96B391E8

Tablel.AdverseReactionsOccurrit)巴in≧10%ofPatients
TYKER月1,250mg/day+
Capecitabine
Capecitabine
2I500mg′m2′day
2ナ000mg′m2′day
(N=198)
All
Grades■
(N=191)
Grade Grade
All
3
4
%
%
%
Diarrhea
65
13
Nausea
44
2
Vomiting
26
Stomatitis
DyspepSla
14
Reactions
Gastrointestinaldisorders
Grades■
Grade Grade
3
4
%
%
%
40
10
0
0
43
2
0
2
0
21
2
0
0
0
<1
0
<l
0
3
0
0
0
51
14
0
S最mandsubcutaneoustissue
disorders
Palmar−plantarerythrodysesthesia
53
12
Rash†
28
2
0
14
DⅣSkin
10
0
0
6
0
0
15
0
0
12
2
0
0
7
<1
0
0
6
<1
0
0
8
2
0
0
6
0
0
Generaldisordersand
administrativesiteconditions
Mucosal inflammation
0
MⅦSCⅥloskeletalandcon血eCtive
tissuedisorders
Pain in extremity
12
Backpain
Respiratoけ,thoracIC,and
mediastinaldisorders
Dyspnea
Psychiatricdisorders
Insomnia
12
10
3
<1
126 *NationalCancerInstituteCommonTemlinologyCriteriaforAdverseEvents,VerSion3・
127†Grade3dermatitisacneiformwasreportedin<1%ofpatientsinTYKERBpluscapecitabine
128
129
group.
TabIe2.SelectedLaboratoryAbtLOrmalities
TYKERBl,250mg/mZ′day+
CaT)eCitabine2,000mg/m2/day
AllGrades
Grade3
Grade4
Capecitabine2,500mg′m2/day
AllGrades事
Grade3
Grade4
%
%
%
%
Hemoglobin
56
<1
0
53
Platelets
18
<l
0
17
Neutrophils
22
3
<1
31
2
Hepatic
TotalBilirubin
45
4
0
30
3
0
2
く1
2
0
2
0
Parameters
%
%
ⅡematologlC
49
37
AST
ALT
131
132
133
134
135
136
137
138
43
33
0
<l
<1
0
’NationalCancerInstituteCommonTerminoJogyCriteriaforAdverseEvents,VerSion3・
DecreasesinLe托VentricularEiectionFraction:Duetopotentialcardiactoxicity
withHER2(ErbB2)inhibitors,LVEFwasmonitoredinclinicaltrialsatapproximately8−Week
intervals.LVEFdecreaseswerede丘nedasslgnSOrSymptOmSOfdeteriorationinleftventricular
cardiacfunctionthatare≧Grade3(NCICTCAE),Ora≧20%decreaseinleftventricularcardiac
qection丘actionrelativetobaselinewhichisbelowtheinstitutionrslowerlimitofnormal・
Among198patientswhopatientsreceivedlapatinib/capecitabinecombinationtreatment,3
139 experiencedgrade2andonehadgrade3LVEFadversereactions(NCICTC3・0)・/馳e
140 好か〃f〃騨α批けrecα〟Jわ旧作・〃・ノ
141 7
DRUG lNTERACTlONS
142 7.1 EfFectsofLapatinibonDrugMetabolizingEnzymeSandDrugTransport
143 Systems
144
LapatinibinhibitsCYP3A4andCYP2C8invitroatclinicallyrelevantCOnCentrations・
145 CautionshouldbeexercisedanddosereductionoftheconcomitantsubstratedrugShouldbe
146 consideredwhendosinglapatinibconcurrentIywithmedicationswithnarrowtherapeutic
147 windowsthataresubstratesofCYP3A40rCYP2C8.Lapatinibdidnotsignificantlyinhibitthe
148 fo1lowlngenZymeSinhumanlivermicrosomes‥CYPIA2,CYP2C9,CYP2C19,andCYP2D60r
149 UGTenzymeSinvitro,however,theclinicalsignificanCeisunknown・
150
LapatinibinhibitshumanP−glycoprotein・IfTYKERBisadministeredwithdrugSthatare
151 substratesofPgp,1nCreaSedconcentrationsofthesubstratedrugarelikely,andcautionshouldbe
152 exercised.
