Gemmis Injection 8 mg/ml Gemcitbine (Gemcitbine HCl) is nucleoside nlogue tht exhibits nti-tumor ctivity. The empiricl formul for Gemcitbine HCl is C 9H 11F 2N O.HCl. It hs moleculr weight of 299.66. Gemcitbine HCl is 2 -deoxy-2,2 -difluorocytidine monohydro-chloride (β-isomer). Gemcitbine HCl is white to off-white solid. It is soluble in wter, slightly soluble in methnol, nd prcticlly insoluble in ethnol nd polr orgnic solvents. [Composition] Ech ml contins 8 mg Gemcitbine HCl, with ech mpule of 6.0 ml or 0.0 ml; ech mpule contins Gemcitbine HCl 228 mg or 110 mg, nmely Gemcitbine 200 mg or 1000 mg per mpule. [Indictions] Its indictions include non-smll cell lung cncer (NSCLC), pncretic cncer, nd bldder cncer. Gemcitbine nd pclitxel my be combined for nthrcycline-treted ptients with loclly recurred brest cncer tht is surgiclly non-resectble or metsttic. It cn lso be used in ovrin cncer tht hs been treted with pltinum-bsed drugs but recurs t n intervl of more thn 6, s second-line therpy. NSCLC Gemcitbine nd combined use with cispltin is the tretment for inoperble, loclly-dvnced (stge III or IIIb) or metsttic (stge IV) NSCLC s the first-line drug. Gemcitbine is used for the pllitive tretment of loclly-dvnced or metsttic NSCLC dult ptients. Pncretic cncer Gemcitbine is tretment of loclly-mlignnt (inoperble stge II or III) or metsttic (stge IV) pncretic denocrcinom s first-line drug of choice. Gemcitbine cn lso be used in ptients treted with 5-FU. Bldder cncer: metsttic trnsitionl cell crcinom of the urothelium (TCC of the urothelium) Gemcitbine with combined use with cispltin is tretment of stge- (loclly-dvnced or metsttic) metsttic TCC of urothelium, s first-line drug of choice. [Dosge nd dministrtion] (Restricted to physicin s use only) Gemcitbine HCl is only given by intrvenous infusion (IVF). Adult Monotherpy: Pncretic cncer Gemcitbine is used with dose of 1000 mg/m 2 given by 0-minute IVF, once week for t most 7 weeks (or until toxicity develops up to the extent tht we hve to lower the dose or discontinue), nd then one week off. The subsequent dosge is once weekly for weeks nd off in the th week. Dose djustment Dosge should be djusted in ccordnce to the severity of ptient s hemtologicl toxicity (plese refer to the wrnings). Women nd the elderly hve lower clernce, nd women hve lower tolernce to the subsequent dosge schedule (plese refer to humn phrmcokinetics (PK) nd remrks). When receiving Gemcitbine, ptients should hve pre-dose complete blood cell count (CBC), including leukocytes differentil count nd pltelets counts. If there is ny myelo-suppression effect, we should refer to the Dosge djustment tble to modify the doses or discontinue. Tble 1. Dosge djustment tble Absolute grnulocytes count (AGC) ( 10 6 /L) Pltelet count ( 10 6 /L) Percentge of full dose (%) 1,000 nd 100,000 100 500-999 or 50,000-99,000 75 <500 or <50,000 Discontinution Renl nd heptic function, including trnsminse nd serum cretinine, should be checked before therpy, nd regulrly fterwrds. For ptients who hve mrked renl or heptic impirment, Gemcitbine should be used with gret precution, becuse the dt of clinicl tril results re insufficient to provide those ptients with definite dose recommendtion. For ptients who hve completed the whole tretment course, if the bsolute grnulocytes count (AGC) exceeds 1,500 10 6 /L, nd the pltelet count hs nidus over 100,000 10 6 /L, s well s non-hemtologicl toxicity not over WHO Clss 1, then the subsequent tretment course my increse dose by 25%. If ptient cn tolerte the course of the incresed dose, nmely AGC over 1,500 10 6 /L, pltelet count nidus over 100,000 10 6 /L, nd non-hemtologicl toxicity not over WHO Clss 1, the subsequent tretment my increse the dose by 20%. Combined with other drugs (ccording to the literture) NSCLC There re two tretment regimens tht hve been studied, but which one is superior is still undecided (plese refer to clinicl tril). For the therpy regimen tht tkes weeks s course, for every 28 dys, on the 1 st, 8 th, nd 15 th dys, Gemcitbine 1000 mg/m 2 is given, s IVF 0 minutes; on the 1 st dy fter Gemcitbine IVF, cispltin 100 mg/m 2 is given intrvenously (IV). For the therpy regimen tht tkes weeks s course, for every 21 dys, on the 1 st nd 8 th dys, Gemcitbine 1250 mg/m 2 is given IVF 0 minutes; on the 1 st dy fter Gemcitbine IVF, cispltin 100 mg/m 2 is given IV. For cispltin s dosge nd hydrtion, plese refer to the drug pckging insert. Dosge djustment Gemcitbine nd cispltin both hve dose djustment ccording to hemtologicl toxicity. Gemcitbine s dosge djustment is bsed upon the grnulocytes nd pltelets counts on the drug dy. When receiving Gemcitbine, ptient should hve pre-dose CBC, including leukocyte differentil counts nd pltelet counts. If bone mrrow suppression develops, the dose hs to be djusted or discontinued ccording to dosge djustment tble. For cispltin s dosge djustment, plese refer to the mnufcturer s drug pckging insert. Generlly speking, when severe (grde or ) non-hemtologicl toxicity develops, except hir loss or nuse/vomiting, the combined therpy of Gemcitbine nd cispltin should follow physicin s decision, to discontinue tretment or lower dose by 50%. With combined use with cispltin, the ptient s serum cretinine, potssium, clcium, nd mgnesium should be monitored closely ( / serum cretinine toxicity hs incidence of 5% in combined therpy. For cispltin monotherpy, it is 2%.) Brest cncer We tke 21 dys s course, G (1250 mg/m 2 ) IVF 0 minutes on dys 1 nd 8; on dy 1 before Gemcitbine IVF, pclitxel (175 mg/m 2 ) IVF hours should be given. Ptient should hve pre-dose CBC, including differentil count. Before ech course, we must ensure ptient s AGC 1,500 10 6 /L nd pltelet count 100,000 10 6 /L. Dosge djustment Ptients my hve to djust their Gemcitbine dose becuse of hemtologicl toxicity. Gemcitbine s dosge djustment is bsed upon the grnulocyte nd pltelet counts on drug dy (dy 8). If bone mrrow suppression is shown, Gemcitbine must hve dosge djustment ccording to the levels in the tble below. Tble 2. Levels of Gemcitbine lowering dose djustment on dy 8 For the group of Gemcitbine combined with Pclitxel Absolute grnulocytes count (AGC) ( 10 6 /L) Pltelet count ( 10 6 /L) Percentge of full dose (%) 1200 nd 75,000 100 1000-1199 or 50,000-75,000 75 700-999 nd 50,000 50 <700 or <50,000 Discontinution Generlly speking, when severe (grde or ) non-hemtologicl toxicity develops, except hir loss or nuse/vomiting, prescribing physicin s decision must be complied with to discontinue or lower 50% dose. For Pclitxel dosge djustment, plese refer to pckging insert. Ovrin cncer We tke 21 dys s one course, Gemcitbine (1000 mg/m 2 ) IVF 0 minutes