objective response rate) was demonstrated in patients with
KITexon9mutationwith800mg(versus400mg),althoughoverallsurvival(OS)wasnotimpacted.
ThehigherdosedidnotdemonstrateadifferenceintimetoprogressionorOSpatientswithKitexon
11mutationorwildtypestatus(DebiecRychter,2006Heinrich,2008).
DFSP:Oral:400mgtwicedaily
HES/CEL:Oral:400mgoncedaily
HES/CEL with FIP1L1PDGFR fusion kinase: Oral: Initiate at 100 mg once daily titrate up to a
maximumof400mgoncedaily(iftolerated)ifinsufficientresponsetolowerdose
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MDS/MPD:Oral:400mgoncedaily
Ph+ALL(relapsedorrefractory):Oral:600mgoncedaily
Ph+CML:Oral
Chronic phase: 400 mg once daily may be increased to 600 mg daily, if tolerated, for disease
progression,lackofhematologicresponseafter3months,lackofcytogeneticresponseafter6
12 months, or loss of previous hematologic or cytogenetic response ranges up to 800 mg/day
(400mgtwicedaily)areincludedintheNCCNCMLguidelines(v.3.2013)
Acceleratedphaseorblastcrisis:600mgoncedailymaybeincreasedto800mgdaily(400mg/dose
twice daily), if tolerated, for disease progression, lack of hematologic response after 3 months,
lack of cytogenetic response after 612 months, or loss of previous hematologic or cytogenetic
response
DosingadjustmentwithconcomitantstrongCYP3A4inducers:Children, Adolescents, and Adults: Avoid
concomitant use of strong CYP3A4 inducers (eg, dexamethasone, carbamazepine, phenobarbital,
phenytoin, rifabutin, rifampin) if concomitant use cannot be avoided, increase imatinib dose by at least
50%withcarefulmonitoring.
Dosingadjustmentforrenalimpairment:
Mildimpairment(CrCl4059mL/minute):Adults:Maximumrecommendeddose:600mg/day
Moderateimpairment(CrCl2039mL/minute):Children,Adolescents,andAdults:Decreaserecommended
starting dose by 50% dose may be increased as tolerated maximum recommended dose: 400
mg/day
Severe impairment (CrCl <20 mL/minute): Use caution in adults with severe impairment, a dose of 100
mg/dayhasbeentolerated(Gibbons,2008)
Dosingadjustmentforhepaticimpairment:Children,Adolescents,andAdults:
Baseline:
Mildtomoderateimpairment:Noadjustmentnecessary
Severeimpairment:Reducedoseby25%
During therapy (hepatotoxicity): Withhold treatment until toxicity resolves may resume if appropriate
(dependingoninitialseverityofadverseevent)
Ifelevationsofbilirubin>3timesULNorlivertransaminases>5timesULNoccur,withholdtreatment
until bilirubin <1.5 times ULN and transaminases <2.5 times ULN. Resume treatment at a
reduceddoseasfollows:
Children, Adolescents, and Adults: If current dose 340 mg/m2/day, reduce dose to 260
mg/m2/daymaximumdoserange:300400mg
Adults:
Ifinitialdose400mg,reducedoseto300mg
Dosingadjustmentforothernonhematologicadversereactions:Withholdtreatmentuntiltoxicityresolves
mayresumeifappropriate(dependingoninitialseverityofadverseevent)
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Dosingadjustmentforhematologicadversereactions:
ChronicphaseCML(Initialdose:Children:340mg/m2/dayorAdults:400mg/day),ASM,MDS/MPD,and
HES/CEL (initial dose: 400 mg/day), or GIST (initial dose: 400 mg): If ANC <1 x 109/L and/or
platelets<50x109/L:WithholduntilANC1.5x109/Landplatelets75x109/Lresumetreatmentat
previous dose. For recurrent neutropenia and/or thrombocytopenia, withhold until recovery and
reinstitutetreatmentatareduceddoseasfollows:
ChildrenandAdolescents:Ifinitialdose340mg/m2/day,reducedoseto260mg/m2/day
Adults:Ifinitialdose400mg/day,reducedoseto300mg/day
CML(acceleratedphaseorblastcrisis)andPH+ALL:Adults(initialdose:600mg):IfANC<0.5x109/L
and/orplatelets<10x109/L,establishwhethercytopeniaisrelatedtoleukemia(bonemarrowaspirate
orbiopsy).Ifunrelatedtoleukemia,reducedoseto400mg/day.Ifcytopeniapersistsforanadditional
2weeks,furtherreducedoseto300mg/day.Ifcytopeniapersistsfor4weeksandisstillunrelatedto
leukemia,withholdtreatmentuntilANC1x109/Landplatelets20x109/L,thenresumetreatment
at300mg/day.
ASMassociatedwitheosinophiliaandHES/CELwithFIP1L1PDGFRfusionkinase(startingdose:100
mg/day):Adults:IfANC<1x109/Land/orplatelets<50x109/L:WithholduntilANC1.5x109/Land
platelets75x109/Lresumetreatmentatpreviousdose.
DFSP(initialdose:800mg/day): Adults: If ANC <1 x 109/L and/or platelets <50 x 109/L , withhold until
ANC1.5x109/Landplatelets75x109/L resume treatment at reduced dose of 600 mg/day. For
recurrentneutropeniaand/orthrombocytopenia,withholduntilrecoveryandreinstitutetreatmentwitha
furtherdosereductionto400mg/day.
DosageForms:US Excipientinformationpresentedwhenavailable(limited,particularlyforgenerics)
consultspecificproductlabeling.
Tablet,Oral:
Gleevec:100mg,400mg[scored]
GenericEquivalentAvailable:US No
Administration Hazardousagentuseappropriateprecautionsforhandlinganddisposal(NIOSH2014
[group1]).Shouldbeadministeredorallywithamealandalargeglassofwater.Donotcrushtabletstablets
maybedispersedinwaterorapplejuice(using~50mLfor100mgtablet,~200mLfor400mgtablet)stiruntil
tabletdissolvesandadministerimmediately.DosinginchildrenmaybeonceortwicedailywhentreatingCML
andoncedailyforPh+ALL.Inadults,doses600mgmaybegivenoncedaily800mgdoseshouldbe
administeredas400mgtwicedaily.Fordailydosing800mg,the400mgtabletsshouldbeusedtoreduce
ironexposure(tabletsarecoatedwithferricoxide).
Storage/Stability Storeat25C(77F)excursionspermittedbetween15Cto30C(59Fto86F).