153 7.2 Drug$thatlnhibitorInduceCytochromeP4503A4Enzymes
154
LapatinibundergoesextensivemetabolismbyCYP3A4,andconcomitantadministration
155 0fstronginl1ibitorsorinducersofCYP3A4alterlapatinibconcentrationssigni坑cantly(kee
156 鮎toconazoleafdCarbammepinesections,below).Dosea4justmentofJapatinibshouldbe
157 consideredfbrpatientswhomustreceiveconcomitantstronginhibitorsorconcomitantstrong
158 inducersofCYP3A4enzymes/豆eeDosageandAd椚inistrationP.?〃.
159
KetoconazoJe:Inhealthysu叫ectsreceivingketoconazole,aCYP3A4inhibitor,at
160 200mgtwicedai1yfor7days,SyStemicexposure(AUC)tolapatinibwasincreasedto
161 approximately3.6−fbldofcontrolandhalf−1iftincreasedtol・7−fbldofcontrol・
162
Carbamazepine:Inhealthysu叫ectsreceivingtheCYP3A4inducer,Carbamazeplne,at
163 100mgtwicedailyfor3daysand200mgtwicedailyfbr17days,SyStemicexposure(AUC)to
164 lapatinibwasdecreasedapproximately72%・
165 7.3 DrugsthatlnhibitDrugTransportSystems
166
LapatinibisasubstrateoftheefnuxtransporterP−glycoprotein(Pgp,ABCBl)・If
167 TYKERBisadministeredwithdrugSthatinl1ibitPgp,1nCreaSedconcentrationsoflapatinibare
168 1ikeけ,andcautionshouldbeexercised.
169 7.4 0therChemotherapyAgents
170
Inaseparatestudy,COnCOmitantadministrationoflapatinibwithcapeCitabinedidnot
171 meaningfu11yalterthepharmacokineticsofeitheragent(orthemetabolitesofcapecitabine)・
172 8
USEINSPECIFICPOPULATtON
173 8.1 Pregnancy
174
ル曙〝α〝α叫〃ヴ♪βgg駒川ん騨α〝dJナビcα〟Jわ〝∫(エjル
175 8.3 NurslngMo仙ers
Itisnotknownwhetherlapatinibisexcretedinhumanmilk.BecausemanydrugSare
177 excretedinhumanmilkandbecauseofthepotentialforseriousadversereactionsinnurslng
176
178 infantsfi・OmTYKERB,adecisionshouldbemadewhethertodiscorLtinuenurslngOrtO
179 discontinuethedrug,takinglntOaCCOunttheimportanceofthedrugtOthemother.
180 8.4
181
PediatHcU$e
182
GeriatricU$e
183
8.5
ThesafetyandeffbctivenessofTYKERBinpediatricpatientshavenotbeenestablished・
0fthetotalnumberofmetastaticbreastcanCerpatientsinclinicalstudiesofTYKERBin
184 combinationwithcapecitabineOi=198),17%were65yearsofageandolder,andl%were
185 75yearsofageandolder・Nooveralldi脆rencesinsafttyorefftctivenessofthecombinationof
186 TYKERBandcapecitabinewereobservedbetweenthesesu句ectsandyoungersu叫ects,and
187 0therreportedclinicalexpenenCehasnotidentineddifftrencesinresponsesbetweentheelderly
188 andyoungerpatients,butgreatersensitivityOfsomeolderindividualscannOtberu1edout・
189 8.6 Renallmpalrment
Lapatinibpharmacokineticshavenotbeenspec摘ca11ystudiedinpatientswithrenal
191impalrmentOrinpatientsundergoinghemodialysis・ThereisnoexpenenCewithTYKERBin
192 patientswithsevererenalimpalrment・However,renalimpalrmentisunlikelytoaffbctthe
193 pharmacokineticsoflapatinibgiventhatlessthan2%(1apatinibandmetabolites)ofan
190
194 administereddoseiseliminatedbythekidneys.