on dys 1 nd 8. On dy 1, fter Gemcitbine IVF, Crbopltin IVF AUC is given. Ptient s pre-dose CBC, including differentil counts, should be checked. Before ech course, we must ensure ptient s AGC 1500 10 6 /L, nd pltelet count 100,000 10 6 /L. Dosge djustment During the tretment course, for hemtologicl toxicity, the Gemcitbine dosge is djusted ccording to grnulocyte nd pltelet counts on the drug dy (dy 8). If there is ny bone mrrow suppression, the Gemcitbine dosge is djusted ccording to the levels in Tble. Tble. Levels of Gemcitbine lowering dose djustment on dy 8 For the group of Gemcitbine combined with Crbopltin Absolute grnulocytes count (AGC) ( 10 6 /L) Pltelet count ( 10 6 /L) Percentge of full dose (%) 1500 nd 100,000 100 1000-199 nd/or 75,000-99,999 50 <1000 nd/or <75,000 Discontinution Generlly speking, when severe (grde or ) non-hemtologicl toxicity develops, except hir loss or nuse/vomiting, prescribing physicin s decision must be complied with to discontinue or lower 50% dose. For crbopltin s dosge djustment, plese refer to its pckging insert. For the regimen of subsequent therpy, the combined therpy of Gemcitbine with Crbopltin should hve the dosge djustment bsed upon observed toxic rection. If there is ny hemtologicl toxicity s below, Gemcitbine s dose should be lowered to 800 mg/m 2, IVF on dys 1 nd 8: AGC <500 10 6 /L over 5 dys AGC <100 10 6 /L over dys Febrile neutropeni Pltelet count <25,000 10 6 /L Tretment dely due to toxicity over 1 week 1
In the course of subsequent therpy, if the initil dose hs been lowered, but the bove toxicity rections still recur, Gemcitbine s dose should be djusted to 800 mg/m 2, IVF only on dy 1. Bldder cncer: metsttic TCC of urothelium We tke 28 dys s course, with Gemcitbine 1000 mg/m 2 IVF 0 minutes on dys 1, 8, nd 15 of ech course. On dy 1 of ech course, fter Gemcitbine IVF, cispltin 70 mg/m 2 IV is given. The -week course is defined s tretment course. For cispltin s dosge nd hydrtion, plese refer to its pckging insert. Dosge djustment plese refer to NSCLC s dosge djustment. Gemcitbine cn be injected t the outptient clinic (OPD). Drug Interctions: When Gemcitbine (1250 mg/m 2 on Dys 1 nd 8) nd cispltin (75 mg/m 2 on Dy 1) were dministered in NSCLC ptients, the clernce of gemcitbine on Dy 1 ws 128 L/hr/m 2 nd on Dy 8 ws 107 L/hr/m 2. The clernce of cispltin in the sme study ws reported to be.9 ml/min/m 2 with corresponding hlf-life of 1 hours (see Drug Interctions under PRECAUTIONS). Anlysis of dt from metsttic brest cncer ptients shows tht, on verge, Gemcitbine hs little or no effect on the phrmcokinetics (clernce nd hlf-life) of pclitxel nd pclitxel hs little or no effect on the phrmcokinetics of Gemcitbine. Dt from NSCLC ptients demonstrte tht Gemcitbine nd crbopltin given in combintion does not lter the phrmcokinetics of Gemcitbine or crbopltin compred to dministrtion of either single-gent. However, due to wide confidence intervls nd smll smple size, interptient vribility my be observed. [CONTRAINDICATION ] Gemcitbine is contrindicted in those ptients with known hypersensitivity to the drug (see ergic under ADVERSE REACTIONS). [WARNINGS] (According to literture) Cution Prolongtion of the infusion time beyond 60 minutes nd more frequent thn weekly dosge hve been shown to increse toxicity (see CLINICAL STUDIES). Hemtology Gemcitbine cn suppress bone mrrow function s mnifested by leukopeni, thrombocytopeni, nd nemi (see ADVERSE REACTIONS), nd myelosuppression is usully the dose-limiting toxicity. Ptients should be monitored for myelosuppression during therpy. See DOSAGE AND ADMINISTRATION for recommended dose djustments. Pulmonry Pulmonry toxicity hs been reported with the use of Gemcitbine. In cses of severe lung toxicity, Gemcitbine therpy should be discontinued immeditely nd pproprite supportive cre mesures instituted (see Pulmonry under Single-Agent Use nd under Post-mrketing experience in ADVERSE REACTIONS section). Renl Hemolytic Uremic Syndrome (HUS) nd/or renl filure hve been reported following one or more doses of Gemcitbine. Renl filure leding to deth or requiring dilysis, despite discontinution of therpy, hs been rrely reported. The mjority of the cses of renl filure leding to deth were due to HUS (see Renl under Single-Agent Use nd under Post-mrketing experience in ADVERSE REACTIONS section). Heptic Serious heptotoxicity, including liver filure nd deth, hs been reported very rrely in ptients receiving Gemcitbine lone or in combintion with other potentilly heptotoxic drugs (see Heptic under Single-Agent Use nd under Post-mrketing experience in ADVERSE REACTIONS section). Pregnncy Pregnncy Ctegory D. Gemcitbine cn cuse fetl hrm when dministered to pregnnt womn. Gemcitbine is embryotoxic cusing fetl mlformtions (cleft plte, incomplete ossifiction) t doses of 1.5 mg/kg/dy in mice (bout 1/200 the recommended humn dose on mg/m 2 bsis). Gemcitbine is fetotoxic cusing fetl mlformtions (fused pulmonry rtery, bsence of gll bldder) t doses of 0.1 mg/kg/dy in rbbits (bout 1/600 the recommended humn dose on mg/m 2 bsis). Embryotoxicity ws chrcterized by decresed fetl vibility, reduced live litter sizes, nd developmentl delys. There re no studies of Gemcitbine in pregnnt women. If Gemcitbine is used during pregnncy, or if the ptient becomes pregnnt while tking Gemcitbine, the ptient should be pprised of the potentil hzrd to the fetus. [PRECAUTIONS] (According to literture) Generl Ptients receiving therpy with Gemcitbine should be monitored closely by physicin experienced in the use of cncer chemotherpeutic gents. Most dverse events re reversible nd do not need to result in discontinution, lthough doses my need to be withheld or reduced. There ws greter tendency in women, especilly older women, not to proceed to the next cycle. Lbortory Tests Ptients receiving Gemcitbine should be monitored prior to ech dose with complete blood count (CBC), including differentil nd pltelet count. Suspension or modifiction of therpy should be considered when mrrow suppression is detected (see DOSAGE AND ADMINISTRATION). Lbortory evlution of renl nd heptic function should be performed prior to initition of therpy nd periodiclly therefter (see WARNINGS). Crcinogenesis, Mutgenesis, Impirment of Fertility Long-term niml studies to evlute the crcinogenic potentil of Gemcitbine hve not been conducted. Gemcitbine induced forwrd muttions in vitro in mouse lymphom (L5178Y) ssy nd ws clstogenic in n in vivo mouse micronucleus ssy. Gemcitbine ws negtive when tested using the Ames, in vivo sister chromtid exchnge, nd in vitro chromosoml berrtion ssys, nd did not cuse unscheduled DNA synthesis in vitro. Gemcitbine I.P. doses of 0.5 