Protectfrommoisture.
Use
TreatmentofnewlydiagnosedPhiladelphiachromosomepositive(Ph+)acutelymphoblasticleukemia(ALL)in
combinationwithchemotherapy(FDAapprovedinages1year)treatmentofnewlydiagnosedPh+
chronicmyeloidleukemia(CML)inchronicphase(FDAapprovedinages1yearandadults)
Treatmentof(thefollowingindications:FDAapprovedinadults):Ph+acutelymphoblasticleukemia(ALL)
(relapsedorrefractory),gastrointestinalstromaltumors(GIST)kitpositive(CD117),includingunresectable
and/ormetastaticmalignantandadjuvanttreatmentfollowingcompleteresection,aggressivesystemic
mastocytosis(ASM)withoutD816VcKitmutation(orcKitmutationstatusunknown),
dermatofibrosarcomaprotuberans(DFSP)(unresectable,recurrent,and/ormetastatic),hypereosinophilic
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syndrome(HES)and/orchroniceosinophilicleukemia(CEL),myelodysplastic/myeloproliferativedisease
(MDS/MPD)associatedwithplateletderivedgrowthfactorreceptor(PDGFR)generearrangements
Hasalsobeenusedinthetreatmentofdesmoidtumors(softtissuesarcoma)poststemcelltransplant
(allogeneic)followuptreatmentinCML
MedicationSafetyIssues
Soundalike/lookalikeissues:
Imatinibmaybeconfusedwithaxitinib,dasatinib,erlotinib,gefitinib,ibrutinib,idelalisib,nilotinib,
nintedanib,PONATinib,SORAfenib,SUNItinib,vandetanib
Highalertmedication:
ThismedicationisinaclasstheInstituteforSafeMedicationPractices(ISMP)includesamongitslistof
drugclasseswhichhaveaheightenedriskofcausingsignificantpatientharmwhenusedinerror.
AdverseReactions Adversereactionslistedasacompositeofdataacrossmanytrials,exceptwhere
notedforaspecificindication.
Cardiovascular:Cardiacfailure,chestpain,edema(includesaggravatededema,anasarca,ascites,pericardial
effusion, peripheral edema, pulmonary edema, and superficial edema), facial edema, flushing,
hypertension,hypotension,palpitations,pleuraleffusion
Central nervous system: Anxiety, cerebral hemorrhage, chills, depression, dizziness, fatigue, headache,
hypoesthesia,insomnia,pain,paresthesia,peripheralneuropathy,rigors,tastedisorder
Dermatologic: Alopecia, dermatitis (GIST), diaphoresis (GIST), erythema, nail disease, night sweats (CML),
pruritus,skinphotosensitivity,skinrash,xeroderma
Endocrine & metabolic: decreased serum albumin, fluid retention (Ph+ CML, pleural effusion, pericardial
effusion, ascites, or pulmonary edema), hyperkalemia, hyperglycemia, hypocalcemia, hypokalemia (more
commoninPh+ALL[pediatric]grades3/4),hypophosphatemia,increasedlactatedehydrogenase,weight
gain,weightloss
Gastrointestinal: abdominal distension, abdominal pain, anorexia, constipation, decreased appetite, diarrhea,
dyspepsia, flatulence, gastritis, gastroenteritis, gastroesophageal reflux, gastrointestinal hemorrhage,
increasedserumlipase(CMLgrades3/4),nausea,stomatitis,vomiting,xerostomia
Hematologic & oncologic: Anemia, eosinophilia, febrile neutropenia, hemorrhage, hypoproteinemia, leukopenia
(GIST),lymphocytopenia,neutropenia,pancytopenia,purpura,thrombocytopenia
Hepatic: Increased alkaline phosphatase, increased serum ALT, increased serum AST, increased serum
bilirubin,increasedserumtransaminases
Infection:Infection(morecommoninPh+ALL[pediatric]grades3/4),influenza(Ph+CML)
Neuromuscular&skeletal:arthralgia,backpain,jointswelling,limbpain,musclecramps,musculoskeletalpain
(morecommoninadults),myalgia,ostealgia,weakness
Ophthalmic: Blurred vision, conjunctival hemorrhage, conjunctivitis, dry eyeseyelid edema (Ph+ CML),
increasedlacrimation(DFSP,GIST),periorbitaledema
Renal:Increasedserumcreatinine
Respiratory:cough,dyspnea,epistaxis,flulikesymptoms,hypoxia,nasopharyngitis,oropharyngealpain(Ph+
CML), pharyngitis (CML), pharyngolaryngeal pain, pneumonia (CML), pneumonitis (Ph+ ALL [pediatric]
grades3/4),rhinitis(DFSP),sinusitis,upperrespiratorytractinfection,
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Miscellaneous:Fever
Rare but important or lifethreatening: Actinic keratosis, acute generalized exanthematous pustulosis,
anaphylactic shock, angina pectoris, angioedema, aplastic anemia, arthritis, ascites, atrial fibrillation,
avascular necrosis of bones, bullous rash, cardiac arrest, cardiac arrhythmia, cardiac tamponade,
cardiogenic shock, cataract, cellulitis, cerebral edema, decreased linear skeletal growth rate (children),
diverticulitis, DRESS syndrome, dyschromia, embolism, erythema multiforme, exfoliative dermatitis,
fungal infection, gastric ulcer, gastrointestinal obstruction, gastrointestinal perforation, glaucoma, gout,
hearing loss, hematemesis, hematoma, hematuria, hemolytic anemia, hepatic failure, hepatic necrosis,
hepatitis, hepatotoxicity, herpes simplex infection, herpes zoster, hypercalcemia, hyperkalemia,
hypersensitivity angiitis, hyperuricemia, hypomagnesemia, hyponatremia, hypophosphatemia,
hypothyroidism, IgA vasculitis, increased intracranial pressure, inflammatory bowel disease, interstitial
pneumonitis, interstitial pulmonary disease, intestinal obstruction, left ventricular dysfunction, lichen
planus,lowerrespiratorytractinfection,lymphadenopathy,macularedema,melena,memoryimpairment,
migraine, myocardial infarction, myopathy, optic neuritis, osteonecrosis (hip), ovarian cyst (hemorrhagic),
palmarplantar erythrodysesthesia, pancreatitis, papilledema, pericarditis, psoriasis, pulmonary fibrosis,
pulmonaryhemorrhage,pulmonaryhypertension,Raynaudsphenomenon,renalfailure,respiratoryfailure,
restlesslegsyndrome,retinalhemorrhage,rhabdomyolysis,rupturedcorpuslutealcyst,sciatica,seizure,
sepsis, StevensJohnson syndrome, subconjunctival hemorrhage, subdural hematoma, Sweet syndrome,
syncope, tachycardia, telangiectasia (gastric antral), thrombocythemia, thrombosis, toxic epidermal
necrolysis,tumorhemorrhage(GIST),tumorlysissyndrome,urinarytractinfection,vitreoushemorrhage
Contraindications
Therearenocontraindicationslistedinthemanufacturer'sUSlabeling.
