HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include ll the informtion needed to use GEMZAR sfely nd effectively. See full prescribing informtion for GEMZAR. GEMZAR (gemcitbine for injection) Powder, Lyophilized, For Solution For Intrvenous Use Initil U.S. Approvl: 1996 ---------------------------- INDICATIONS AND USAGE --------------------------- Gemzr is nucleoside metbolic inhibitor indicted for: Ovrin cncer in combintion with crbopltin (1.1) Brest cncer in combintion with pclitxel (1.2) Non-smll cell lung cncer in combintion with cispltin (1.3) Pncretic cncer s single-gent (1.4) ----------------------- DOSAGE AND ADMINISTRATION ---------------------- Gemzr is for intrvenous use only. Ovrin cncer: 1000 mg/m 2 over 30 minutes on Dys 1 nd 8 of ech 21-dy cycle (2.1) Brest cncer: 1250 mg/m 2 over 30 minutes on Dys 1 nd 8 of ech 21-dy cycle (2.2) Non-smll cell lung cncer: 4-week schedule, 1000 mg/m 2 over 30 minutes on Dys 1, 8, nd 15 of ech 28-dy cycle: 3-week schedule; 1250 mg/m 2 over 30 minutes on Dys 1 nd 8 of ech 21-dy cycle (2.3) Pncretic cncer: 1000 mg/m 2 over 30 minutes once weekly for up to 7 weeks (or until toxicity necessittes reducing or holding dose), followed by week of rest from tretment. Subsequent cycles should consist of infusions once weekly for 3 consecutive weeks out of every 4 weeks (2.4) Dose Reductions or discontinution my be needed bsed on toxicities (2.1-2.4) ---------------------- DOSAGE FORMS AND STRENGTHS --------------------- 200 mg vil for injection (3) 1 g vil for injection (3) ------------------------------- CONTRAINDICATIONS ------------------------------ Ptients with known hypersensitivity to gemcitbine (4) ------------------------ WARNINGS AND PRECAUTIONS ----------------------- Infusion time nd dose frequency: Incresed toxicity with infusion time >60 minutes or dosing more frequently thn once weekly. (5.1) Hemtology: Monitor for myelosuppression, which cn be dose-limiting. (5.2, 5.7) Pulmonry toxicity: Discontinue Gemzr immeditely for severe pulmonry toxicity. (5.3) Renl: Monitor renl function prior to initition of therpy nd periodiclly therefter. Use with cution in ptients with renl impirment. Cses of hemolytic uremic syndrome (HUS) nd/or renl filure, some ftl, hve occurred. Discontinue Gemzr for HUS or severe renl toxicity. (5.4) Heptic: Monitor heptic function prior to initition of therpy nd periodiclly therefter. Use with cution in ptients with heptic impirment. Serious heptotoxicity, including liver filure nd deth, hve occurred. Discontinue Gemzr for severe heptic toxicity. (5.5) Pregnncy: Cn cuse fetl hrm. Advise women of potentil risk to the fetus. (5.6, 8.1) Rdition toxicity. My cuse severe nd life-thretening toxicity. (5.8) ------------------------------- ADVERSE REACTIONS ------------------------------ The most common dverse rections for the single-gent ( 20%) re nuse nd vomiting, nemi, ALT, AST, neutropeni, leukopeni, lkline phosphtse, proteinuri, fever, hemturi, rsh, thrombocytopeni, dyspne (6.1) To report SUSPECTED ADVERSE REACTIONS, contct Eli Lilly nd Compny t 1-800-LillyRx (1-800-545 5979) or FDA t 1-800-FDA-1088 or www.fd.gov/medwtch. See 17 for PATIENT COUNSELING INFORMATION 1 Revised: 02/2011 FULL PRESCRIBING INFORMATION: CONTENTS* 1 INDICATIONS AND USAGE 1.1 Ovrin Cncer 1.2 Brest Cncer 1.3 Non-Smll Cell Lung Cncer 1.4 Pncretic Cncer 2 DOSAGE AND ADMINISTRATION 2.1 Ovrin Cncer 2.2 Brest Cncer 2.3 Non-Smll Cell Lung Cncer 2.4 Pncretic Cncer 2.5 Preprtion nd Administrtion Precutions 2.6 Preprtion for Intrvenous Infusion Administrtion 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 5.1 Infusion Time 5.2 Hemtology 5.3 Pulmonry 5.4 Renl 5.5 Heptic 5.6 Pregnncy 5.7 Lbortory Tests 5.8 Rdition Therpy 6 ADVERSE REACTIONS 6.1 Clinicl Trils Experience 6.2 Post-Mrketing Experience 7 DRUG INTERACTIONS 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnncy 8.3 Nursing Mothers 8.4 Peditric Use 8.5 Geritric Use 8.6 Renl 8.7 Heptic 8.8 Gender 10 OVERDOSAGE 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12.1 Mechnism of Action 12.2 Phrmcodynmics 12.3 Phrmcokinetics 13 NONCLINICAL TOXICOLOGY 13.1 Crcinogenesis, Mutgenesis, Impirment of Fertility 14 CLINICAL STUDIES 14.1 Ovrin Cncer 14.2 Brest Cncer 14.3 Non-Smll Cell Lung Cncer (NSCLC) 14.4 Pncretic Cncer 14.5 Other Clinicl Studies 15 REFERENCES 16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied 16.2 Storge nd Hndling 17 PATIENT COUNSELING INFORMATION 17.1 Low Blood Cell Counts 17.2 Pregnncy 17.3 Nursing Mothers * Sections or subsections omitted from the full prescribing informtion re not listed