195 8.7 HepaticLmpalrment
196
Thepharmacokineticsoflapatinibwereexaminedins叫ectswithmoderate(n=8)or
197 severe(n=4)hepaticimpairment(Child−PughClassB/C,reSPeCtively)andin8healthycontrol
198 s叫ects・Systemicexposure(AUC)tolapatinibafterasingleorallOOmg−dos?increased
199 approximately14%and63%insu叫ectswithmoderateandseverehepaticimpatrment,
200 respectively.AdministrationofTYKERBinpatjentswithseverehepaticimpalrmentShouldbe
201 undertakenwithcautionduetoincreasedexposuretothedrug・Adosereductionshouldbe
202 consideredforpatientswithseverehepaticimpairmentheeDosageandAdhinistrationP・初・
203 10 0VERDOSAGE
204
ThereisnoknownantidotefbroverdosesofTYKERB.Themaximumoraldosesof
205 1apatinibthathavebeenadministeredinclinicaltrialsarel,800mgoncedai1y・More斤equent
206 1ngeStionofTYKERBcouldresultinserumCOnCentratiorlSeXCeedirlgthoseobservedinclinica1
207 trialsandcouldresultinincreasedtoxicity.Therefbre,misseddosesshouldnotbereplacedand
208 dosingshouldresumewiththenextscheduleddailydose.
209
Therehasbeenareportofonepatientwhotook3,000mgofTYKERBforlOdays・This
210 patienthadgrade3diarrheaandvomltlngOnDaylO.TheeventresoIvedfollowlngIVhydration
211 andinterruPtJOnOftreatmentwithTYKERBandletrozole・
212
Becauselapatinibisnotsign靖cantlyrenallyexcretedandishighlyboundtoplasma
213 proteins,hemodialysiswouldnotbeexpectedtobeanefftctivemethodtoenhancethe
214 eliminationoflapatinib.
215 11 DESCRIPT10N
216
Lapatinibisasmallmoleculeandamemberofthe4−anilinoqumazolineclassofkinase
217 inhibitors・Itispresentasthemonohydrateoftheditosylatesalt,withchemicalname N−(3−
218 chloro−4−([(3−nuOrOphenyl)methyl]oxy)phenyl)−6−[5−(([2−
219 (methylsulfonyl)ethyl】amino)methyl)−2−furanyl]−4−quinazolinaminebis(4−
220 methylbenzenesulfonate)monohydrate.IthasthemolecularformulaC29H26CIFN404S
221(C7H803S)2H20andamolecularweightof943.5.Lapatinibditosylatemonohydratehasthe
222 fo1lowlngChemicalstruCture:
2●HきC
●H20
224
Lapatinibisayellowsolid,anditssolubilityinwaterisO▼007mg/mLandinO・1NHClis
225 0.001mg/mLat250C・
223
Each250mgtabletofTYKERBcontains405mgoflapatinibditosylatemonohydrate,
227 equlValentto398mgoflapatinibditosylateor250mglapatinibfreebase.
226
TheinactivelngredientsofTYKERBare:TabIetCore:Magnesiumstearate,
229 microcrysta11inecellulose,pOVidone,SOdiumstarchglycolate.CoatitLg:OrangefilmLCOat:
230 FD&Cye1lowNo,6/sunsetyellowFCFaluminumlake,hypromellose,maCrOgOl仲EG400,
231 polysorbate80,titaniumdioxide.
228
232 12 CLINICALPHARMACOLOGY
233 12.1 Mechani$mOfAc朋On
234
Lapatinibisa4−anilinoquinazolinekinaseinhibitoroftheintracellulartyrosinekinase
235 domainsofbothEpidermalGrow血FactorReceptor(EGFR[ErbBl])andofHumanEpiderma1
236 ReceptorType2(HER−2[ErbB2])receptors(estimatedKiapPvaluesof3nMand13nM,
237 respeCtively)withadissociationhalfllifbof≧300minutes.LapatinibinhibitsErbB−driventumOr
238 cellgrow山invitroandinvariousanimalmodels.