Canadianlabeling:Hypersensitivitytoimatiniboranycomponentoftheformulation
Warnings/Precautions
Concernsrelatedtoadverseeffects:
Bone marrow suppression: May cause bone marrow suppression (anemia, neutropenia, and
thrombocytopenia),usuallyoccurringwithinthefirstseveralmonthsoftreatment.Mediandurationof
neutropenia is 2 to 3 weeks median duration of thrombocytopenia is 3 to 4 weeks. Monitor blood
counts weekly for the first month, biweekly for the second month, and as clinically necessary
thereafter. In chronic myeloid leukemia (CML), cytopenias are more common in accelerated or blast
phasethaninchronicphase.
Cardiovascular effects: Severe heart failure (HF) and left ventricular dysfunction (LVD) have been
reported (occasionally), usually in patients with comorbidities and/or risk factors. Carefully monitor
patientswithpreexistingcardiacdiseaseorriskfactorsforHForhistoryofrenalfailure.Withinitiation
of imatinib treatment, cardiogenic shock and/or LVD have been reported in patients with
hypereosinophilic syndrome and cardiac involvement (reversible with systemic steroids, circulatory
support and temporary cessation of imatinib). Patients with high eosinophil levels and an abnormal
echocardiogramorabnormalserumtroponinlevelmaybenefitfromprophylacticsystemicsteroids(for
1to2weeks)withtheinitiationofimatinib.
Dermatologic reactions: Severe bullous dermatologic reactions, including erythema multiforme and
StevensJohnson syndrome, have been reported recurrence has been described with rechallenge.
Case reports of successful resumption at a lower dose (with corticosteroids and/or antihistamine)
havebeendescribedhowever,somepatientsmayexperiencerecurrentreactions.Drugreactionwith
eosinophilia and systemic symptoms (DRESS) has been reported. Symptoms of DRESS include
fever, severe skin eruption, lymphadenopathy, hematologic abnormalities (eosinophilia or atypical
lymphocytes), and internal organ involvement. If symptoms of DRESS occur, interrupt therapy and
consider permanently discontinuing symptoms regressed upon discontinuation of therapy, however,
symptomsrecurredinallcaseswhenrechallenged.
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Driving/heavy machinery: Caution is recommended while driving/operating motor vehicles and heavy
machinery when taking imatinib advise patients regarding side effects such as dizziness, blurred
vision,orsomnolence.Reportsofaccidentshavebeenreceived,butitisunclearifimatinibhasbeen
thedirectcauseinanycase.
Fluidretention/edema:Oftenassociatedwithfluidretention,weightgain,andedema(riskincreaseswith
higher doses and age >65 years) occasionally serious and may lead to significant complications,
including pleural effusion, pericardial effusion, pulmonary edema, and ascites. Monitor regularly for
rapidweightgainorothersigns/symptomsoffluidretention.Usewithcautioninpatientswherefluid
accumulation may be poorly tolerated, such as in cardiovascular disease (HF or hypertension) and
pulmonarydisease.
GItoxicity:Imatinibisassociatedwithamoderateemeticpotentialantiemeticsmayberecommended
to prevent nausea and vomiting (Dupuis, 2011 Roila, 2010). May cause GI irritation take with food
andwatertominimizeirritation.Therehavebeenrarereports(includingfatalities)ofGIperforation.
Hemorrhage:Severehemorrhage(grades3and4)hasbeenreportedwithuse,includingGIhemorrhage
and/or tumor hemorrhage. The incidence of hemorrhage is higher in patients with gastrointestinal
stromal tumors (GIST) (GI tumors may have been hemorrhage source). Gastric antral vascular
ectasia(ararecauseofgastrointestinalbleeding)hasalsobeenreported,at~1year(range:6daysto
7years)aftertherapyinitiation(GleevecCanadianproductlabeling,2015Alshehry,2014SaadAldin,
2012).MonitorforGIsymptomswithtreatmentinitiation.
Hepatotoxicity: Hepatotoxicity may occur fatal hepatic failure and severe hepatic injury requiring liver
transplantation have been reported with both short and longterm use monitor liver function prior to
initiation and monthly or as needed thereafter therapy interruption or dose reduction may be
necessary. Transaminase and bilirubin elevations, and acute liver failure have been observed with
imatinibincombinationwithchemotherapy.
Tumor lysis syndrome: Tumor lysis syndrome (TLS), including fatalities, has been reported in patients
with acute lymphoblastic leukemia (ALL), CML eosinophilic leukemias, and GIST. Risk for TLS is
higherinpatientswithahightumorburdenorhighproliferationratemonitorclosely.Correctclinically
significantdehydrationandtreathighuricacidlevelspriortoinitiationofimatinib.
Diseaserelatedconcerns:
Hepatic impairment: Use with caution in patients with hepatic impairment dosage adjustment
recommendedinpatientswithsevereimpairment.
Gastric surgery: Imatinib exposure may be reduced in patients who have had gastric surgery (eg,
bypass, major gastrectomy, or resection) monitor imatinib trough concentrations (Liu, 2011
Pavlovsky,2009,Yoo,2010).
Renalimpairment:Usewithcautioninpatientswithrenalimpairmentdosageadjustmentrecommended
formoderateandsevererenalimpairment.
Thyroiddisease:Hypothyroidismhasbeenreportedinthyroidectomypatientswhowerereceivingthyroid
hormonereplacementtherapypriortoinitiationofimatinibmonitorthyroidfunction.Theaverageonset
forimatinibinducedhypothyroidismis2weeksconsiderdoublinglevothyroxinedosesuponinitiation
ofimatinib(Hamnvik,2011).
Concurrentdrugtherapyissues:
Drugdrug interactions: Potentially significant interactions may exist, requiring dose or frequency
adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions
databaseformoredetailedinformation.
Specialpopulations:
Elderly:Theincidenceofedemawasincreasedwithageolderthan65yearsinCMLandGISTstudies.