mg/kg/dy (bout 1/700 the humn dose on mg/m 2 bsis) in mle mice hd n effect on fertility with moderte to severe hypospermtogenesis, decresed fertility, nd decresed implnttions. In femle mice, fertility ws not ffected but mternl toxicities were observed t 1.5 mg/kg/dy I.V. (bout 1/200 the humn dose on mg/m 2 bsis) nd fetotoxicity or embryolethlity 2 ws observed t 0.25 mg/kg/dy I.V. (bout 1/100 the humn dose on mg/m bsis). Pregnncy Ctegory D. See WARNINGS. Nursing Mothers According to literture, it is not known whether Gemcitbine or its metbolites re excreted in humn milk. Becuse mny drugs re excreted in humn milk nd becuse of the potentil for serious dverse rections from Gemcitbine in nursing infnts, the mother should be wrned nd decision should be mde whether to discontinue nursing or to discontinue the drug, tking into ccount the importnce of the drug to the mother nd the potentil risk to the infnt. Elderly Ptients According to the literture, Gemcitbine clernce is ffected by ge (see CLINICAL PHARMACOLOGY). There is no evidence, however, tht unusul dose djustments (i.e., other thn those lredy recommended in the DOSAGE AND ADMINISTRATION section) re necessry in ptients over 65, nd in generl, dverse rection rtes in the single-gent sfety dtbse of 979 ptients were similr in ptients bove nd below 65. / thrombocytopeni ws more common in the elderly. Gender According to the literture, Gemcitbine clernce is ffected by gender (see CLINICAL PHARMACOLOGY). In the single-gent sfety dtbse (979 ptients), however, there is no evidence tht unusul dose djustments (i.e., other thn those lredy recommended in the DOSAGE AND ADMINISTRATION section) re necessry in women. In generl, in single-gent studies of Gemcitbine, dverse rection rtes were similr in men nd women, but women, especilly older women, were more likely not to proceed to subsequent cycle nd to experience / neutropeni nd thrombocytopeni. Peditric Ptients According to the literture, the effectiveness of Gemcitbine in peditric ptients hs not been demonstrted. Gemcitbine ws evluted in Phse 1 tril in peditric ptients with refrctory leukemi nd determined tht the mximum tolerted dose ws 10 mg/m 2 /min for 60 minutes three times weekly followed by one week rest period. Gemcitbine ws lso evluted in Phse 2 tril in ptients with relpsed cute lymphoblstic leukemi (22 ptients) nd cute myelogenous leukemi (10 ptients) using 10 mg/m 2 /min for 60 minutes three times weekly followed by one week rest period. Toxicities observed included bone mrrow suppression, febrile neutropeni, elevtion of serum trnsminses, nuse, nd rsh/desqumtion, which were similr to those reported in dults. No meningful clinicl ctivity ws observed in this Phse 2 tril. Ptients with Renl or Heptic Impirment According to the literture, Gemcitbine should be used with cution in ptients with preexisting renl impirment or heptic insufficiency s there is insufficient informtion from clinicl studies to llow cler dose recommendtion for these ptient popultions. Administrtion of Gemcitbine in ptients with concurrent liver metstses or pre-existing medicl history of heptitis, lcoholism, or liver cirrhosis my led to excerbtion of the underlying heptic insufficiency. Drug Interctions According to the literture, no specific drug interction studies hve been conducted. For informtion on the phrmcokinetics of Gemcitbine nd cispltin in combintion, see Drug Interctions under CLINICAL PHARMACOLOGY section. Rdition Therpy According to the literture, for Gemcitbine nd concurrent therpeutic-dose rdition, sfe nd effective regimen hs not been estblished. A pttern of tissue injury typiclly ssocited with rdition toxicity hs been reported in ssocition with concurrent nd non-concurrent use of Gemcitbine. Non-concurrent (given >7 dys prt) Anlysis of the dt does not indicte enhnced toxicity when Gemcitbine is dministered more thn 7 dys before or fter rdition, other thn rdition recll. Dt suggests tht Gemcitbine cn be strted fter the cute effects of rdition hve been resolved or t lest one week fter rdition. Concurrent (given together or 7 dys prt) Pre-clinicl nd clinicl studies hve shown tht Gemcitbine hs rdiosensitizing ctivity. Toxicity ssocited with this multimodlity therpy is dependent on mny different fctors, including dose of Gemcitbine, frequency of Gemcitbine dministrtion, dose of rdition, rdiotherpy plnning technique, the trget tissue, nd trget volume. In single tril, where Gemcitbine t dose of 1000 mg/m 2 ws dministered concurrently for up to 6 consecutive weeks with therpeutic thorcic rdition to ptients with non-smll cell 2
lung cncer, significnt toxicity in the form of severe, nd potentilly life-thretening mucositis, especilly esophgitis nd pneumonitis ws observed, prticulrly in ptients receiving lrge volumes of rdiotherpy (medin tretment volumes 795 cm ). Subsequent studies hve been reported nd suggest tht Gemcitbine dministered t lower doses with concurrent rdiotherpy hs predictble nd less severe toxicity. However, the optimum regimen for sfe dministrtion of Gemcitbine with therpeutic doses of rdition hs not yet been determined in ll tumor types. [Single-gent dverse rection] (According to the literture) Gemcitbine hs been used in wide vriety of mlignncies, both s single-gent nd in combintion with other cytotoxic drugs. Myelosuppression is the principl dose-limiting toxicity with Gemcitbine therpy. Dosge djustments for hemtologic toxicity, plese refer to the DOSAGE AND ADMINISTRATION section. The dt in Tble re bsed on 979 ptients receiving Gemcitbine s single-gent dministered weekly s 0-minute infusion for tretment of wide vriety of mlignncies. The Gemcitbine strting doses rnged from 800 to 1250 mg/m 2. Dt re lso shown for the subset of ptients with pncretic cncer treted in 5 clinicl studies. The frequency of ll grdes nd severe (WHO or ) dverse events were generlly similr in the single-gent sfety dtbse of 979 ptients nd the subset of ptients with pncretic cncer. Adverse rections reported in the single-gent sfety dtbse resulted in discontinution of Gemcitbine therpy in bout 10% of ptients. In the comprtive tril in pncretic cncer, the discontinution rte for dverse rections ws 1.