239
Anadditiveeffbctwasdemonstratedinaninvitrostudywhenlapatiniband5−FU(the
240 activemetaboliteofcapeCitabine)wereusedincombinationinthe4tumOrCelllinestested.The
241 grow仙inhibitorye脆ctsoflapatinibwereevaluatedintrastuzumaトconditionedcelllines.
242 Lapatinibretainedsigni丘cantactivityagainstbreastcanCerCelllinesselectedfbrlong−term
243 grow也intrasttmabべ:Ontalnlngmediuminvitro.Theseinvitro貞ndingssuggestnon−CrOSS−
244 resistancebetweenthesetwoagents.
245 12.3 Pharmacokjnetics
246
AbsorDtion:AbsorptionfbllowlngOraladministrationofTYKERBisincompleteand
247 variable.SerumCOnCentrationsappearafteramedianlagtimeofO.25hours(rangeOto
248 1.5hour)・Peakp】asmaconcentrations(Cmax)oflapatinibareachievedapproximately4hours
249 afteradministration.DailydosingofTYKERBresultsinachievementofsteadystatewithin6to
250 7days,indicatlnganefEbctivehalfこ1ifeof24hours.
251
Atthedoseofl,250mgdaiIy,Steadystategeometricmean(95%con貞denceinterval)
252 valuesofCmaxwere2・43mcg/mL(1・57to3.77mcg/mL)andAUCwere36.2mcg.hr/mL(23.4
253 to56mcg・hr/mL).
254
Divideddai1ydosesofTYKERBresultedinapproximately2−foldhigherexposureat
255 steadystate(steadystateAUC)comparedtothesametotaldoseadministeredoncedaily.
256
Systemicexposuretolapatinibisincreasedwhenadministeredwithfood,I.apatinibAUC
257 valueswereapproximately3−and4一fo1dhigher(Cmaxapproximately2.5−and3−fbldhigher)
258 whenadministeredwithalowfat(5%fat−500calories)orwithahighfat(50%fat−1,000
259 calories)meal,reSpeCtively.
260
Distribution二Lapatinibishighlybound(>99%)toalbuminandalpha−1acid
261 glycoprotein・Invitrostudiesindicatethatlapatinibisasubstrateforthetransportersbreast
262 cancerresistanCePrOtein(BCRP,ABCG2)andP−glycoprotein(Pgp,ABCBl).Lapatinibhasalso
263 beenshowninvitrotoinhibittheseefnuxtransporters,aSWellasthehepaticuptaketransporter
264 0ATPIBl,atClinica11yrelevantconcentrations.
Metabolism:Lapatinibundergoesextensivemetabotism,PrlmarilybyCYP3A4and
266 CYP3A5,withminorcontributjons丘●omCYP2C19andCYP2C8toavarietyofoxidated
265
267 metabolites,nOneOfwhichaccountsfbrmorethan14%ofthedoserecoveredinthefbcesor
268 10%oflapatinibconcentrationinplasma・
269
Eliminatjon:AtcJinjcaldoses,theterminalphasehalflliftfo1lowlngaSingledosewas
270 14.2hours;aCCumulationwithrepeateddosingindicatesanefftctivehalf二1ifeof24hours.
271
EliminationoflapatinibispredominantJythroughmetabolismbyCYP3A4/5with
272 rlegligib]e(q%)renalexcretion.Recoveryofparentlapatinibinf己cesaccountsforamedianof
273 27%(range3to67%)ofanoraldose.