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Pediatric: Growth retardation has been reported in children receiving imatinib for the treatment of CML
generally where treatment was initiated in prepubertal children growth velocity was usually restored
aspubertalagewasreached(Shima,2011).Monitorgrowthclosely.
Specialhandling:
Hazardousagent:Useappropriateprecautionsforhandlinganddisposal(NIOSH2014[group1]).
Warnings:AdditionalPediatricConsiderations Growthretardationhasbeenreportedin
prepubescentchildrenreceivingimatinibforthetreatmentofCML(Bansal,2012Rastogi,2012Shima,2011)
themajorityofthepreliminarydatareportedstatisticallysignificantdecreasesinheightSD(standarddeviation)
scoreslesscommonlyreportedaredecreasesinweightSDscoresordecreasedBMIincidenceandextentof
growthretardationaswellasotherrelatedriskfactorshavenotbeenfullycharacterizedreportedincidence
fromreportsishighlyvariable(48%to71%),withonsetduringthefirstyearoftherapyandpersistingwith
treatment.Onereportsuggeststhatgrowthvelocitywasrestoredaspubertalagewasreachedhowever,in
otherreports,patientsdidnothaveimprovementinheightvelocityandgeneticallypredictedadultheightswere
notachieved.Monitorgrowthclosely.
Metabolism/TransportEffects SubstrateofCYP1A2(minor),CYP2C19(minor),CYP2C8(minor),
CYP2C9(minor),CYP2D6(minor),CYP3A4(major),PglycoproteinNote:AssignmentofMajor/Minor
substratestatusbasedonclinicallyrelevantdruginteractionpotentialInhibitsBCRP,CYP2C9(weak),
CYP2D6(weak),CYP3A4(moderate),Pglycoprotein
DrugInteractions
(Foradditionalinformation:LaunchLexiInteractDrugInteractionsProgram)
Acetaminophen:MayenhancethehepatotoxiceffectofImatinib.RiskC:Monitortherapy
Apixaban:CYP3A4Inhibitors(Moderate)mayincreasetheserumconcentrationofApixaban.RiskC:Monitor
therapy
Aprepitant:CYP3A4Inhibitors(Moderate)mayincreasetheserumconcentrationofAprepitant.RiskX:Avoid
combination
ARIPiprazole:CYP3A4Inhibitors(Moderate)mayincreasetheserumconcentrationofARIPiprazole.
Management:Monitorforincreasedaripiprazolepharmacologiceffects.Aripiprazoledoseadjustmentsmay
ormaynotberequiredbasedonconcomitanttherapyand/orindication.Consultfullinteractionmonograph
forspecificrecommendations.RiskC:Monitortherapy
ARIPiprazole:CYP2D6Inhibitors(Weak)mayincreasetheserumconcentrationofARIPiprazole.
Management:Monitorforincreasedaripiprazolepharmacologiceffects.Aripiprazoledoseadjustmentsmay
ormaynotberequiredbasedonconcomitanttherapyand/orindication.Consultfullinteractionmonograph
forspecificrecommendations.RiskC:Monitortherapy
Avanafil:CYP3A4Inhibitors(Moderate)mayincreasetheserumconcentrationofAvanafil.Management:The
maximumavanafiladultdoseis50mgper24hourperiodwhenusedtogetherwithamoderateCYP3A4
inhibitor.Patientsreceivingsuchacombinationshouldalsobemonitoredmorecloselyforevidenceof
adverseeffects.RiskD:Considertherapymodification
BCG(Intravesical):ImmunosuppressantsmaydiminishthetherapeuticeffectofBCG(Intravesical).RiskX:
Avoidcombination
BCG(Intravesical):MyelosuppressiveAgentsmaydiminishthetherapeuticeffectofBCG(Intravesical).Risk
X:Avoidcombination
Bosentan:MaydecreasetheserumconcentrationofCYP3A4Substrates.RiskC:Monitortherapy
Bosentan:CYP3A4Inhibitors(Moderate)mayincreasetheserumconcentrationofBosentan.Management:
ConcomitantuseofbothaCYP2C9inhibitorandaCYP3Ainhibitororasingleagentthatinhibitsboth
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enzymeswithbosentanislikelytocausealargeincreaseinserumconcentrationsofbosentanandisnot
recommended.Seemonographfordetails.RiskC:Monitortherapy
Bosutinib:CYP3A4Inhibitors(Moderate)mayincreasetheserumconcentrationofBosutinib.RiskX:Avoid
combination
Brexpiprazole:CYP3A4Inhibitors(Moderate)mayincreasetheserumconcentrationofBrexpiprazole.
Management:Thebrexpiprazoledoseshouldbereducedto25%ofusualifusedtogetherwithbotha
moderateCYP3A4inhibitorandastrongormoderateCYP2D6inhibitor,orifamoderateCYP3A4inhibitor
isusedinaCYP2D6poormetabolizer.RiskC:Monitortherapy
Bromocriptine:CYP3A4Inhibitors(Moderate)mayincreasetheserumconcentrationofBromocriptine.RiskD:
Considertherapymodification
Budesonide(Systemic):CYP3A4Inhibitors(Moderate)mayincreasetheserumconcentrationofBudesonide
(Systemic).Management:Considerreducingtheoralbudesonidedosewhenusedtogetherwitha
CYP3A4inhibitorortemporarilystoppingbudesonidetherapyduringCYP3A4inhibitoruse.Monitor
patientscloselyforsigns/symptomsofcorticosteroidexcess.RiskD:Considertherapymodification
Budesonide(Systemic,OralInhalation):CYP3A4Inhibitors(Moderate)mayincreasetheserumconcentration
ofBudesonide(Systemic,OralInhalation).Management:Considerreducingtheoralbudesonidedose
whenusedtogetherwithaCYP3A4inhibitor.Thisinteractionislikelylessseverewithorallyinhaled
budesonide.Monitorpatientscloselyforsigns/symptomsofcorticosteroidexcess.RiskD:Consider
therapymodification
Budesonide(Topical):CYP3A4Inhibitors(Moderate)mayincreasetheserumconcentrationofBudesonide
(Topical).Management:PerUSprescribinginformation,avoidthiscombination.Canadianproductlabeling
doesnotrecommendstrictavoidance.Ifcombined,monitorforexcessiveglucocorticoideffectsas
budesonideexposuremaybeincreased.RiskD:Considertherapymodification
Cannabis:CYP3A4Inhibitors(Moderate)mayincreasetheserumconcentrationofCannabis.More
specifically,tetrahydrocannabinolandcannabidiolserumconcentrationsmaybeincreased.RiskC:
Monitortherapy
Cilostazol:CYP3A4Inhibitors(Moderate)mayincreasetheserumconcentrationofCilostazol.Management:
Considerreducingthecilostazoldoseto50mgtwicedailyinadultpatientswhoarealsoreceiving
moderateinhibitorsofCYP3A4.RiskD:Considertherapymodification
CloZAPine:MyelosuppressiveAgentsmayenhancetheadverse/toxiceffectofCloZAPine.Specifically,the
riskforagranulocytosismaybeincreased.RiskX:Avoidcombination
CoccidioidesimmitisSkinTest:ImmunosuppressantsmaydiminishthediagnosticeffectofCoccidioides
immitisSkinTest.RiskC:Monitortherapy
Colchicine:CYP3A4Inhibitors(Moderate)mayincreasetheserumconcentrationofColchicine.Management:
ReducecolchicinedoseasdirectedwhenusingwithamoderateCYP3A4inhibitor,andincrease
monitoringforcolchicinerelatedtoxicity.Useextracautioninpatientswithimpairedrenaland/orhepatic
function.RiskD:Considertherapymodification
CycloSPORINE(Systemic):ImatinibmayincreasetheserumconcentrationofCycloSPORINE(Systemic).