2 FULL PRESCRIBING INFORMATION 1 INDICATIONS AND USAGE 1.1 Ovrin Cncer Gemzr in combintion with crbopltin is indicted for the tretment of ptients with dvnced ovrin cncer tht hs relpsed t lest 6 months fter completion of pltinum-bsed therpy. 1.2 Brest Cncer Gemzr in combintion with pclitxel is indicted for the first-line tretment of ptients with metsttic brest cncer fter filure of prior nthrcycline-contining djuvnt chemotherpy, unless nthrcyclines were cliniclly contrindicted. 1.3 Non-Smll Cell Lung Cncer Gemzr is indicted in combintion with cispltin for the first-line tretment of ptients with inoperble, loclly dvnced (Stge IIIA or IIIB), or metsttic (Stge IV) non-smll cell lung cncer. 1.4 Pncretic Cncer Gemzr is indicted s first-line tretment for ptients with loclly dvnced (nonresectble Stge II or Stge III) or metsttic (Stge IV) denocrcinom of the pncres. Gemzr is indicted for ptients previously treted with 5-FU. 2 DOSAGE AND ADMINISTRATION Gemzr is for intrvenous use only. Gemzr my be dministered on n outptient bsis. 2.1 Ovrin Cncer Gemzr should be dministered intrvenously t dose of 1000 mg/m 2 over 30 minutes on Dys 1 nd 8 of ech 21-dy cycle. Crbopltin AUC 4 should be dministered intrvenously on Dy 1 fter Gemzr dministrtion. Ptients should be monitored prior to ech dose with complete blood count, including differentil counts. Ptients should hve n bsolute grnulocyte count 1500 x 10 6 /L nd pltelet count 100,000 x 10 6 /L prior to ech cycle. Dose Modifictions Gemzr dosge djustment for hemtologicl toxicity within cycle of tretment is bsed on the grnulocyte nd pltelet counts tken on Dy 8 of therpy. If mrrow suppression is detected, Gemzr dosge should be modified ccording to guidelines in Tble 1. Tble 1: Dy 8 Dosge Reduction Guidelines for Gemzr in Combintion with Crbopltin Absolute grnulocyte count Pltelet count % of full dose (x 10 6 /L) (x 10 6 /L) 1500 And 100,000 100 1000-1499 And/Or 75,000-99,999 50 <1000 And/Or <75,000 Hold In generl, for severe (Grde 3 or 4) non-hemtologicl toxicity, except nuse/vomiting, therpy with Gemzr should be held or decresed by 50% depending on the judgment of the treting physicin. For crbopltin dosge djustment, see mnufcturer s prescribing informtion. Dose djustment for Gemzr in combintion with crbopltin for subsequent cycles is bsed upon observed toxicity. The dose of Gemzr in subsequent cycles should be reduced to 800 mg/m 2 on Dys 1 nd 8 in cse of ny of the following hemtologic toxicities: Absolute grnulocyte count <500 x 10 6 /L for more thn 5 dys Absolute grnulocyte count <100 x 10 6 /L for more thn 3 dys Febrile neutropeni Pltelets <25,000 x 10 6 /L Cycle dely of more thn one week due to toxicity If ny of the bove toxicities recur fter the initil dose reduction, for the subsequent cycle, Gemzr should be given on Dy 1 only t 800 mg/m 2. 2.2 Brest Cncer Gemzr should be dministered intrvenously t dose of 1250 mg/m 2 over 30 minutes on Dys 1 nd 8 of ech 21-dy cycle. Pclitxel should be dministered t 175 mg/m 2 on Dy 1 s 3-hour intrvenous infusion before Gemzr dministrtion. Ptients should be monitored prior to ech dose with complete blood count, including differentil counts. Ptients should hve n bsolute grnulocyte count 1500 x 10 6 /L nd pltelet count 100,000 x 10 6 /L prior to ech cycle. Dose Modifictions Gemzr dosge djustment for hemtologicl toxicity is bsed on the grnulocyte nd pltelet counts tken on Dy 8 of therpy. If mrrow suppression is detected, Gemzr dosge should be modified ccording to the guidelines in Tble 2. Tble 2: Dy 8 Dosge Reduction Guidelines for Gemzr in Combintion with Pclitxel Absolute grnulocyte count Pltelet count % of full dose