274
EffectsofAqe、Gender.orRace:Studiesofthee脆ctsofage,gender,OrraCeOnthe
275 pharmacokineticsoflapatinibhavenotbeenperformed・
276 12.4 QTProIongation
TheQTprolongationpotentialoflapatinibwasassessedaspar[ofanuncontrolled,Open−
278 1abeldoseescalationstudyinadvancedcancerpatients.Eighty−Onepatientsreceiveddailydoses
279 0flapatinibrangingfrom175mg/daytol,800mg/day.SerialECGswerecollectedonDayland
280 Day14toevaluatetheefftctoflapatiniborlQTintervals・Thirteenofthe81subjectswerefbund
281 tohaveeitherQTcF(correctedQTbytheFriedericiamethod)>480msecoranincreaseinQTcF
282 >60msecbyautomatedmachine−readevaluationofECG.Analysisofthedatasuggesteda
283 relationshipbetweenJapatinibcorlCentrationandtheQTcinterval・
277
284 13 NONCL(NICALTOXICOLOGY
285 13.1Carcinogenesis,Mutagenesis,lmpairmentofFertitity
286
Two−yearCarCinogenicitystudieswithlapatinibareongoing・
287
LapatinibwasnotcJastogenicormutagerlicintheChirleSehamsterovarychromosome
288 aberrationassay,microbialmutagenesis(Ames)assay,humanlymphocytechromosome
289 aberrationassayortheinvivoratbonemarrowchromosomeaberrationassayatsmgledosesup
290 to2,000m釘kg.However,animpurityinthedrugPrOduct(upto4ppmor8mcg/day)was
291 genotoxicwhentestedaloneinbothinvitroandinvivoassays・
292
Therewerenoefftctsonmaleorfbmaleratmatingorftrtilityatdosesupto
293 120mgn(g/dayinftmalesand180mgn(g/dayinmales(approxifr)ately6・4timesand2・6times
294 theexpeCtedhumanclinicalexposurebasedonAUC,reSPeCtively)・Theefftctoflapatinibon
295 humanftrtilityisunknown.However,WhenfemaIeratsweregivenoraldosesoflapatinibdurin
296 breedingandthroughthenrst6daysofgestation,aSignificantdecreaseinthenumberoflive
297 fetuseswasseenat120mg几g/dayandinthefbtalbodyweightsat≧60m釘kg/day
298 (approximately6.4timesand33timestheexpectedhumanclinicalexposurebasedonAUC,
299 respectively).
300 14 CLINICALSTUDJES
TheefncacyandsafbtyofTYKERBincombinationwithcapecitabineinbreastcancer
301
302 wereevaluatedinarandomized,Phase3trial.PatientseligiblefbrenrollmenthadHER2
303 (ErbB2)over−eXpreSSing(IHC3+orIHC2+confirmedbyFISH),1ocallyadvancedormetastatic
304 breastcancer,PrOgreSSlngafterprlOrtreatmentthatincludedanthracyclines,taXaneS,and
305 trastuzumab.
306
PatientswererandomizedtoreceiveeitherTYKERBl,250mgoncedaily(continuously)
307
308
309
310
311
312
313
314
315
pluscapecitabine2,000mg/m2/dayonDaysl−14every21days,OrtOreCeivecapeCitabinealone
atadoseof2,500mg/m2/dayonDaysl−14every21days・Theendpointwastimetoprogression
(TTP).TTPwasdefinedastimefromrandomizationtotumorprogressionordeathrelatedto
breastcancer.Basedontheresultsofapre−SpeC摘edinterimanalysis,furtherenrollmentwas
discontinued.Threehundredandninety−nine(399)patientswereenrolledinthisstudy.The
medianagewas53yearsand14%wereolderthan65years.Ninety−OnePerCent(91%)were
Caucasian.NinetyーSeVenperCent(97%)hadstageIVbreastcancer,48%wereestrogenreceptor+
(ER+)orprogesteronereceptor+(PR+),and95%wereErbB2IHC3+orlHC2+withFISH
confirmation.Approximately95%ofpatientshadpriortreatmentwithanthracyclines,taXaneS,
316 andtrastuzumab.
317
EfncacyanalysesfourmonthsaftertheinterimanalysISarepreSentedinTable3,Figure
318 1,andFigure2.