RiskC:Monitortherapy
CYP3A4Inducers(Moderate):MaydecreasetheserumconcentrationofCYP3A4Substrates.RiskC:Monitor
therapy
CYP3A4Inducers(Strong):MaydecreasetheserumconcentrationofImatinib.Management:Avoidconcurrent
useofimatinibwithstrongCYP3A4inducerswhenpossible.Ifsuchacombinationmustbeused,
increaseimatinibdosebyatleast50%andmonitorthepatient'sclinicalresponseclosely.RiskD:
CYP3A4Inhibitors(Moderate):MayincreasetheserumconcentrationofImatinib.RiskC:Monitortherapy
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CYP3A4Inhibitors(Strong):MayincreasetheserumconcentrationofImatinib.RiskC:Monitortherapy
CYP3A4Substrates:CYP3A4Inhibitors(Moderate)maydecreasethemetabolismofCYP3A4Substrates.
RiskC:Monitortherapy
Dabrafenib:MaydecreasetheserumconcentrationofCYP3A4Substrates.Management:Seekalternativesto
theCYP3A4substratewhenpossible.Ifconcomitanttherapycannotbeavoided,monitorclinicaleffects
ofthesubstrateclosely(particularlytherapeuticeffects).RiskD:Considertherapymodification
Dapoxetine:CYP3A4Inhibitors(Moderate)mayincreasetheserumconcentrationofDapoxetine.Management:
Thedoseofdapoxetineshouldbelimitedto30mg/daywhenusedtogetherwithamoderateinhibitorof
CYP3A4.RiskD:Considertherapymodification
Deferasirox:MaydecreasetheserumconcentrationofCYP3A4Substrates.RiskC:Monitortherapy
Denosumab:Mayenhancetheadverse/toxiceffectofImmunosuppressants.Specifically,theriskforserious
infectionsmaybeincreased.RiskC:Monitortherapy
Dexamethasone(Systemic):MaydecreasetheserumconcentrationofImatinib.Management:Avoid
concurrentuseofimatinibwithdexamethasonewhenpossible.Ifsuchacombinationmustbeused,
increaseimatinibdosebyatleast50%andmonitorclinicalresponseclosely.RiskD:Considertherapy
modification
Dipyrone:Mayenhancetheadverse/toxiceffectofMyelosuppressiveAgents.Specifically,theriskfor
agranulocytosisandpancytopeniamaybeincreasedRiskX:Avoidcombination
Dofetilide:CYP3A4Inhibitors(Moderate)mayincreasetheserumconcentrationofDofetilide.RiskC:Monitor
therapy
Domperidone:CYP3A4Inhibitors(Moderate)mayincreasetheserumconcentrationofDomperidone.RiskX:
Avoidcombination
DOXOrubicin(Conventional):CYP3A4Inhibitors(Moderate)mayincreasetheserumconcentrationof
DOXOrubicin(Conventional).Management:SeekalternativestomoderateCYP3A4inhibitorsinpatients
treatedwithdoxorubicinwheneverpossible.OneU.S.manufacturer(PfizerInc.)recommendsthatthese
combinationsbeavoided.RiskD:Considertherapymodification
Dronabinol:CYP3A4Inhibitors(Moderate)mayincreasetheserumconcentrationofDronabinol.RiskC:
Monitortherapy
Echinacea:MaydiminishthetherapeuticeffectofImmunosuppressants.RiskD:Considertherapy
modification
Eletriptan:CYP3A4Inhibitors(Moderate)mayincreasetheserumconcentrationofEletriptan.Management:
Theuseofeletriptanwithin72hoursofamoderateCYP3A4inhibitorshouldbeavoided.RiskD:Consider
therapymodification
Eliglustat:CYP3A4Inhibitors(Moderate)mayincreasetheserumconcentrationofEliglustat.Management:
Useshouldbeavoidedundersomecircumstances.Seefulldruginteractionmonographfordetails.Risk
D:Considertherapymodification
Enzalutamide:MaydecreasetheserumconcentrationofCYP3A4Substrates.Management:Concurrentuseof
enzalutamidewithCYP3A4substratesthathaveanarrowtherapeuticindexshouldbeavoided.Useof
enzalutamideandanyotherCYP3A4substrateshouldbeperformedwithcautionandclosemonitoring.