(x 10 6 /L) (x 10 6 /L) 1200 And >75,000 100 1000-1199 Or 50,000-75,000 75 700-999 And 50,000 50 <700 Or <50,000 Hold 3 In generl, for severe (Grde 3 or 4) non-hemtologicl toxicity, except lopeci nd nuse/vomiting, therpy with Gemzr should be held or decresed by 50% depending on the judgment of the treting physicin. For pclitxel dosge djustment, see mnufcturer s prescribing informtion. 2.3 Non-Smll Cell Lung Cncer Two schedules hve been investigted nd the optimum schedule hs not been determined [see Clinicl Studies (14.3)]. With the 4-week schedule, Gemzr should be dministered intrvenously t 1000 mg/m 2 over 30 minutes on Dys 1, 8, nd 15 of ech 28-dy cycle. Cispltin should be dministered intrvenously t 100 mg/m 2 on Dy 1 fter the infusion of Gemzr. With the 3-week schedule, Gemzr should be dministered intrvenously t 1250 mg/m 2 over 30 minutes on Dys 1 nd 8 of ech 21-dy cycle. Cispltin t dose of 100 mg/m 2 should be dministered intrvenously fter the infusion of Gemzr on Dy 1. See prescribing informtion for cispltin dministrtion nd hydrtion guidelines. Dose Modifictions Dosge djustments for hemtologic toxicity my be required for Gemzr nd for cispltin. Gemzr dosge djustment for hemtologicl toxicity is bsed on the grnulocyte nd pltelet counts tken on the dy of therpy. Ptients receiving Gemzr should be monitored prior to ech dose with complete blood count (CBC), including differentil nd pltelet counts. If mrrow suppression is detected, therpy should be modified or suspended ccording to the guidelines in Tble 3. For cispltin dosge djustment, see mnufcturer s prescribing informtion. In generl, for severe (Grde 3 or 4) non-hemtologicl toxicity, except lopeci nd nuse/vomiting, therpy with Gemzr plus cispltin should be held or decresed by 50% depending on the judgment of the treting physicin. During combintion therpy with cispltin, serum cretinine, serum potssium, serum clcium, nd serum mgnesium should be crefully monitored (Grde 3/4 serum cretinine toxicity for Gemzr plus cispltin ws 5% versus 2% for cispltin lone). 2.4 Pncretic Cncer Gemzr should be dministered by intrvenous infusion t dose of 1000 mg/m 2 over 30 minutes once weekly for up to 7 weeks (or until toxicity necessittes reducing or holding dose), followed by week of rest from tretment. Subsequent cycles should consist of infusions once weekly for 3 consecutive weeks out of every 4 weeks. Dose Modifictions Dosge djustment is bsed upon the degree of hemtologic toxicity experienced by the ptient [see Wrnings nd Precutions (5.2)]. Clernce in women nd the elderly is reduced nd women were somewht less ble to progress to subsequent cycles [see Wrnings nd Precutions (5.2) nd Clinicl Phrmcology (12.3)]. Ptients receiving Gemzr should be monitored prior to ech dose with complete blood count (CBC), including differentil nd pltelet count. If mrrow suppression is detected, therpy should be modified or suspended ccording to the guidelines in Tble 3. Tble 3: Dosge Reduction Guidelines Absolute grnulocyte count (x 10 6 /L) Pltelet count (x 10 6 /L) % of full dose 1000 And 100,000 100 500-999 Or 50,000-99,999 75 <500 Or <50,000 Hold Lbortory evlution of renl nd heptic function, including trnsminses nd serum cretinine, should be performed prior to initition of therpy nd periodiclly therefter. Gemzr should be dministered with cution in ptients with evidence of significnt renl or heptic impirment s there is insufficient informtion from clinicl studies to llow cler dose recommendtion for these ptient popultions. Ptients treted with Gemzr who complete n entire cycle of therpy my hve the dose for subsequent cycles incresed by 25%, provided tht the bsolute grnulocyte count (AGC) nd pltelet ndirs exceed 1500 x 10 6 /L nd 100,000 x 10 6 /L, respectively, nd if non-hemtologic toxicity hs not been greter thn WHO Grde 1. If ptients tolerte the subsequent course of Gemzr t the incresed dose, the dose for the next cycle cn be further incresed by 20%, provided gin tht the AGC nd pltelet ndirs exceed 1500 x 10 6 /L nd 100,000 x 10 6 /L, respectively, nd tht non-hemtologic toxicity hs not been greter thn WHO Grde 1. 2.5 Preprtion nd Administrtion Precutions Cution should be exercised in hndling nd prepring Gemzr solutions. The use of gloves is recommended. If Gemzr solution contcts the skin or mucos, immeditely wsh the skin thoroughly with sop nd wter or rinse the mucos with copious mounts of wter. Although cute derml irrittion hs not been observed in niml studies, 2 of 3 rbbits exhibited drug-relted systemic toxicities (deth, hypoctivity, nsl dischrge, shllow brething) due to derml bsorption.