% for the Gemcitbine rm nd.8% for the 5-FU rm. WHO-grded lbortory events re listed in Tble, regrdless of cuslity. Non-lbortory dverse events listed in Tble or discussed below were those reported, regrdless of cuslity, for t lest 10% of ll ptients, except the ctegories of Extrvstion, ergic, nd Crdiovsculr nd certin specific events under the Renl, Pulmonry, nd Infection ctegories. Tble 5 presents the dt from the comprtive tril of Gemcitbine nd 5-FU in pncretic cncer for the sme dverse events s those in Tble, regrdless of incidence. Tble. Selected WHO-d Adverse Events in Ptients Receiving Single-Agent Gemcitbine: WHO (% incidence) Ptients Pncretic Cncer Ptients b Disconti nutions (%) c Ptients Lbortory d Anemi 68 7 1 7 8 2 <1 Leukopeni 62 9 <1 6 8 1 <1 Neutropeni 6 19 6 61 17 7 - Thrombocytopeni 2 1 6 7 <1 <1 Heptic <1 ALT 68 8 2 72 10 1 AST 67 6 2 78 12 5 Alkline Phosphtse 55 7 2 77 16 Bilirubin 1 2 <1 26 6 2 Renl <1 Proteinuri 5 <1 0 2 <1 0 Hemturi 5 <1 0 2 0 0 BUN 16 0 0 15 0 0 Cretinine 8 <1 0 6 0 0 Non-lbortory e Nuse nd Vomiting 69 1 1 71 10 2 <1 Pin 8 9 <1 2 6 <1 <1 Fever 1 2 0 8 2 0 <1 Rsh 0 <1 0 28 <1 0 <1 Dyspne 2 <1 10 0 <1 <1 Constiption 2 1 <1 1 <1 0 Dirrhe 19 1 0 0 0 0 Hemorrhge 17 <1 <1 2 <1 <1 Infection 16 1 <1 10 2 <1 <1 Alopeci 15 <1 0 16 0 0 0 Stomtitis 11 <1 0 10 <1 0 <1 Somnolence 11 <1 <1 11 2 <1 <1 Presthesis 10 <1 0 10 <1 0 0 bsed on criteri from the World Helth Orgniztion (WHO). N=699-97; ll ptients with lbortory or non-lbortory dt. b N=161-21; ll pncretic cncer ptients with lbortory or non-lbortory dt. c N=979. d Regrdless of cuslity. e Tble includes non-lbortory dt with incidence for ll ptients 10%. pproximtely 60% of the ptients, non-lbortory events were grded only if ssessed to be possibly drug-relted. Tble 5. Selected WHO-d Adverse Events From Comprtive Tril of Gemcitbine nd 5-FU in Pncretic Cncer: WHO (% incidence) Gemcitbine 5-FU b For Lbortory c Anemi 65 7 5 0 0 Leukopeni 71 10 0 15 2 0 Neutropeni 62 19 7 18 2 Thrombocytopeni 7 10 0 15 2 0 Heptic ALT 72 8 2 8 0 0 AST 72 10 2 52 2 0 Alkline Phosphtse 71 16 0 6 10 Bilirubin 16 2 2 25 6 Renl Proteinuri 10 0 0 2 0 0 Hemturi 1 0 0 0 0 0 BUN 8 0 0 10 0 0 Cretinine 2 0 0 0 0 0 Non-lbortory d Nuse nd Vomiting 6 10 58 5 0 Pin 10 2 0 7 0 0 Fever 0 0 0 16 0 0 Rsh 2 0 0 1 0 0 Dyspne 6 0 0 0 0 Constiption 10 0 11 2 0 Dirrhe 2 2 0 1 5 0 Hemorrhge 0 0 0 2 0 0 Infection 8 0 0 2 0 Alopeci 18 0 0 16 0 0 Stomtitis 1 0 0 15 0 0 Somnolence 5 2 0 7 2 0 Presthesis 2 0 0 2 0 0 bsed on criteri from the World Helth Orgniztion (WHO). N=58-6; ll Gemcitbine ptients with lbortory or non-lbortory dt. b N=61-6; ll 5-FU ptients with lbortory or non-lbortory dt. c Regrdless of cuslity. d Non-lbortory events were grded only if ssessed to be possibly drug-relted. According to the literture, in studies in pncretic cncer myelosuppression is the dose-limiting toxicity with Gemcitbine, but <1% of ptients discontinued therpy for either nemi, leukopeni, or thrombocytopeni. Red blood cell trnsfusions were required by 19% of ptients. The incidence of sepsis ws less thn 1%. Petechie or mild blood loss (hemorrhge), from ny cuse, ws reported in 16% of ptients; less thn 1% of ptients required pltelet trnsfusions. Ptients should be monitored for myelosuppression during Gemcitbine therpy nd dosge modified or suspended ccording to the degree of hemtologic toxicity (see DOSAGE AND ADMINISTRATION). Gstrointestinl According to the literture, nuse nd vomiting were commonly reported (69%) but were usully of mild to moderte severity. Severe nuse nd vomiting (WHO /) occurred in <15% of ptients. Dirrhe ws reported by 19% of ptients, nd stomtitis by 11% of ptients. Heptic According to the literture, in clinicl trils, Gemcitbine ws ssocited with trnsient elevtions of one or both serum trnsminses in pproximtely 70% of ptients, but there ws no evidence of incresing heptic toxicity with either longer durtion of exposure to Gemcitbine or with greter totl cumultive dose. Renl According to the literture, in clinicl trils, mild proteinuri nd hemturi were commonly reported. Clinicl symptoms of the Hemolytic Uremic Syndrome (HUS) were reported in 6 of 229 ptients (0.25%) receiving Gemcitbine in clinicl trils. Four ptients developed HUS during Gemcitbine therpy, two immeditely post-therpy. The dignosis of HUS should be considered if the ptient develops nemi with evidence of microngiopthic hemolysis, elevtion of bilirubin or LDH, reticulocytosis, severe thrombocytopeni, nd/or evidence of renl filure (elevtion of serum cretinine or BUN). Gemcitbine therpy should be discontinued immeditely. Renl filure my not be reversible even with discontinution of therpy nd dilysis my be required. Fever According to the literture, the overll incidence of fever ws 1%. This is in contrst to the incidence of infection (16%) nd indictes tht Gemcitbine my
cuse fever in the bsence of clinicl infection. Fever ws frequently ssocited with other flu-like symptoms nd ws usully mild nd cliniclly mngeble. Rsh According to the literture, rsh ws reported in 0% of ptients. The rsh ws typiclly mculr or finely grnulr mculoppulr pruritic eruption of mild to moderte severity involving the trunk nd extremities. Pruritus ws reported for 1% of ptients. Pulmonry According to the literture, 2% of ptients developed the symptoms of dyspne. The incidence of severe dyspne ws %. Dyspne might result from the underlying disese, such s lung cncer (0%) or the pulmonry mnifesttions of other mlignncy. Dyspne ws occsionlly ccompnied by bronchospsm (<2%). A few reports indicted tht pulmonry interstitil toxicity ccompnied drug-induced pneumoni nd relted to the use of Gemcitbine. During the use of Gemcitbine, there were few lung edem of unknown cuse. Sometimes when symptoms re severe, the drug should be discontinued immeditely nd pproprite supportive cre should be given. Edem According to the literture, edem (1%), peripherl edem (20%), nd generlized edem (<1%) were reported. Less thn 1% of ptients discontinued due to edem. Flu-like Symptoms According to the literture, flu syndrome ws reported for 19% of ptients. Individul symptoms of fever, stheni, norexi, hedche, cough, chills, nd mylgi were commonly reported. Fever nd stheni were lso reported frequently s isolted symptoms. Insomni, rhinitis, sweting, nd mlise were reported infrequently. Less thn 1% of ptients discontinued due to flu-like symptoms. Infections According to the literture, infections were reported for 16% of ptients. Sepsis ws rrely reported (<1%). Alopeci According to the literture, hir loss, usully miniml, ws reported by 15% of ptients. Neurotoxicity According to the literture, there ws 10% incidence of mild presthesis nd <1% rte of severe presthesis. Extrvstion According to the literture, injection-site relted events were reported for % of ptients. There were no reports of injection site necrosis. Gemcitbine is not vesicnt. ergic According to the literture, bronchospsm ws reported for less thn 2% of ptients. Anphylctoid rection hs been reported rrely. Gemcitbine should not be dministered to ptients with known hypersensitivity to this drug (see CONTRAINDICATION). Crdiovsculr According to the literture, 2% of ptients discontinued therpy