RiskD:Considertherapymodification
Eplerenone:CYP3A4Inhibitors(Moderate)mayincreasetheserumconcentrationofEplerenone.Management:
WhenusedconcomitantlywithmoderateinhibitorsofCYP3A4,eplerenonedosingrecommendationsmay
varydependingoninternationallabeling.Consultappropriatelabelingforspecificrecommendations.Risk
Everolimus:CYP3A4Inhibitors(Moderate)mayincreasetheserumconcentrationofEverolimus.Management:
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Everolimusdosereductionsarerequiredforpatientsbeingtreatedforsubependymalgiantcell
astrocytomaorrenalcellcarcinoma.Seeprescribinginformationforspecificdoseadjustmentand
monitoringrecommendations.RiskD:Considertherapymodification
FentaNYL:CYP3A4Inhibitors(Moderate)mayincreasetheserumconcentrationofFentaNYL.Management:
Monitorpatientscloselyforseveraldaysfollowinginitiationofthiscombination,andadjustfentanyldose
asnecessary.RiskD:Considertherapymodification
Fingolimod:ImmunosuppressantsmayenhancetheimmunosuppressiveeffectofFingolimod.Management:
Avoidtheconcomitantuseoffingolimodandotherimmunosuppressantswhenpossible.Ifcombined,
monitorpatientscloselyforadditiveimmunosuppressanteffects(eg,infections).RiskD:Considertherapy
modification
Flibanserin:CYP3A4Inhibitors(Moderate)mayincreasetheserumconcentrationofFlibanserin.RiskX:Avoid
combination
Fludarabine:ImatinibmaydiminishthemyelosuppressiveeffectofFludarabine.Imatinibmaydecreasethe
serumconcentrationofFludarabine.Morespecifically,imatinibmaydecreasetheformationoffludarabine
activemetaboliteFaraATPManagement:Duetotheriskforimpairedfludarabineresponse,consider
discontinuingimatinibtherapyatleast5dayspriortoinitiatingfludarabineconditioningtherapyinCML
patientsundergoingHSCT.RiskD:Considertherapymodification
Gemfibrozil:Maydecreaseserumconcentrationsoftheactivemetabolite(s)ofImatinib.SpecificallyN
desmethylimatinibconcentrationsmaybedecreased.Gemfibrozilmaydecreasetheserumconcentration
ofImatinib.RiskC:Monitortherapy
Halofantrine:CYP3A4Inhibitors(Moderate)mayincreasetheserumconcentrationofHalofantrine.RiskD:
Hydrocodone:CYP3A4Inhibitors(Moderate)mayincreasetheserumconcentrationofHydrocodone.RiskC:
Monitortherapy
Ibrutinib:CYP3A4Inhibitors(Moderate)mayincreasetheserumconcentrationofIbrutinib.Management:Ifa
moderateCYP3Ainhibitormustbeused,considerreducingthedoseofibrutinibto140mgdailyand
monitorcloselyforsignsoftoxicity.RiskX:Avoidcombination
Ibuprofen:MaydecreasetheserumconcentrationofImatinib.Specifically,ibuprofenmaydecreaseintracellular
concentrationsofimatinib,leadingtodecreasedclinicalresponse.Management:Considerusingan
alternativetoibuprofeninpatientswhoarebeingtreatedwithimatinib.Availableevidencesuggestsother
NSAIDsdonotinteractinasimilarmanner.RiskD:Considertherapymodification
Ifosfamide:CYP3A4Inhibitors(Moderate)maydecreaseserumconcentrationsoftheactivemetabolite(s)of
Ifosfamide.RiskC:Monitortherapy
Ivabradine:CYP3A4Inhibitors(Moderate)mayincreasetheserumconcentrationofIvabradine.RiskX:Avoid
combination
Ivacaftor:CYP3A4Inhibitors(Moderate)mayincreasetheserumconcentrationofIvacaftor.Management:
Ivacaftordosereductionsarerequiredconsultprescribinginformationforspecificageandweightbased
recommendations.RiskD:Considertherapymodification
Lansoprazole:MayenhancethedermatologicadverseeffectofImatinib.RiskC:Monitortherapy
Leflunomide:Immunosuppressantsmayenhancetheadverse/toxiceffectofLeflunomide.Specifically,therisk
forhematologictoxicitysuchaspancytopenia,agranulocytosis,and/orthrombocytopeniamaybe
increased.Management:Considernotusingaleflunomideloadingdoseinpatientsreceivingother
immunosuppressants.Patientsreceivingbothleflunomideandanotherimmunosuppressantshouldbe
monitoredforbonemarrowsuppressionatleastmonthly.RiskD:Considertherapymodification
Lomitapide:CYP3A4Inhibitors(Moderate)mayincreasetheserumconcentrationofLomitapide.RiskX:Avoid
combination
http://www.uptodate.com/contents/imatinibpediatricdruginformation?topicKey=DRUG_PED%2F12618&elapsedTimeMs=9&source=search_result&s
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Lurasidone:CYP3A4Inhibitors(Moderate)mayincreasetheserumconcentrationofLurasidone.Management:
U.S.labeling:startat20mg/dayandlimittomaxof80mg/daywithmoderateCYP3A4inhibitor.Canadian
labeling:limittomaxof40mg/daywithmoderateCYP3A4inhibitoravoidconcomitantuseofgrapefruit
products.RiskD:Considertherapymodification
Mitotane:MaydecreasetheserumconcentrationofCYP3A4Substrates.Management:DosesofCYP3A4
substratesmayneedtobeadjustedsubstantiallywhenusedinpatientsbeingtreatedwithmitotane.Risk
Naloxegol:CYP3A4Inhibitors(Moderate)mayincreasetheserumconcentrationofNaloxegol.RiskX:Avoid
combination
Natalizumab:Immunosuppressantsmayenhancetheadverse/toxiceffectofNatalizumab.Specifically,the
riskofconcurrentinfectionmaybeincreased.RiskX:Avoidcombination
NiMODipine:CYP3A4Inhibitors(Moderate)mayincreasetheserumconcentrationofNiMODipine.RiskC:
Monitortherapy
Olaparib:CYP3A4Inhibitors(Moderate)mayincreasetheserumconcentrationofOlaparib.Management:
AvoiduseofmoderateCYP3A4inhibitorsinpatientsbeingtreatedwitholaparib.Ifsuchconcurrentuse
cannotbeavoided,thedoseofolaparibshouldbereducedto200mgtwicedaily.RiskX:Avoid
combination
OxyCODONE:CYP3A4Inhibitors(Moderate)mayenhancetheadverse/toxiceffectofOxyCODONE.
CYP3A4Inhibitors(Moderate)mayincreasetheserumconcentrationofOxyCODONE.Serum
concentrationsoftheactivemetaboliteOxymorphonemayalsobeincreased.RiskD:Considertherapy
modification
PAZOPanib:BCRP/ABCG2InhibitorsmayincreasetheserumconcentrationofPAZOPanib.RiskX:Avoid
combination
Pglycoprotein/ABCB1Inducers:MaydecreasetheserumconcentrationofPglycoprotein/ABCB1Substrates.
Pglycoproteininducersmayalsofurtherlimitthedistributionofpglycoproteinsubstratestospecific
cells/tissues/organswherepglycoproteinispresentinlargeamounts(e.g.,brain,Tlymphocytes,testes,
etc.).RiskC:Monitortherapy
Pglycoprotein/ABCB1Inhibitors:MayincreasetheserumconcentrationofPglycoprotein/ABCB1Substrates.