4 Procedures for proper hndling nd disposl of nti-cncer drugs should be considered. Severl guidelines on this subject hve been published [see References (15)]. 2.6 Preprtion for Intrvenous Infusion Administrtion The recommended diluent for reconstitution of Gemzr is 0.9% Sodium Chloride Injection without preservtives. Due to solubility considertions, the mximum concentrtion for Gemzr upon reconstitution is 40 mg/ml. Reconstitution t concentrtions greter thn 40 mg/ml my result in incomplete dissolution, nd should be voided. To reconstitute, dd 5 ml of 0.9% Sodium Chloride Injection to the 200-mg vil or 25 ml of 0.9% Sodium Chloride Injection to the 1-g vil. Shke to dissolve. These dilutions ech yield gemcitbine concentrtion of 38 mg/ml which includes ccounting for the displcement volume of the lyophilized powder (0.26 ml for the 200-mg vil or 1.3 ml for the 1-g vil). The totl volume upon reconstitution will be 5.26 ml or 26.3 ml, respectively. Complete withdrwl of the vil contents will provide 200 mg or 1 g of gemcitbine, respectively. Prior to dministrtion the pproprite mount of drug must be diluted with 0.9% Sodium Chloride Injection. Finl concentrtions my be s low s 0.1 mg/ml. Reconstituted Gemzr is cler, colorless to light strw-colored solution. After reconstitution with 0.9% Sodium Chloride Injection, the ph of the resulting solution lies in the rnge of 2.7 to 3.3. The solution should be inspected visully for prticulte mtter nd discolortion prior to dministrtion, whenever solution or continer permit. If prticulte mtter or discolortion is found, do not dminister. When prepred s directed, Gemzr solutions re stble for 24 hours t controlled room temperture 20 to 25 C (68 to 77 F) [see USP Controlled Room Temperture]. Discrd unused portion. Solutions of reconstituted Gemzr should not be refrigerted, s crystlliztion my occur. The comptibility of Gemzr with other drugs hs not been studied. No incomptibilities hve been observed with infusion bottles or polyvinyl chloride bgs nd dministrtion sets. 3 DOSAGE FORMS AND STRENGTHS Gemzr (gemcitbine for injection, USP) is white to off-white lyophilized powder vilble in sterile single-use vils contining 200 mg or 1 g gemcitbine. 4 CONTRAINDICATIONS Gemzr is contrindicted in those ptients with known hypersensitivity to the drug. 5 WARNINGS AND PRECAUTIONS Ptients receiving therpy with Gemzr should be monitored closely by physicin experienced in the use of cncer chemotherpeutic gents. 5.1 Infusion Time Cution Prolongtion of the infusion time beyond 60 minutes nd more frequent thn weekly dosing hve been shown to increse toxicity [see Clinicl Studies (14.5)]. 5.2 Hemtology Gemzr cn suppress bone mrrow function s mnifested by leukopeni, thrombocytopeni, nd nemi [see Adverse Rections (6.1)], nd myelosuppression is usully the dose-limiting toxicity. Ptients should be monitored for myelosuppression during therpy [see Dosge nd Administrtion (2.1, 2.2, 2.3, nd 2.4)]. 5.3 Pulmonry Pulmonry toxicity hs been reported with the use of Gemzr. In cses of severe lung toxicity, Gemzr therpy should be discontinued immeditely nd pproprite supportive cre mesures instituted [see Adverse Rections (6.1 nd 6.2)]. 5.4 Renl Hemolytic Uremic Syndrome (HUS) nd/or renl filure hve been reported following one or more doses of Gemzr. Renl filure leding to deth or requiring dilysis, despite discontinution of therpy, hs been reported. The mjority of the cses of renl filure leding to deth were due to HUS [see Adverse Rections (6.1 nd 6.2)]. Gemzr should be used with cution in ptients with preexisting renl impirment s there is insufficient informtion from clinicl studies to llow cler dose recommendtion for these ptient popultions [see Use in Specific Popultions (8.6)]. 5.5 Heptic Serious heptotoxicity, including liver filure nd deth, hs been reported in ptients receiving Gemzr lone or in combintion with other potentilly heptotoxic drugs [see Adverse Rections (6.1 nd 6.2)]. Gemzr should be used with cution in ptients with preexisting heptic insufficiency s there is insufficient informtion from clinicl studies to llow cler dose recommendtion for these ptient popultions. Administrtion of Gemzr in ptients with concurrent liver metstses or preexisting medicl history of heptitis, lcoholism, or liver cirrhosis my led to excerbtion of the underlying heptic insufficiency [see Use in Specific Popultions (8.7)]. 5.6 Pregnncy Gemzr cn cuse fetl hrm when dministered to pregnnt womn. In pre-clinicl studies in mice nd rbbits, gemcitbine ws tertogenic, embryotoxic, nd fetotoxic. There re no dequte nd well-controlled studies of Gemzr in pregnnt women. If this drug is used during pregnncy, or if the ptient becomes pregnnt while tking this drug, the ptient should be pprised of the potentil hzrd to the fetus [see Use in Specific Popultions (8.1)].