with Gemcitbine due to crdiovsculr events such s myocrdil infrction, cerebrovsculr ccident, rrhythmi, nd hypertension. Mny of these ptients hd prior history of crdiovsculr disese. [Adverse rection in combined therpy] (According to the literture) Combintion Use in Non-Smll Cell Lung Cncer In the Gemcitbine plus cispltin versus cispltin study, dose djustments occurred with 5% of Gemcitbine injections nd 17% of cispltin injections on the combintion rm, versus 6% on the cispltin-only rm. Dose djustments were required in greter thn 90% of ptients on the combintion, versus 16% on cispltin. Study discontinutions for possibly drug-relted dverse events occurred in 15% of ptients on the combintion rm nd 8% of ptients on the cispltin rm. In the Gemcitbine plus cispltin versus Etoposide plus cispltin study, dose djustments occurred with 20% of Gemcitbine injections nd 16% of cispltin injections in the Gemcitbine plus cispltin rm compred with 20% of Etoposide injections nd 15% of cispltin injections in the Etoposide plus cispltin rm. In ptients who completed more thn one cycle, dose djustments were reported in 81% of the Gemcitbine plus cispltin ptients, compred with 68% on the Etoposide plus cispltin rm. Discontinutions for possibly drug-relted dverse events occurred in 1% of ptients on the Gemcitbine plus cispltin rm nd in 8% of ptients on the Etoposide plus cispltin rm. The incidence of myelosuppression ws incresed in frequency with Gemcitbine plus cispltin tretment (~90%) compred to tht with the Gemcitbine monotherpy (~60%). With combintion therpy Gemcitbine dosge djustments for hemtologic toxicity were required more often while cispltin dose djustments were less frequently required. Tble 6 presents the sfety dt from the Gemcitbine plus cispltin versus cispltin study in non-smll cell lung cncer. The NCI Common Toxicity Criteri (CTC) were used. The two-drug combintion ws more myelosuppressive with (1.5%) possibly tretment-relted deths, including resulting from myelosuppression with infection nd one cse of renl filure ssocited with pncytopeni nd infection. No deths due to tretment were reported on the cispltin rm. Nine cses of febrile neutropeni were reported on the combintion therpy rm compred to 2 on the cispltin rm. More ptients required RBC nd pltelet trnsfusions on the Gemcitbine plus cispltin rm. Tble 6. Selected CTC-d Adverse Events From Comprtive Tril of Gemcitbine Plus Cispltin Versus Single-Agent Cispltin in NSCLC: CTC (% incidence) Gemcitbine plus Cispltin Cispltin b Lbortory c Anemi 89 22 67 6 1 RBC Trnsfusion d 9 1 Leukopeni 82 5 11 25 2 1 Neutropeni 79 22 5 20 1 Thrombocytopeni 85 25 25 1 1 Pltelet Trnsfusions d 21 <1 Lymphocytes 75 25 18 51 12 5 Heptic Trnsminse 22 2 1 10 1 0 Alkline Phosphtse 19 1 0 1 0 0 Renl Proteinuri 2 0 0 18 0 0 Hemturi 15 0 0 1 0 0 Cretinine 8 <1 1 2 <1 Other Lbortory Hyperglycemi 0 0 2 0 Hypomgnesemi 0 17 2 0 Hypoclcemi 18 2 0 7 0 <1 Non-lbortory e Nuse 9 25 2 87 20 <1 Vomiting 78 11 12 71 10 9 Alopeci 5 1 0 0 0 Neuro Motor 5 12 0 15 0 Constiption 28 0 21 0 0 Neuro Hering 25 6 0 21 6 0 Dirrhe 2 2 2 1 0 0 Neuro Sensory 2 1 0 18 1 0 Infection 18 2 12 1 0 Fever 16 0 0 5 0 0 Neuro Corticl 16 1 9 1 0 Neuro Mood 16 1 0 10 1 0 Locl 15 0 0 6 0 0 Neuro Hedche 1 0 0 7 0 0 Stomtitis 1 1 0 5 0 0 Hemorrhge 1 1 0 0 0 Dyspne 12 11 2 Hypotension 12 1 0 7 1 0 Rsh 11 0 0 0 0 bsed on Common Toxicity Criteri (CTC). Tble includes dt for dverse events with incidence 10% in either rm. N=217-25; ll Gemcitbine plus cispltin ptients with lbortory or non-lbortory dt. Gemcitbine t 1000 mg/m 2 on Dys 1, 8, nd 15 nd cispltin t 100 mg/m 2 on Dy 1 every 28 dys. b N=21-28; ll cispltin ptients with lbortory or non-lbortory dt. Cispltin t 100 mg/m 2 on Dy 1 every 28 dys. c Regrdless of cuslity. d Percent of ptients receiving trnsfusions. Percent trnsfusions re not CTC-grded events. e Non-lbortory events were grded only if ssessed to be possibly drug-relted. Myelosuppression occurred more frequently on the combintion rm, nd in possibly tretment-relted deths myelosuppression ws observed. Sepsis ws reported in % of ptients on the Gemcitbine plus cispltin rm compred to 1% on the cispltin rm. Pltelet trnsfusions were required in 21% of ptients on the combintion rm nd <1% of ptients on the cispltin rm. Hemorrhgic events occurred in 1% of ptients on the combintion rm nd % on the cispltin rm. However, severe hemorrhgic events were rre. Red blood cell trnsfusions were required in 9% of the ptients on the Gemcitbine plus cispltin rm, versus 1% on the cispltin rm. The dt suggests cumultive nemi with continued Gemcitbine plus cispltin use. Nuse nd vomiting despite the use of ntiemetics occurred slightly more often with Gemcitbine plus cispltin therpy (78%) thn with cispltin lone (71%). In studies with single-gent Gemcitbine, lower incidence of nuse nd vomiting (58% to 69%) ws reported. Renl function bnormlities, hypomgnesemi, neuromotor, neurocorticl, nd neurocerebellr toxicity occurred more often with Gemcitbine plus cispltin thn with cispltin monotherpy. Neurohering toxicity ws similr on both rms. Crdic dysrrhythmis of or greter were reported in 7 (%) ptients treted with Gemcitbine plus cispltin compred to one (<1%) dysrrhythmi reported
with cispltin therpy. Hypomgnesemi nd hypoklemi were ssocited with one rrhythmi on the Gemcitbine plus cispltin combintion rm. Tble 7 presents dt from the rndomized study of Gemcitbine plus cispltin (combined therpy 1) versus etoposide plus cispltin (combined therpy 2) in 15 ptients with NSCLC for the sme WHO-grded dverse events s those in Tble 5. One deth (1.5%) ws reported on the Gemcitbine plus cispltin rm due to febrile neutropeni ssocited with renl filure which ws possibly tretment-relted. No deths relted to tretment occurred on the Etoposide plus cispltin rm. The overll incidence of neutropeni on the Gemcitbine plus cispltin rm ws less thn on the Etoposide plus cispltin rm (28% versus 56%). nemi nd / thrombocytopeni were more common on the Gemcitbine plus cispltin rm. On the Gemcitbine plus cispltin rm, 7% of prticipnts were hospitlized due to febrile neutropeni compred to 12% on the Etoposide plus cispltin rm. More thn twice s mny ptients hd dose reductions or omissions of scheduled dose of Gemcitbine s compred to Etoposide, which my explin the differences in the incidence of neutropeni nd febrile neutropeni between tretment rms. Flu syndrome ws reported by % of ptients on the Gemcitbine plus cispltin rm with none reported on the comprtor rm. Eight ptients (12%) on the Gemcitbine plus cispltin rm reported edem compred to one ptient (2%) on the Etoposide plus cispltin rm. Tble 7. Selected WHO-d Adverse Events From Comprtive