319
Table3.EmcacyRes山ts
IndependemtAssessme山■
TYKERB
InvestigatorAssessment
TYKERB
1,ヱ50mg/day+
1,ヱ50mg/day+
Capecitabine
Capecitabine
Capecitabime
Capecitabine
2,000mg/m2/day 2,500m変/m2/day 2,000mg/m2/day 2,500mg/m2/day
(N=201)
(N=1!I8)
NumberofTTPevemts
82
MedianTTP,Weeks
27.1
(25th,75th,Percentile),
102
18.6
(17.4,49.4)
weeks
HazardRatio
(95%CI)
pvalue
Re叩OnSeRate(%)
(95%CI)
(9.1,36.9)
(N=198)
(N=201)
23.9
126
18.3
(12.0,44.0)
(6.9,35.7)
121
0.57
0.72
(0.43,0.77)
(0.56,0.92)
0.00013
0.00762
23.7
(18.0,30.3)
13.9
(9.5,19.5)
31.8
17.4
(25.4,38.8)
(12.4,23.4)
321 TTP=Timetoprogression.
322 ■Thetime舟omlasttumorassessmenttothedatacut−0ffdatewas>100daysinapproximately
323 30%ofpatientsintheindependentassessment.Thepre−SPeCifiedassessmentintervalwas420r
324 S4days.
325
326 Figurel・Kaplan−MeierEstimatesbrIndependentReviewPanel−eVaIuatedTimeto
327 IIrogression
び乍≡領空腎丘智妄言∈占
Tint(W由短)
328
329 Figure2・Kaplan−MeierEstimatesforInvestigatorAssessmentTitnetoProgrcssion
逆†音一拍型ぎdα卓﹄巨コU
Tir恨帥岨廟
Atthetime。f。。datedanalysis,30%。f。atientshaddiedandthedataforsurviva1
332 analysisarenotmature・Fi氏y一員vepatients(28%)intheTYKERBpluscapecitabinegroupand
333 64suqects(32%)inthecapecitabinegrouphaddied・
334 16 日OWSUPPLJED/STORAGEANDHANDLJNG
335
The250mgtabletsofTYKERBareoval,biconvex,Orange,andmm−COatedwith
336 GSXJGdebossedononesideandareavai1ablein:
BottIesof150tablets:NDCO173−0752−00
337
338
Storeat250C(770F);eXCurSionspermittedto150to300C(59to860F)[seeUSP
339 ControlledRoomTemperattlre].
340 17 PAT]ENTCOUNSELING]NFORMAT10N
341
ぶ飢∴Fβ山一御r(,VedPαJね〝Jエαあピノf′智〃7り
342 17.1Decrea$edLeftVentricularEjectionFraction
343
PatientsshouldbeinformedthatTYKERBhasbeenreportedtodecreaseleftventricular
344 qectionfractionwhichmayresultinshortnessofbreath,Palpitations,and/orfatigue・Patients
345 shouldinformtheirphysicianiftheydevelopthesesymptomswhiletakingTYKERB・
346 17.2 Diarrhea
347
PatientsshouldbeinformedthatTYKERBoftencausesdiarrheawhichmaybeseverein
348 somecases.Patientsshouldbetoldhowtomanageand/orpreventdiarrheaandtoinformtheir
349 physicianifseverediarrheaoccursduringtreatmentwithTYKERB・
350 17,3 Druglnteractions
351
TYKERBmaylnteraCtWithmanydrugS;therefore,patientsshouldbeadvisedtoreport
352 totheirhealthcareprovidertheuseofanyotherprescript10nOrnOnpreSCrlPtionmedicationor
353 herbalproducts.
354 17.4 Food
355
PatientsshouldbeinformedoftheimportanceoftakingTYKERBatleastonehour
356 beforeoronehourafterameal,incontrasttocapecitabinewhichshouldbetakenwithfoodor
357 within30minutesafterfood.
358 17.5 DividedDosing
359
ThedoseofTYKERBshouldnotbedivided.Patientsshouldbeadvisedofthe
360 importanceoftakingTYKERBoncedaily,1nCOntraSttOCaPeCitabinewhichistakentwicedaily・
36117.6 FDAApprovedPatientLabeling
362
PHARMACIST−DETACHHEREANDGIVEINSTRUCTIONSTOPATIENT
364 17.6 FDA−ApprovedPatientLabeling
365
366
PATIENT INFORMATION
367
TYKERB㊥(TIE−Curb)
(1apatinib)tablets
370
371 ReadthisleanetbeforeyoustarttakingTYKERBandeachtimeyougetare創1.Theremaybe
372 newinformation.Thisinfbrmationdoesnottaketheplaceoftalkingwithyourdoctoraboutyour
373 medicalconditionortreatment.