5.7 Lbortory Tests Ptients receiving Gemzr 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 Dosge nd Administrtion (2.1, 2.2, 2.3, nd 2.4)]. Lbortory evlution of renl nd heptic function should be performed prior to initition of therpy nd periodiclly therefter [see Dosge nd Administrtion (2.4)]. 5.8 Rdition Therpy A pttern of tissue injury typiclly ssocited with rdition toxicity hs been reported in ssocition with concurrent nd non-concurrent use of Gemzr. Non-concurrent (given >7 dys prt) Anlysis of the dt does not indicte enhnced toxicity when Gemzr is dministered more thn 7 dys before or fter rdition, other thn rdition recll. Dt suggest tht Gemzr cn be strted fter the cute effects of rdition hve resolved or t lest one week fter rdition. Concurrent (given together or 7 dys prt) Preclinicl nd clinicl studies hve shown tht Gemzr hs rdiosensitizing ctivity. Toxicity ssocited with this multimodlity therpy is dependent on mny different fctors, including dose of Gemzr, frequency of Gemzr dministrtion, dose of rdition, rdiotherpy plnning technique, the trget tissue, nd trget volume. In single tril, where Gemzr 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 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 4795 cm 3 ]. Subsequent studies hve been reported nd suggest tht Gemzr dministered t lower doses with concurrent rdiotherpy hs predictble nd less severe toxicity. However, the optimum regimen for sfe dministrtion of Gemzr with therpeutic doses of rdition hs not yet been determined in ll tumor types. 6 ADVERSE REACTIONS 6.1 Clinicl Trils Experience Becuse clinicl trils re conducted under widely vrying conditions, dverse rection rtes observed in the clinicl trils of drug cnnot be directly compred to rtes in the clinicl trils of nother drug nd my not reflect the rtes observed in prctice. Most dverse rections re reversible nd do not need to result in discontinution, lthough doses my need to be withheld or reduced. Gemzr hs been used in wide vriety of mlignncies, both s single-gent nd in combintion with other cytotoxic drugs. Single-Agent Use: Myelosuppression is the principl dose-limiting toxicity with Gemzr therpy. Dosge djustments for hemtologic toxicity re frequently needed [see Dosge nd Administrtion (2.1, 2.2, 2.3, nd 2.4)]. The dt in Tble 4 re bsed on 979 ptients receiving Gemzr s single-gent dministered weekly s 30-minute infusion for tretment of wide vriety of mlignncies. The Gemzr 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 Grde 3 or 4) dverse rections 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 Gemzr therpy in bout 10% of ptients. In the comprtive tril in pncretic cncer, the discontinution rte for dverse rections ws 14.3% for the Gemzr rm nd 4.8% for the 5-FU rm. All WHO-grded lbortory dverse rections re listed in Tble 4, regrdless of cuslity. Non-lbortory dverse rections listed in Tble 4 or discussed below were those reported, regrdless of cuslity, for t lest 10% of ll ptients, except the ctegories of Extrvstion, Allergic, nd Crdiovsculr nd certin specific dverse rections under the Renl, Pulmonry, nd Infection ctegories. Tble 4: Selected WHO-Grded Adverse Rections in Ptients Receiving Single-Agent Gemzr WHO Grdes (% incidence) All Ptients b Pncretic Cncer Ptients c Discontinutions (%) d All Grdes Grde 3 Grde 4 All Grdes Grde 3 Grde 4 All Ptients Lbortory e Hemtologic Anemi 68 7 1 73 8 2 <1 Leukopeni 62 9 <1 64 8 1 <1 Neutropeni 63 19 6 61 17 7 - Thrombocytopeni 24 4 1 36 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 4 Bilirubin 13 2 <1 26 6 2 Renl <1 5
Proteinuri 45 <1 0 32 <1 0 Hemturi 35 <1 0 23 0 0 BUN 16 0 0 15 0 0 Cretinine 8 <1 0 6 0 0 Non-lbortory f Nuse nd Vomiting 69 13 1 71 10 2 <1 Fever 41 2 0 38 2 0 <1 Rsh 30 <1 0 28 <1 0 <1 Dyspne 23 3 <1 10 0 <1 <1 Dirrhe 19 1 0 30 3 0 0 Hemorrhge 17 <1 <1 4 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 Grde bsed on criteri from the World Helth Orgniztion (WHO). b N=699-974; ll ptients with lbortory or non-lbortory dt. c N=161-241; ll pncretic cncer ptients with lbortory or non-lbortory dt. d N=979. e Regrdless of cuslity. f Tble includes non-lbortory dt with incidence for ll ptients 10%. For pproximtely 60% of the ptients, non-lbortory dverse rections were grded only if ssessed to be possibly drug-relted. 6 Hemtologic In studies in pncretic cncer myelosuppression is the dose-limiting toxicity with Gemzr, 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 Gemzr therpy nd dosge modified or suspended ccording to the degree of hemtologic toxicity [see Dosge nd Administrtion (2.1, 2.2, 2.3, nd 2.4)]. Gstrointestinl Nuse nd vomiting were commonly reported (69%) but were usully of mild to moderte severity. Severe nuse nd vomiting (WHO Grde 3/4) occurred in <15% of ptients. Dirrhe ws reported by 19% of ptients, nd stomtitis by 11% of ptients. Heptic In clinicl trils, Gemzr 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 Gemzr or with greter totl cumultive dose. Serious heptotoxicity, including liver filure nd deth, hs been reported very rrely in ptients receiving Gemzr lone or in combintion with other potentilly heptotoxic drugs [see Adverse Rections (6.2)]. Renl In clinicl trils, mild proteinuri nd hemturi were commonly reported. Clinicl findings consistent with the Hemolytic Uremic Syndrome (HUS) were reported in 6 of 2429 ptients (0.25%) receiving Gemzr in clinicl trils. Four ptients developed HUS on Gemzr therpy, 2 immeditely posttherpy. 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). Gemzr therpy should be discontinued immeditely. Renl filure my not be reversible even with discontinution of therpy nd dilysis my be required [see Adverse Rections (6.2)]. Fever The overll incidence of fever ws 41%. This is in contrst to the incidence of infection (16%) nd indictes tht Gemzr 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 Rsh ws reported in 30% 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 13% of ptients. Pulmonry In clinicl trils, dyspne, unrelted to underlying disese, hs been reported in ssocition with Gemzr therpy. Dyspne ws occsionlly ccompnied by bronchospsm. Pulmonry toxicity hs been reported with the use of Gemzr [see Adverse Rections (6.2)]. The etiology of these effects is unknown. If such effects develop, Gemzr should be discontinued. Erly use of supportive cre mesures my help meliorte these conditions. Edem Edem (13%), peripherl edem (20%), nd generlized edem (<1%) were reported. Less thn 1% of ptients discontinued due to edem. Flu-like Symptoms 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. Infection Infections were reported for 16% of ptients. Sepsis ws rrely reported (<1%). Alopeci Hir loss, usully miniml, ws reported by 15% of ptients.