Tril of Gemcitbine Plus Cispltin Versus Etoposide Plus Cispltin in NSCLC: WHO (% incidence) Gemcitbine plus Cispltin Etoposide plus Cispltin b Lbortory c Anemi 88 22 0 77 1 2 RBC Trnsfusions d 29 21 Leukopeni 86 26 87 6 7 Neutropeni 88 6 28 87 20 56 Thrombocytopeni 81 9 16 5 8 5 Pltelet Trnsfusions d 8 Heptic ALT 6 0 0 12 0 0 AST 0 0 11 0 0 Alkline Phosphtse 16 0 0 11 0 0 Bilirubin 0 0 0 0 0 0 Renl Proteinuri 12 0 0 5 0 0 Hemturi 22 0 0 10 0 0 BUN 6 0 0 0 0 Cretinine 2 0 0 2 0 0 Non-lbortory e,f Nuse nd Vomiting 96 5 86 19 7 Fever 6 0 0 0 0 Rsh 10 0 0 0 0 Dyspne 1 0 1 0 0 Constiption 17 0 0 15 0 0 Dirrhe 1 1 1 1 0 2 Hemorrhge 9 0 0 Infection 28 1 21 8 0 Alopeci 77 1 0 92 51 0 Stomtitis 20 0 18 2 0 Somnolence 0 0 2 0 Presthesis 8 0 0 16 2 0 bsed on criteri from the World Helth Orgniztion (WHO). N=67-69; ll Gemcitbine plus cispltin ptients with lbortory or non-lbortory dt. Gemcitbine t 1250 mg/m 2 on Dys 1 nd 8 nd cispltin t 100 mg/m 2 on Dy 1 every 21 dys. b N=57-6; ll cispltin plus Etoposide ptients with lbortory or non-lbortory dt. Cispltin t 100 mg/m 2 on Dy 1 nd I.V. Etoposide t 100 mg/m 2 on Dys 1, 2, nd every 21 dys. c Regrdless of cuslity. d Percentge of ptients receiving trnsfusions. Percent trnsfusions re not CTC-grded events. e Non-lbortory events were grded only if ssessed to be possibly drug-relted. f Pin dt ws not collected. Combintion Use in Brest Cncer According to literture, in the Gemcitbine plus pclitxel versus pclitxel study, dose reductions occurred with 8% of Gemcitbine injections nd 5% of pclitxel injections on the combintion rm, versus 2% on the pclitxel rm. On the combintion rm, 7% of Gemcitbine doses were omitted nd <1% of pclitxel doses were omitted, compred to <1% of pclitxel doses on the pclitxel rm. A totl of 18 ptients (7%) on the Gemcitbine plus pclitxel rm nd 12 (5%) on the pclitxel rm discontinued the study becuse of dverse events. There were two deths in study or within 0 dys fter study drug discontinution tht were possibly drug-relted, one on ech rm. Tble 8 presents the sfety dt occurrences of 10% (ll grdes) from the Gemcitbine plus pclitxel versus pclitxel study in brest cncer. Tble 8. Adverse Events From Comprtive Tril of Gemcitbine Plus Pclitxel Versus Single-Agent Pclitxel in Brest Cncer: CTC (% incidence) Gemcitbine plus Pclitxel (N=262) Pclitxel (N=259) Lbortory b Anemi 69 6 1 51 <1 Neutropeni 69 1 17 1 7 Thrombocytopeni 26 5 <1 7 <1 <1 Leukopeni 21 10 1 12 2 0 Heptobiliry ALT 18 5 <1 6 <1 0 AST 16 2 0 5 <1 0 Non-lbortory c Alopeci 90 1 92 19 Neuropthy-sensory 6 5 <1 58 0 Nuse 50 1 0 1 0 Ftigue 0 6 <1 28 1 <1 Mylgi 0 <1 Vomiting 29 2 0 15 2 0 Arthrlgi 2 0 22 2 <1 Dirrhe 20 0 1 2 0 Anorexi 17 0 0 12 <1 0 Neuropthy-motor 15 2 <1 10 <1 0 Stomtitis/phryngitis 1 1 <1 8 <1 0 Fever 1 <1 0 0 0 Constiption 11 <1 0 12 0 0 Bone pin 11 2 0 10 <1 0 Pin-other 11 <1 0 8 <1 0 Rsh/desqumtion 11 <1 <1 5 0 0 bsed on Common Toxicity Criteri (CTC) Version 2.0 (ll grdes included, nd incidence 10%). b Regrdless of cuslity. c Non-lbortory events were grded only if ssessed to be possibly drug-relted. The following re the cliniclly relevnt dverse events tht occurred in >1% nd <10% (ll grdes) of ptients on either rm. In prentheses re the incidences of nd dverse events (Gemcitbine plus pclitxel versus pclitxel): febrile neutropeni (5.0% versus 1.2%), infection (0.8% versus 0.8%), dyspne (1.9% versus 0), nd llergic rection/hypersensitivity (0 versus 0.8%). No differences in the incidence of lbortory nd non-lbortory events were observed in ptients 65 yers or older, s compred to ptients younger thn 65. Combintion Use in Ovrin Cncer According to the literture, in the Gemcitbine plus crbopltin versus crbopltin study, dose reductions occurred with 10.% of Gemcitbine injections nd 1.8% of crbopltin injections on the combintion rm, versus.8% on the crbopltin lone rm. On the combintion rm, 1.7% of Gemcitbine doses were omitted nd 0.2% of crbopltin doses were omitted, compred to 0% of crbopltin doses on the crbopltin lone rm. Tble 9 presents the sfety dt for Gemcitbine plus crbopltin versus crbopltin, including ll dverse events (ll grdes) with incidence 10%. Two groups hd no significnt differences in discontinution rtes due to dverse rection. Combined-gent nd single-gent groups hd respective incidence of 10.9% nd 9.8%. Tble 9. Adverse Events from Comprtive Tril of Gemcitbine Plus Crbopltin Versus Single-Agent Crbopltin in Ovrin Cncer CTC (% incidence) Gemcitbine plus Crbopltin (N=175) Crbopltin (N=17) Lbortory b Anemi 86 22 6 75 9 2 RBC Trnsfusions c 8 15 Neutropeni 90 2 29 58 11 1 Leukemi 86 8 5 70 6 <1 Thrombocytopeni 78 0 5 57 10 1 5
Pltelet Trnsfusions c 9 Non-lbortory d Alopeci 9 0 0 18 0 0 Neuropthy-sensory 0 1 0 27 2 0 Nuse 69 0 61 2 0 Ftigue 9 2 <1 29 2 0 Vomiting 2 0 1 <1 Dirrhe 15 2 0 8 0 0 Anorexi 16 <1 0 8 0 0 Stomtitis/phryngitis 21 <1 0 12 0 0 Constiption 0 5 0 2 2 0 bsed on Common Toxicity Criteri (CTC) Version 2.0 (ll grdes included, nd incidence 10%). b Regrdless of cuslity. c Percentge of ptients receiving trnsfusions. Trnsfusions re not CTC-grded events. Blood trnsfusions included both pcked red blood cells nd whole blood. d Non-lbortory events were grded only if ssessed to be possibly drug-relted. In ddition to blood product trnsfusions s listed in Tble 9, myelosuppression ws lso mnged with hemtopoetic gents. These gents were dministered more frequently with combintion therpy thn with monotherpy (grnulocyte growth fctors: 2.6% nd 10.1%, respectively; erythropoetic gents: 7.% nd.9%, respectively). The following re the cliniclly relevnt dverse events, regrdless of cuslity, tht occurred in >1% nd <10% (ll grdes) of ptients on either rm. In prentheses re the incidences of nd dverse events (Gemcitbine plus crbopltin versus crbopltin): AST or ALT elevtion (0 versus 1.2%), dyspne (1.1% versus 1.7%), febrile neutropeni (1.1% versus 0), hemorrhgic event (1.7% versus 0%), hypersensitivity rection (2.