Pglycoproteininhibitorsmayalsoenhancethedistributionofpglycoproteinsubstratestospecific
cells/tissues/organswherepglycoproteinispresentinlargeamounts(e.g.,brain,Tlymphocytes,testes,
etc.).RiskC:Monitortherapy
Pimecrolimus:Mayenhancetheadverse/toxiceffectofImmunosuppressants.RiskX:Avoidcombination
Pimozide:CYP3A4Inhibitors(Moderate)mayincreasetheserumconcentrationofPimozide.RiskX:Avoid
combination
Propacetamol:MayenhancethehepatotoxiceffectofImatinib.RiskC:Monitortherapy
Propafenone:CYP3A4Inhibitors(Moderate)mayincreasetheserumconcentrationofPropafenone.RiskC:
Monitortherapy
Ranolazine:CYP3A4Inhibitors(Moderate)mayincreasetheserumconcentrationofRanolazine.Management:
Limittheranolazineadultdosetoamaximumof500mgtwicedailyinpatientsconcurrentlyreceiving
moderateCYP3A4inhibitors(e.g.,diltiazem,verapamil,erythromycin,etc.).RiskD:Considertherapy
modification
RifamycinDerivatives:MaydecreasetheserumconcentrationofImatinib.Management:Avoidconcurrentuse
ofimatinibwiththerifamycinderivativeswhenpossible.Ifsuchacombinationmustbeused,increase
imatinibdosebyatleast50%andmonitorthepatient'sclinicalresponseclosely.RiskD:Consider
therapymodification
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Roflumilast:MayenhancetheimmunosuppressiveeffectofImmunosuppressants.RiskD:Considertherapy
modification
Salmeterol:CYP3A4Inhibitors(Moderate)mayincreasetheserumconcentrationofSalmeterol.RiskC:
Monitortherapy
Saxagliptin:CYP3A4Inhibitors(Moderate)mayincreasetheserumconcentrationofSaxagliptin.RiskC:
Monitortherapy
Siltuximab:MaydecreasetheserumconcentrationofCYP3A4Substrates.RiskC:Monitortherapy
Simeprevir:CYP3A4Inhibitors(Moderate)mayincreasetheserumconcentrationofSimeprevir.RiskX:Avoid
combination
Simvastatin:ImatinibmaydecreasethemetabolismofSimvastatin.RiskC:Monitortherapy
SipuleucelT:ImmunosuppressantsmaydiminishthetherapeuticeffectofSipuleucelT.RiskC:Monitor
therapy
Sonidegib:CYP3A4Inhibitors(Moderate)mayincreasetheserumconcentrationofSonidegib.Management:
AvoidconcomitantuseofsonidegibandmoderateCYP3A4inhibitorswhenpossible.Whenconcomitant
usecannotbeavoided,limitCYP3A4inhibitorusetolessthan14daysandmonitorforsonidegibtoxicity
(particularlymusculoskeletaladversereactions).RiskD:Considertherapymodification
StJohnsWort:MayincreasethemetabolismofImatinib.RiskD:Considertherapymodification
Suvorexant:CYP3A4Inhibitors(Moderate)mayincreasetheserumconcentrationofSuvorexant.RiskD:
Tacrolimus(Topical):Mayenhancetheadverse/toxiceffectofImmunosuppressants.RiskX:Avoid
combination
Tetrahydrocannabinol:CYP3A4Inhibitors(Moderate)mayincreasetheserumconcentrationof
Tetrahydrocannabinol.RiskC:Monitortherapy
Tocilizumab:MaydecreasetheserumconcentrationofCYP3A4Substrates.RiskC:Monitortherapy
Tofacitinib:ImmunosuppressantsmayenhancetheimmunosuppressiveeffectofTofacitinib.Management:
Concurrentusewithantirheumaticdosesofmethotrexateornonbiologicdiseasemodifyingantirheumatic
drugs(DMARDs)ispermitted,andthiswarningseemsparticularlyfocusedonmorepotent
immunosuppressants.RiskX:Avoidcombination
Tolvaptan:CYP3A4Inhibitors(Moderate)mayincreasetheserumconcentrationofTolvaptan.RiskX:Avoid
combination
Topotecan:BCRP/ABCG2InhibitorsmayincreasetheserumconcentrationofTopotecan.RiskD:Consider
therapymodification
Trabectedin:CYP3A4Inhibitors(Moderate)mayincreasetheserumconcentrationofTrabectedin.RiskX:
Avoidcombination
Trastuzumab:MayenhancetheneutropeniceffectofImmunosuppressants.RiskC:Monitortherapy
Ulipristal:CYP3A4Inhibitors(Moderate)mayincreasetheserumconcentrationofUlipristal.Management:This
isspecificforwhenulipristalisbeingusedforsigns/symptomsofuterinefibroids(Canadianindication).
Whenulipristalisusedasanemergencycontraceptive,patientsreceivingthiscombinationshouldbe
monitoredforulipristaltoxicity.RiskX:Avoidcombination
Vaccines(Inactivated):ImmunosuppressantsmaydiminishthetherapeuticeffectofVaccines(Inactivated).
Management:Vaccineefficacymaybereduced.Completeallageappropriatevaccinationsatleast2
weekspriortostartinganimmunosuppressant.Ifvaccinatedduringimmunosuppressanttherapy,
revaccinateatleast3monthsafterimmunosuppressantdiscontinuation.RiskD:Considertherapy
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modification
Vaccines(Live):Immunosuppressantsmayenhancetheadverse/toxiceffectofVaccines(Live).
ImmunosuppressantsmaydiminishthetherapeuticeffectofVaccines(Live).Management:Avoiduseof
liveorganismvaccineswithimmunosuppressantsliveattenuatedvaccinesshouldnotbegivenforat
least3monthsafterimmunosuppressants.RiskX:Avoidcombination
Vilazodone:CYP3A4Inhibitors(Moderate)mayincreasetheserumconcentrationofVilazodone.RiskC:
Monitortherapy
Vindesine:CYP3A4Inhibitors(Moderate)mayincreasetheserumconcentrationofVindesine.RiskC:Monitor
therapy
Warfarin:ImatinibmayenhancetheanticoagulanteffectofWarfarin.Imatinibmaydecreasethemetabolismof
Warfarin.RiskD:Considertherapymodification
Zopiclone:CYP3A4Inhibitors(Moderate)mayincreasetheserumconcentrationofZopiclone.Management:
Thestartingadultdoseofzopicloneshouldnotexceed3.75mgifcombinedwithamoderateCYP3A4
inhibitor.Monitorpatientsforsignsandsymptomsofzopiclonetoxicityiftheseagentsarecombined.Risk
Zuclopenthixol:CYP3A4Inhibitors(Moderate)mayincreasetheserumconcentrationofZuclopenthixol.Risk
C:Monitortherapy
FoodInteractions FoodmayreduceGIirritation.Grapefruitjuicemayincreaseimatinibplasma
concentration.Management:Takewithamealandalargeglassofwater.Avoidgrapefruitjuice.Maintain
adequatehydration,unlessinstructedtorestrictfluidintake.