Neurotoxicity There ws 10% incidence of mild presthesis nd <1% rte of severe presthesis. Extrvstion Injection-site relted events were reported for 4% of ptients. There were no reports of injection site necrosis. Gemzr is not vesicnt. Allergic Bronchospsm ws reported for less thn 2% of ptients. Anphylctoid rection hs been reported rrely. Gemzr should not be dministered to ptients with known hypersensitivity to this drug [see Contrindictions (4)]. Crdiovsculr During clinicl trils, 2% of ptients discontinued therpy with Gemzr due to crdiovsculr events such s myocrdil infrction, cerebrovsculr ccident, rrhythmi, nd hypertension. Mny of these ptients hd prior history of crdiovsculr disese [see Adverse Rections (6.2)]. Combintion Use in Non-Smll Cell Lung Cncer: In the Gemzr plus cispltin versus cispltin study, dose djustments occurred with 35% of Gemzr 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 rections occurred in 15% of ptients on the combintion rm nd 8% of ptients on the cispltin rm. With medin of 4 cycles of Gemzr plus cispltin tretment, 94 of 262 ptients (36%) experienced totl of 149 hospitliztions due to possibly tretment-relted dverse rections. With medin of 2 cycles of cispltin tretment, 61 of 260 ptients (23%) experienced 78 hospitliztions due to possibly tretment-relted dverse rections. In the Gemzr plus cispltin versus etoposide plus cispltin study, dose djustments occurred with 20% of Gemzr injections nd 16% of cispltin injections in the Gemzr plus cispltin rm compred with 20% of etoposide injections nd 15% of cispltin injections in the etoposide plus cispltin rm. With medin of 5 cycles of Gemzr plus cispltin tretment, 15 of 69 ptients (22%) experienced 15 hospitliztions due to possibly tretment-relted dverse rections. With medin of 4 cycles of etoposide plus cispltin tretment, 18 of 66 ptients (27%) experienced 22 hospitliztions due to possibly tretment-relted dverse rections. In ptients who completed more thn one cycle, dose djustments were reported in 81% of the Gemzr plus cispltin ptients, compred with 68% on the etoposide plus cispltin rm. Study discontinutions for possibly drug-relted dverse rections occurred in 14% of ptients on the Gemzr plus cispltin rm nd in 8% of ptients on the etoposide plus cispltin rm. The incidence of myelosuppression ws incresed in frequency with Gemzr plus cispltin tretment (~90%) compred to tht with the Gemzr monotherpy (~60%). With combintion therpy Gemzr dosge djustments for hemtologic toxicity were required more often while cispltin dose djustments were less frequently required. Tble 5 presents the sfety dt from the Gemzr 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 4 (1.5%) possibly tretment-relted deths, including 3 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 Gemzr plus cispltin rm. Myelosuppression occurred more frequently on the combintion rm, nd in 4 possibly tretment-relted deths myelosuppression ws observed. Sepsis ws reported in 4% of ptients on the Gemzr 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 14% of ptients on the combintion rm nd 4% on the cispltin rm. However, severe hemorrhgic events were rre. Red blood cell trnsfusions were required in 39% of the ptients on the Gemzr plus cispltin rm, versus 13% on the cispltin rm. The dt suggest cumultive nemi with continued Gemzr plus cispltin use. Nuse nd vomiting despite the use of ntiemetics occurred more often with Gemzr plus cispltin therpy (78%) thn with cispltin lone (71%). In studies with single-gent Gemzr, lower incidence of nuse nd vomiting (58% to 69%) ws reported. Renl function bnormlities, hypomgnesemi, neuromotor, neurocorticl, nd neurocerebellr toxicity occurred more often with Gemzr plus cispltin thn with cispltin monotherpy. Neurohering toxicity ws similr on both rms. Crdic dysrrhythmis of Grde 3 or greter were reported in 7 (3%) ptients treted with Gemzr plus cispltin compred to one (<1%) Grde 3 dysrrhythmi reported with cispltin therpy. Hypomgnesemi nd hypoklemi were ssocited