374
375 WhatisTYKERB?
376 TYKERBisusedwiththemedicinecapecitabineforthetreatmentofpatientswithadvancedor
377 metastaticbreastcancerthatisHER2positive,andwhohavealreadyhadcertainotherbreast
378 cancertreatments.
379
380 BeforeyoustarttakingTYXERB,tellyourdoctoraboutallofyourmedicalconditions,
3きIincluding汀you:
382 ・haveheartproblems.
383 ・haveliverproblems.YoumayneedalowerdoseofTYKERB.
384 ・arepregnantOrmaybecomepregnant.TYKERBmayharmanunbornbaby・Ifyoubecome
385
pregnantduringtreatmentwithTYKERB,tellyourdoctorassoonaspossible・
386 ・arebreastfieding.ItisnotknownifTYKERBpassesintoyourbreastmilkorifitcanharm
387
yourbaby・Ifyouareawomanwhohasorwi11haveababy,talkwithyourdoctoraboutthe
388
bestwaytofbedyourbaby・
389
390 Tellyourdoctoraboutallthemedicinesyoutake,includingprescrlPt10nandnonprescrlption
391 medicinesandherbalanddietarysupplements.TYKERBandmanyothermedicinesmayinteract
392 witheachother.Yourdoctorneedstoknowwhatmedicinesyoutakesoheorshecanchoosethe
393 rightdoseofTYKERBforyou・
394
395 Especiallyte11yourdoctorifyoutake:
396 ・antibioticsandanti−fungals(drugSuSedtotreatinftctions)
397 ・HTV(AIDS)treatments
398 ・anticonvulsantdrugS(drugSuSedtotreatseizures)
399 ・Calciumchannelblockers(drugsusedtotreatcertainheartdisordersorhighbloodpressure)
400 ・antidepressants
401 ・drugSuSedforstomachulcers
4
2
0
つJ
0
4
・St.Jolm’sWortorotherherbalsupplements
Knowthemedicinesyoutake.Keepalistofyourmedicineswithyoutoshowyourdoctor・Do
4
nottakeothermedicinesduringtreatmentwithTYKERBwithout伽stcheckingwithyour
5
doctor.
′hV
BecauseTYKERBisglVenWithanotherdrugCalledcapecitabine,yOuShouldalsodiscusswith
yourdoctororpharmacistanymedicinesthatshouldbeavoidedwhentakingcapecitabine・
7
1
4
l
l
l
4
00
l
4
IIowshouldItakeTYKERB?
● TakeTYKERBexactlyasyourdoctorhastoldyou・TYKERBandcapecitabinearetakenin
1
4
l
4
0ノ
l
4
l
21daycycles.TheusualdoseofTYKERBisl,250mg(5tablets)takenbymouth,Onetime
adayondayslto21・Yourdoctorwi11tellyouthedoseofcapecitabineyoushouldtake
4
andwhenyoushouldtakeit.
●
●
4
1
4
O
4
TYKERBshouldbetakenatleastonehourbefore,OratleastonehouraRerfood.
Donoteatordrinkgrape伽itproductswhiletakingTYKERB・
●
4
2
4
Yourdoctormaya4justyourdoseofTYKERβdependingonhowyoutoleratethe
2
つJ
treatment.
2
4
つん
IfyouforgettotakeyourdoseofTYKERB,takeitassoonasyourememberthatday・If
youmissaday,donotdoubleyourdosethenextday・Justskipthemisseddose・
42
4
4
4
O
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Serioussidee晩ctsinclude:
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・heartproblems
・decreasedpumplngOfbloodfromtheheart
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・SeVerediarrhea,Whichmayleadtoyoubecomingdehydrated
Commonsidee批ctsofTYKERBincombinationwithcapeCitabineinclude:
● diarrhea
・red,painfulhandsandfbet
● nauSea
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● VOmltlng
● tiredness
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loss ofappetitete
・indigestion
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442 TellyourdoctoraboutanysideefftctthatgetsseriousOrthatdoesnotgoaway.
443
444 ThesearenotallthesideefftctswithTYKERRAskyourdoctororpharmacistfbrmore
445 information.