% versus 2.9%), motor neuropthy (0.6% versus 0), nd rsh/desqumtion (0.6% versus 0). No differences in the incidence of lbortory nd non-lbortory events were observed in ptients 65 yers or older, s compred to ptients younger thn 65. Combined use with other drugs in bldder cncer/tcc of the urothelium According to literture, for Gemcitbine plus cispltin versus MVAC, the comprtive study showed, 6% of ptients of the Gemcitbine plus cispltin group did not need dose djustment while 7% of the MVAC group did not. For the proportions of dose discontinution due to tretment-relted dverse rections, Gemcitbine plus cispltin group ws 8% while MVAC group ws 12%. For the proportions of tretment-relted deth, Gemcitbine plus cispltin group ws 1% while MVAC group ws %. In the two clinicl trils, hemtologicl toxicity ws the most common lbortory toxicity. For grde / neutropeni s incidence, Gemcitbine plus cispltin group ws less thn MVAC group (71% vs 82%). For grde- neutropeni s incidence, Gemcitbine plus cispltin group ws significntly less thn MVAC group (0% vs 65%). For grde / nemi s incidence, Gemcitbine plus cispltin group ws higher thn MVAC group (27% vs 18%). For grde-/ thrombocytopeni s incidence, Gemcitbine plus cispltin group ws higher thn MVAC group (58% vs. 21%). In no rm ws there ny reported grde- hemorrhge, only few reported grde- hemorrhge (<2%). In the 9 course treted with Gemcitbine plus cispltin, 51 ptients (25%) needed trnsfusion of pcked red blood cell (prbc), 7 ptients (18%) needed trnsfusion of pltelets (PLT). In the 792 courses treted with MVAC, 28 ptients (1%) needed trnsfusion of prbc, nd 17 ptients (8%) needed trnsfusion of PLT. In phse-2 non-rndomized clinicl tril for treting TCC of the urothelium, cispltin of dose of 100 mg/m 2 plus Gemcitbine resulted in cliniclly significnt hemtologicl toxicity (refer to CLINICAL STUDIES). Tble 10 shows 05 ptients with stge- metsttic TCC of the urothelium who were rndomly treted with Gemcitbine plus cispltin or MVAC for their study results. The WHO grde of dverse rections is identicl to Tble 5, lso including the NCI s common toxicity criteri grding nd dverse rection of neuro-hering. Tble 10. Gemcitbine plus cispltin versus MVAC for treting metsttic TCC of the urothelium for compring clinicl tril dverse rection, ccording to WHO grding (incidence%) Gemcitbine plus cispltin MVAC b Lbortory test c Hemtology Anemi 9 2 86 16 2 PRBC trnsfusion d 25 1 Leukocytopeni 92 7 9 6 18 Neuropeni 91 1 0 89 17 65 Thrombocytopeni 86 29 29 6 8 1 PLT trnsfusion d 18 8 Heptic ALT 29 1 0 28 2 0 AST 0 1 0 28 2 0 Alkline phosphtse 17 2 1 19 1 0 Bilirubin 5 0 0 8 1 0 Renl Proteinuri 9 0 0 1 1 0 Hemturi 18 5 0 21 2 0 BUN 6 1 0 7 0 0 Cretinine 2 0 0 2 1 0 Non-lbortory test e Nuse/vomiting 78 22 0 86 19 2 Fever 21 0 0 0 0 Skin rsh 2 0 0 16 0 1 Dyspne 28 1 21 Constiption 8 2 0 9 1 Dirrhe 2 0 8 1 Hemorrhge 2 2 0 15 2 0 Infection 2 2 1 7 10 5 Alopeci 61 11 0 89 5 1 Stomtitis 20 1 0 66 18 Mlise 17 1 0 0 1 Presthesi 26 1 0 25 1 0 Neuro-hering f 19 2 0 1 2 1 Grding s WHO s rules N=191-200; ll Gemcitbine plus cispltin group ptients lb or non-lb dt; every 28 dys s cycle; dy 1, 8, nd 15 on Gemcitbine 1000 mg/m 2 ; dy 2 on cispltin 70 mg/m 2. b N=186-19; ll MVAC group ptients lb or non-lb dt; every 28 dys s cycle; dy 1, 15, 22 on methotrexte 0 mg/m 2 ; dy 2, 15, 22 on vinblstine mg/m 2 ; dy 2 on doxorubicin 0 mg/m 2 nd cispltin 70 mg/m 2. c Regrdless of cuse. d Percentge of the ptients who needed trnsfusion. e Non-lb dt ws grded fter being ssessed to be drug-relted. f d by NCI s common toxicity criteri. [OVERDOSAGE] (According to the literture) There is no known ntidote for overdoses of Gemcitbine. In the event of suspected overdose, the ptient should be monitored with pproprite blood counts nd should receive supportive therpy, s necessry. According to literture, myelosuppression, presthesis, nd severe rsh were the principl toxicities seen when single dose s high s 5700 mg/m 2 ws dministered by I.V. infusion over 0 minutes every 2 weeks to severl ptients in Phse 1 study. [POST-MARKETING EXPERIENCE] (According to the literture) The following dverse events hve been identified during post-pprovl use of Gemcitbine. These events hve occurred fter Gemcitbine single-gent use nd Gemcitbine in combintion with other cytotoxic gents. Decisions to include these events re bsed on the seriousness of the event, frequency of reporting, or potentil cusl connection to Gemcitbine. Crdiovsculr Congestive hert filure nd myocrdil infrction hve been reported very rrely with the use of Gemcitbine. Arrhythmis, predominntly suprventriculr in nture, hve been reported very rrely. Vsculr Disorders Clinicl signs of peripherl vsculitis nd gngrene hve been reported very rrely. Skin Cellulitis nd non-serious injection site rections in the bsence of extrvstion hve been rrely reported. Severe skin rections, including desqumtion nd bullous skin eruptions, hve been reported very rrely. Heptic Incresed liver function tests including elevtions in sprtte minotrnsferse (AST), lnine minotrnsferse (ALT), gmm-glutmyl trnsferse (GGT), lkline phosphtse, nd bilirubin levels hve been reported rrely. Serious heptotoxicity including liver filure nd deth hs been reported very rrely in ptients receiving Gemcitbine lone or in combintion with other potentilly heptotoxic drugs. Pulmonry Prenchyml toxicity, including interstitil pneumonitis, pulmonry fibrosis, pulmonry edem, nd dult respirtory distress syndrome (ARDS), hs been reported rrely following one or more doses of Gemcitbine dministered to ptients with vrious mlignncies. Some ptients experienced the onset of pulmonry symptoms up to 2 weeks fter the lst Gemcitbine dose. Respirtory filure nd deth occurred very rrely in some ptients despite discontinution of therpy. Renl Hemolytic-Uremic Syndrome (HUS) nd/or renl filure hve been reported following one or more doses of Gemcitbine. Renl filure leding to deth or requiring dilysis, despite discontinution of therpy, hs been rrely reported. The mjority of the cses of renl filure leding to deth were due to HUS. Injury, Poisoning, nd Procedurl Complictions Rdition recll rections hve been reported (see Rdition Therpy under PRECAUTIONS). 6
[CLINICAL PHARMACOLOGY] (According to the literture) Gemcitbine exhibits cell phse specificity, primrily killing cells undergoing DNA synthesis (S-phse) nd lso blocking the progression of cells through the G1/S-phse boundry. Gemcitbine is metbolized intrcellulrly by nucleoside kinses to the ctive diphosphte (dfdcdp) nd triphosphte (dfdctp) nucleoside. The cytotoxic effect of Gemcitbine is ttributed to combintion of two ctions of the diphosphte nd the triphosphte nucleoside, which leds to inhibition of DNA synthesis. First, Gemcitbine diphosphte inhibits ribonucleotide reductse, which is responsible for ctlyzing the rections tht generte the deoxynucleoside triphosphtes for DNA synthesis. Inhibition of this enzyme by the diphosphte nucleoside cuses reduction in the concentrtions of deoxynucleosides, including dctp. Second, Gemcitbine triphosphte competes with dctp for incorportion into DNA. The reduction in the intrcellulr concentrtion of dctp (by the ction of the diphosphte) enhnces the incorportion of Gemcitbine triphosphte into DNA (self-potentition). After the Gemcitbine nucleotide is incorported into DNA, only one dditionl nucleotide is dded to the growing DNA strnds. After this ddition, there is inhibition of