with one Grde 4 rrhythmi on the Gemzr plus cispltin combintion rm. Tble 6 presents dt from the rndomized study of Gemzr plus cispltin versus etoposide plus cispltin in 135 ptients with NSCLC. One deth (1.5%) ws reported on the Gemzr 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 Grde 4 neutropeni on the Gemzr plus cispltin rm ws less thn on the etoposide plus cispltin rm (28% versus 56%). Sepsis ws experienced by 2% of ptients on both tretment rms. Grde 3 nemi nd Grde 3/4 thrombocytopeni were more common on the Gemzr plus cispltin rm. RBC trnsfusions were given to 29% of the ptients who received Gemzr plus cispltin versus 21% of ptients who received etoposide plus cispltin. Pltelet trnsfusions were given to 3% of the ptients who received Gemzr plus cispltin versus 8% of ptients who received etoposide plus cispltin. Grde 3/4 nuse nd vomiting were lso more common on the Gemzr plus cispltin rm. On the Gemzr 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 Gemzr 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 3% of ptients on the Gemzr plus cispltin rm with none reported on the comprtor rm. Eight ptients (12%) on the Gemzr plus cispltin rm reported edem compred to one ptient (2%) on the etoposide plus cispltin rm. 7
8 Tble 5: Selected CTC-Grded Adverse Rections From Comprtive Tril of Gemzr Plus Cispltin Versus Single-Agent Cispltin in NSCLC CTC Grdes (% incidence) Gemzr plus Cispltin b Cispltin c All Grdes Grde 3 Grde 4 All Grdes Grde 3 Grde 4 Lbortory d Hemtologic Anemi 89 22 3 67 6 1 RBC Trnsfusion e 39 13 Leukopeni 82 35 11 25 2 1 Neutropeni 79 22 35 20 3 1 Thrombocytopeni 85 25 25 13 3 1 Pltelet Trnsfusions e 21 <1 Lymphocytes 75 25 18 51 12 5 Heptic Trnsminse 22 2 1 10 1 0 Alkline Phosphtse 19 1 0 13 0 0 Renl Proteinuri 23 0 0 18 0 0 Hemturi 15 0 0 13 0 0 Cretinine 38 4 <1 31 2 <1 Other Lbortory Hyperglycemi 30 4 0 23 3 0 Hypomgnesemi 30 4 3 17 2 0 Hypoclcemi 18 2 0 7 0 <1 Non-lbortory f Nuse 93 25 2 87 20 <1 Vomiting 78 11 12 71 10 9 Alopeci 53 1 0 33 0 0 Neuro Motor 35 12 0 15 3 0 Neuro Hering 25 6 0 21 6 0 Dirrhe 24 2 2 13 0 0 Neuro Sensory 23 1 0 18 1 0 Infection 18 3 2 12 1 0 Fever 16 0 0 5 0 0 Neuro Corticl 16 3 1 9 1 0 Neuro Mood 16 1 0 10 1 0 Locl 15 0 0 6 0 0 Neuro Hedche 14 0 0 7 0 0 Stomtitis 14 1 0 5 0 0 Hemorrhge 14 1 0 4 0 0 Dyspne 12 4 3 11 3 2 Hypotension 12 1 0 7 1 0 Rsh 11 0 0 3 0 0 Grde bsed on Common Toxicity Criteri (CTC). Tble includes dt for dverse rections with incidence 10% in either rm. b N=217-253; ll Gemzr plus cispltin ptients with lbortory or non-lbortory dt. Gemzr t 1000 mg/m 2 on Dys 1, 8, nd 15 nd cispltin t 100 mg/m 2 on Dy 1 every 28 dys. c N=213-248; ll cispltin ptients with lbortory or non-lbortory dt. Cispltin t 100 mg/m 2 on Dy 1 every 28 dys. d Regrdless of cuslity. e Percent of ptients receiving trnsfusions. Percent trnsfusions re not CTC-grded events. f Non-lbortory events were grded only if ssessed to be possibly drug-relted. Tble 6: Selected WHO-Grded Adverse Rections From Comprtive Tril of Gemzr Plus Cispltin Versus Etoposide Plus Cispltin in NSCLC WHO Grdes (% incidence) Gemzr plus Cispltin b Etoposide plus Cispltin c Lbortory d Hemtologic All Grdes Grde 3 Grde 4 All Grdes Grde 3 Grde 4
Anemi 88 22 0 77 13 2 RBC Trnsfusions e 29 21 Leukopeni 86 26 3 87 36 7 Neutropeni 88 36 28 87 20 56 Thrombocytopeni 81 39 16 45 8 5 Pltelet Trnsfusions e 3 8 Heptic ALT 6 0 0 12 0 0 AST 3 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 4 0 0 Cretinine 2 0 0 2 0 0 Non-lbortory f,g Nuse nd Vomiting 96 35 4 86 19 7 Fever 6 0 0 3 0 0 Rsh 10 0 0 3 0 0 Dyspne 1 0 1 3 0 0 Dirrhe 14 1 1 13 0 2 Hemorrhge 9 0 3 3 0 3 Infection 28 3 1 21 8 0 Alopeci 77 13 0 92 51 0 Stomtitis 20 4 0 18 2 0 Somnolence 3 0 0 3 2 0 Presthesis 38 0 0 16 2 0 Grde bsed on criteri from the World Helth Orgniztion (WHO). N=67-69; ll Gemzr plus cispltin ptients with lbortory or non-lbortory dt. Gemzr t 1250 mg/m 2 on Dys 1 nd 8 nd cispltin t 100 mg/m 2 on Dy 1 every 21 dys. N=57-63; ll cispltin plus etoposide ptients