PregnancyRiskFactor D(showtable)
PregnancyImplications Adverseeventshavebeenobservedinanimalreproductionstudies.Women
ofchildbearingpotentialareadvisednottobecomepregnant(femalepatientsandfemalepartnersofmale
patients)highlyeffectivecontraceptionisrecommended.TheCanadianlabelingrecommendswomenof
childbearingpotentialhaveanegativepregnancytest(urineorserum)withasensitivityofatleast25mIU/mL
within1weekpriortotherapyinitiation.Casereportsofpregnancieswhileontherapy(bothmalesandfemales)
includereportsofspontaneousabortion,minorabnormalities(hypospadias,pyloricstenosis,andsmallintestine
rotation)atorshortlyafterbirth,andothercongenitalabnormalitiesincludingskeletalmalformations,
hypoplasticlungs,exomphalos,kidneyabnormalities,hydrocephalus,cerebellarhypoplasia,andcardiac
defects.
RetrospectivecasereportsofwomenwithCMLincompletehematologicresponse(CHR)withcytogenic
response(partialorcomplete)whointerruptedimatinibtherapyduetopregnancy,demonstratedalossof
responseinsomepatientswhileofftreatment.At18monthsaftertreatmentreinitiationfollowingdelivery,CHR
wasagainachievedinallpatientsandcytogenicresponsewasachievedinsomepatients.Cytogenetic
responseratesmaynotbeatashighascomparedtopatientswith18monthsofuninterruptedtherapy(Ault,
2006Pye,2008).
MonitoringParameters CBC(weeklyforfirstmonth,biweeklyforsecondmonth,thenperiodically
thereafter),liverfunctiontests[atbaselineandmonthlyorasclinicallyindicatedmorefrequently(atleast
weekly)inpatientswithmoderatetoseverehepaticimpairment(Ramanathan,2008)],renalfunction,serum
electrolytes(includingcalcium,phosphorus,potassium,andsodiumlevels)bonemarrowcytogenetics(in
CMLat6,12,and18months)fatigue,weight,andedema/fluidstatusconsiderechocardiogramandserum
troponinlevelsinpatientswithHES/CEL,andinpatientswithMDS/MPDorASMwithhigheosinophillevels
inpediatricpatients,alsomonitorserumglucose,albumin,andgrowthparameters(height,weight,BMI)
Gastricsurgery(eg,bypass,majorgastrectomy,orresection)patients:Monitorimatinibtroughconcentrations
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(Liu,2011Pavlovsky,2009,Yoo,2010)
Thyroidfunctiontesting(Hamnvik,2011):
Preexistinglevothyroxinetherapy:ObtainbaselineTSHlevels,thenmonitorevery4weeksuntillevels
andlevothyroxinedosearestable,thenmonitorevery2months
Withoutpreexistingthyroidhormonereplacement:TSHatbaseline,thenevery4weeksfor4months,then
every23months
Monitorforsigns/symptomsofCHFinpatientsatriskforcardiacfailureorpatientswithpreexistingcardiac
diseasesomesuggestabaselineevaluationofleftventricularejectionfractionpriortoinitiationofimatinib
therapyinallpatientswithknownunderlyingheartdiseaseorinelderlypatients.Monitorforsigns/symptomsof
gastrointestinalirritationorperforationanddermatologictoxicities.
MechanismofAction InhibitsBcrAbltyrosinekinase,theconstitutiveabnormalgeneproductofthe
Philadelphiachromosomeinchronicmyeloidleukemia(CML).Inhibitionofthisenzymeblocksproliferationand
inducesapoptosisinBcrAblpositivecelllinesaswellasinfreshleukemiccellsinPhiladelphiachromosome
positiveCML.Alsoinhibitstyrosinekinaseforplateletderivedgrowthfactor(PDGF),stemcellfactor(SCF),c
Kit,andcellulareventsmediatedbyPDGFandSCF.
Pharmacokinetics(Adultdataunlessnoted)
Absorption:Rapid
Proteinbinding:~95%toalbuminandalpha1acidglycoprotein(parentdrugandmetabolite)
Metabolism: Hepatic via CYP3A4 (minor metabolism via CYP1A2, CYP2D6, CYP2C9, CYP2C19) primary
metabolite(active):Ndemethylatedpiperazinederivative(CGP74588)severehepaticimpairment(bilirubin
>310timesULN)increasesAUCby45%to55%forimatinibanditsactivemetabolite,respectively
Bioavailability: 98% may be decreased in patients who have had gastric surgery (eg, bypass, total or partial
resection)
Halflifeelimination:
Children:Parentdrug:~15hours
Adults:Parentdrug:~18hoursNdesmethylmetabolite:~40hours
Timetopeakserumconcentration:24hours(adultsandchildren)
Elimination: Feces (68% primarily as metabolites, 20% as unchanged drug) urine (13% primarily as
metabolites,5%asunchangeddrug)
ExtemporaneousPreparations Hazardousagent:Useappropriateprecautionsforhandlingand
disposal(NIOSH2014[group1]).Whenmanipulatingtablets,NIOSHrecommendsdoublegloving,aprotective
gown,andpreparationinacontrolleddeviceifnotpreparedinacontrolleddevice,respiratoryandeye
protectionaswellasventilatedengineeringcontrolsarerecommended(NIOSH,2014).
Anoralsuspensionmaybepreparedbyplacingtablets(whole,donotcrush)inaglassofwaterorapplejuice.
Use~50mLfor100mgtablet,or~200mLfor400mgtablet.Stiruntiltabletsaredisintegrated,thenadminister
immediately.Toensurethefulldoseisadministered,rinsetheglassandadministerresidue.
Gleevec(imatinib)[prescribinginformation].EastHanover,NJ:NovartisPharmaceuticalsJanuary2015.
UseofUpToDateissubjecttotheSubscriptionandLicenseAgreement.
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Topic12618Version132.0
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