further DNA synthesis. DNA polymerse epsilon is unble to remove the Gemcitbine nucleotide nd repir the growing DNA strnds (msked chin termintion). In CEM T lymphoblstoid cells, Gemcitbine induces internucleosoml DNA frgmenttion, one of the chrcteristics of progrmmed cell deth. Gemcitbine demonstrted dose-dependent synergistic ctivity with cispltin in vitro. No effect of cispltin on Gemcitbine triphosphte ccumultion or DNA double-strnd breks ws observed. In vivo, Gemcitbine showed ctivity in combintion with cispltin ginst the LX-1 nd CALU-6 humn lung xenogrfts, but miniml ctivity ws seen with the NCI-H60 or NCI-H520 xenogrfts. Gemcitbine ws synergistic with cispltin in the Lewis lung murine xenogrft. Sequentil exposure to Gemcitbine hours before cispltin produced the gretest interction. [HUMAN Phrmcokinetics] (According to the literture) According to the literture, Gemcitbine disposition ws studied in 5 ptients who received single 1000 mg/m 2 /0 minute infusion of rdiolbeled drug. Within one (1) week, 92% to 98% of the dose ws recovered, lmost entirely in the urine. Gemcitbine (<10%) nd the inctive urcil metbolite, 2 -deoxy-2, 2 -difluorouridine (dfdu), ccounted for 99% of the excreted dose. The metbolite dfdu is lso found in plsm. Gemcitbine plsm protein binding is negligible. The phrmcokinetics of Gemcitbine were exmined in 5 ptients, bout two thirds men, with vrious solid tumors. Phrmcokinetic prmeters were derived using dt from ptients treted for vrying durtions of therpy given weekly with periodic rest weeks nd using both short infusions (<70 minutes) nd long infusions (70 to 285 minutes). The totl Gemcitbine dose vried from 500 to 600 mg/m 2. Gemcitbine phrmcokinetics re liner nd re described by 2-comprtment model. Popultion phrmcokinetic nlyses of combined single nd multiple dose studies showed tht the volume of distribution of Gemcitbine ws significntly influenced by durtion of infusion nd gender. Clernce ws ffected by ge nd gender. Differences in either clernce or volume of distribution bsed on ptient chrcteristics or the durtion of infusion result in chnges in hlf-life nd plsm concentrtions. Tble 11 shows plsm clernce nd hlf-life of gemcitbine following short infusions for typicl ptients by ge nd gender. Tble 11. Age Gemcitbine Clernce nd Hlf-Life for the Typicl Ptient Clernce Men (L/hr/m 2 ) Clernce Women (L/hr/m 2 ) Hlf-Life* Men (min) Hlf-Life* Women (min) 29 92.2 69. 2 9 5 75.7 57.0 8 57 65 55.1 1.5 61 7 79 0.7 0.7 79 9 *Hlf-life for ptients receiving short infusion (<70 min). Gemcitbine hlf-life for short infusions rnged from 2 to 9 minutes, nd the vlue for long infusions vried from 25 to 68 minutes, depending on ge nd gender, reflecting gretly incresed volume of distribution with longer infusions. The lower clernce in women nd the elderly results in higher concentrtions of gemcitbine for ny given dose. The volume of distribution ws incresed with infusion length. Volume of distribution of gemcitbine ws 50 L/m 2 following infusions lsting <70 minutes, indicting tht Gemcitbine, fter short infusions, is not extensively distributed into body tissue. For long infusions, the volume of distribution rose to 70 L/m 2, reflecting slow equilibrtion of Gemcitbine within the tissue comprtment. The mximum plsm concentrtions of dfdu (inctive metbolite) were chieved up to 0 minutes fter discontinution of the infusions nd the metbolite is excreted in urine without undergoing further biotrnsformtion. The metbolite did not ccumulte with weekly dosge, but its elimintion is dependent on renl excretion, nd could ccumulte with decresed renl function. The effects of significnt renl or heptic insufficiency on the disposition of Gemcitbine hve not been ssessed. The ctive metbolite, Gemcitbine triphosphte, cn be extrcted from peripherl blood mononucler cells. The hlf-life of the terminl phse for Gemcitbine triphosphte from mononucler cells rnges from 1.7 to 19. hours. [CLINICAL STUDIES] (According to the literture) Ovrin Cncer Gemcitbine ws studied in rndomized Phse study of 56 ptients with dvnced ovrin cncer tht hd relpsed t lest 6 fter first-line pltinum-bsed therpy. Ptients were rndomized to receive either Gemcitbine 1000 mg/m 2 on Dys 1 nd 8 of 21-dy cycle nd crbopltin AUC dministered fter Gemcitbine on Dy 1 of ech cycle or single-gent crbopltin AUC 5 dministered on Dy 1 of ech 21-dy cycle s the control rm. The primry endpoint of this study ws progression free survivl (PFS). Ptient chrcteristics re shown in Tble 12. The ddition of Gemcitbine to Crbopltin resulted in sttisticlly significnt improvement in PFS nd overll response rte s shown in Tble 1 nd Figure 1. Approximtely 75% of ptients in ech rm received post-study chemotherpy. There ws not significnt difference in overll survivl between rms. Qulity of Life (QOL) The study used EORTC QOL-C0 nd QLQ-OV28 to mesure QOL. QLQ-C0, vlidted, is specific tool to mesure cncer ptient s QOL, including ssessment of psychitric function, disese symptoms, nd toxicity. QLQ-OV28, vlidted, is specific tool to mesure ovrin cncer ptient s QOL s bove mentioned. QOL did not differ significntly between the two groups. Tble 12. Gemcitbine Plus Crbopltin vs Crbopltin in Ovrin Cncer - Bseline Demogrphics nd Clinicl Chrcteristics Gemcitbine/Crbopltin Crbopltin Number of rndomized ptients 178 178 Medin ge, yers 59 58 Rnge 6 to 78 21 to 81 Bseline ECOG performnce sttus 0-1 9% 95% Disese Sttus Evluble 7.9% 2.8% Bidimensionlly mesurble 91.6% 95.5% Pltinum-free intervl b 6-12 9.9% 9.9% >12 59.0% 59.6% First-line therpy Pltinum-txne combintion 70.2% 71.% Pltinum-non-txne combintion 28.7% 27.5% Pltinum monotherpy 1.1% 1.1% Nine ptients (5 on the Gemcitbine plus Crbopltin rm nd on the Crbopltin rm) did not hve bseline Estern Coopertive Oncology Group (ECOG) performnce sttus recorded. b Three ptients (2 on the Gemcitbine plus Crbopltin rm nd 1 on the Crbopltin rm) hd pltinum-free intervl of less thn 6. Tble 1. Gemcitbine Plus Crbopltin Versus Crbopltin in Ovrin Cncer - Results of Efficcy Anlysis Gemcitbine/Crbopltin (N=178) Crbopltin (N=178) PFS Medin (95%, C.I.), 8.6 (8.0, 9.7) 5.8 (5.2, 7.1) p=0.008 Hzrd Rtio (95%, C.I.) 0.72 (0.57, 0.90) Overll Survivl Medin (95%, C.I.), 18.0 (16.2, 20.) 17.(15.2,19.) p=0.8977 Hzrd Rtio (95%, C.I.) 0.98 (0.78, 1.2) Adjusted Hzrd Rtio (95%, 0.86 (0.67, 1.10) C.I.) Overll Response Rte b 7.2% 0.9% p=0.0016 CR 1.6% 6.2% p=0.0092 PR+PRNM 2.6% 2.7% SD 8.2% 8.8% Adjusted for ptient s physicl sttus, tumor loction, nd time to disese progression fter pltinum tretment. b Assessment by doctors of the clinicl tril. Adjusted for ptient s physicl sttus, tumor loction, nd time to disese progression fter pltinum tretment. 7