446
447 Youmayalsogetsideefrtctsfromcapecitabitle・Talktoyourdoctoraboutpossibleside
448 ef托ctswithcapecitabine.
449
450 IIowshouldIstoreTYXERBtablets?
451 ・StoreTYKERBtabletsatroomtemperaturebetween590and860F(15Oto300C).Keepthe
452
containerclosedtightly.
453 ・Donotkeepmedicinethatisoutofdateorthatyounolongerneed.Besurethatifyou
454
throwanymedicineaway,1tlSOutOfthereachofchildren.
455 ・KeepTYKERBanda11medicinesoutofthereachofchildren.
45(i
457 GeneralinbrmationaboutTYKERB
458 Medicinesaresometimesprescribedforconditionsthatarenotmentionedinpatientinformation
459 1eaflets.DonotuseTYKERBforanyotherconditionforwhichitwasnotprescribed.Donot
460 giveTYKERBtootherpeople,eVeniftheyhavethesameconditionthatyouhave.Itmayharm
461 them.
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463 ThisleanetsummarizesthemostimportantinformationaboutTYKERB.Ifyouwouldlikemore
464 information,talkwithyourdoctor.Youcanaskyourdoctororpharmacistforinformationabout
465 TYKERBthatiswrittehforhealthprofヒssionals・Formoreinformationyoucancalltoll−freel−
46(i 888−825−5249.
467
468 WhataretheingredientsinTYKERB?
469 ActiveIngredient:Lapatinib・
470 InactiveIngredieJ)tS:TabletCore:Magnesiumstearate,microcrystallinecellulose,pOVidone,
471 sodiumstarchglycolate.Coating:Orange坑1m−COat:FD&Cyellow#6/sunsetyellowFCF
472 aluminumlake,hypromellose,maCrOgOl/PEG400,POlysorbate80,titaniumdioxide.
473
474 TYKERBTabletsareoval,biconvex,Orange,film−COatedwithGSXJGprintedononeside.
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Revised:March2007
平成19年2月14日
厚生労働省 医薬食品局 審査管理課
中垣 俊郎 課長殿
日本小児神経
理事長 三池
要望書
ビガバトリンについて
点頭てんかんは小児の代表的な難治てんかんである。日本では合成副腎皮質刺激ホル
モン(ACTH)が治療薬として主に使われているが、長期的には発作が抑制されない症
例が多い。また発作が抑制されない症例においては、発達の予後もきわめて不良で、重
度の知的障害を残すことが多い。このため点頭てんかんに対する治療方法の開発は重要
かつ緊急の問題である。
ビガバトリンは、中枢神経系の主たる抑制物質であるγ・7ミノ酪酸(GABA)を増
強する抗てんかん剤として開発された。1989年にイギリスでてんかんに対する臨床使
用が認可され、現在は60ケ国以上の国で市販されている。海外からの報告にしたがえ
ば、ビガバトリンは成人および小児の部分てんかんに対して有効であるばかりでなく、
小児の難治てんかんである点頭てんかんに対しても有効である。さらに、結節性硬化症
を基礎疾患としてもつ症例の点頭てんかんに対しては、ACTHより有効との報告があ
る。視野狭窄の副作用が報告されているが、最近、イタリアのP.Curatolo教授は、ビ
ガバトリンによる視野狭窄は50%が可逆的であると報告した(第9回アジア・オセア
ニア小児神経学会、2007年1月26日、セプ)。
日本では1990年からビガバトリンの臨床治験が始まり視野狭窄の副作用のため中止
されたが、28人においてはビガバトリンが著効し、現在なお服用を続けている。また、
それらの患者以外に難治てんかん患者のなかには主治医を通じて個人輸入のかたちで
ビガバトリンを服用しているものもかなり存在する。
以上のビガバトリンの海外における使用状況、医学論文におけるビガバトリンの有効
性、日本における患者の要望や実態、社会的な動きを総合的に考えると、小児の点頭て
んかんに対し、患者に対する説明と同意のもとにビガバトリンが治療の選択肢の一つと
して使用できるようご高配をよろしくお願いいたします。