with lbortory or non-lbortory dt. Cispltin t 100 mg/m 2 on Dy 1 nd intrvenous etoposide t 100 mg/m 2 on Dys 1, 2, nd 3 every 21 dys. Regrdless of cuslity. Percent of ptients receiving trnsfusions. Percent trnsfusions re not WHO-grded events. Non-lbortory events were grded only if ssessed to be possibly drug-relted. Pin dt were not collected. b c d e f g 9 Combintion Use in Brest Cncer: In the Gemzr plus pclitxel versus pclitxel study, dose reductions occurred with 8% of Gemzr injections nd 5% of pclitxel injections on the combintion rm, versus 2% on the pclitxel rm. On the combintion rm, 7% of Gemzr 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 Gemzr plus pclitxel rm nd 12 (5%) on the pclitxel rm discontinued the study becuse of dverse rections. There were two deths on study or within 30 dys fter study drug discontinution tht were possibly drug-relted, one on ech rm. Tble 7 presents the sfety dt occurrences of 10% (ll grdes) from the Gemzr plus pclitxel versus pclitxel study in brest cncer. Tble 7: Adverse Rections From Comprtive Tril of Gemzr Plus Pclitxel Versus Single-Agent Pclitxel in Brest Cncer CTC Grdes (% incidence) Gemzr plus Pclitxel (N=262) Pclitxel (N=259) All Grdes Grde 3 Grde 4 All Grdes Grde 3 Grde 4 Lbortory b Hemtologic Anemi 69 6 1 51 3 <1 Neutropeni 69 31 17 31 4 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 14 4 92 19 3 Neuropthy-sensory 64 5 <1 58 3 0 Nuse 50 1 0 31 2 0 Ftigue 40 6 <1 28 1 <1 Mylgi 33 4 0 33 3 <1 Vomiting 29 2 0 15 2 0 Arthrlgi 24 3 0 22 2 <1 Dirrhe 20 3 0 13 2 0 Anorexi 17 0 0 12 <1 0 Neuropthy-motor 15 2 <1 10 <1 0 Stomtitis/phryngitis 13 1 <1 8 <1 0 Fever 13 <1 0 3 0 0 Rsh/desqumtion 11 <1 <1 5 0 0 Grde bsed on Common Toxicity Criteri (CTC) Version 2.0 (ll grdes 10%). b Regrdless of cuslity. c Non-lbortory events were grded only if ssessed to be possibly drug-relted. 10 The following re the cliniclly relevnt dverse rections tht occurred in >1% nd <10% (ll grdes) of ptients on either rm. In prentheses re the incidences of Grde 3 nd 4 dverse rections (Gemzr 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: In the Gemzr plus crbopltin versus crbopltin study, dose reductions occurred with 10.4% of Gemzr injections nd 1.8% of crbopltin injections on the combintion rm, versus 3.8% on the crbopltin lone rm. On the combintion rm, 13.7% of Gemzr doses were omitted nd 0.2% of crbopltin doses were omitted, compred to 0% of crbopltin doses on the crbopltin lone rm. There were no differences in discontinutions due to dverse rections between rms (10.9% versus 9.8%, respectively). Tble 8 presents the dverse rections (ll grdes) occurring in 10% of ptients in the ovrin cncer study. Tble 8: Adverse Rections From Comprtive Tril of Gemzr Plus Crbopltin Versus Single-Agent Crbopltin in Ovrin Cncer CTC Grdes (% incidence) Gemzr plus Crbopltin (N=175) Crbopltin (N=174) All Grdes Grde 3 Grde 4 All Grdes Grde 3 Grde 4 Lbortory b Hemtologic Neutropeni 90 42 29 58 11 1 Anemi 86 22 6 75 9 2 Leukopeni 86 48 5 70 6 <1 Thrombocytopeni 78 30 5 57 10 1 RBC Trnsfusions c 38 15 Pltelet Trnsfusions c 9 3 Non-lbortory b Nuse 69 6 0 61 3 0 Alopeci 49 0 0 17 0 0 Vomiting 46 6 0 36 2 <1 Constiption 42 6 1 37 3 0 Ftigue 40 3 <1 32 5 0 Neuropthy-sensory 29 1 0 27 2 0 Dirrhe 25 3 0 14 <1 0 Stomtitis/phryngitis 22 <1 0 13 0 0 Anorexi 16 1 0 13 0 0 b Grde bsed on Common Toxicity Criteri (CTC) Version 2.0 (ll grdes 10%). Regrdless of cuslity.
c Percent of ptients receiving trnsfusions. Trnsfusions re not CTC-grded events. Blood trnsfusions included both pcked red blood cells nd whole blood. 11 In ddition to blood product trnsfusions s listed in Tble 8, myelosuppression ws lso mnged with hemtopoietic gents. These gents were dministered more frequently with combintion therpy thn with monotherpy (grnulocyte growth fctors: 23.6% nd 10.1%, respectively; erythropoietic gents: 7.3% nd 3.9%, respectively). The following re the cliniclly relevnt dverse rections, regrdless of cuslity, tht occurred in >1% nd <10% (ll grdes) of ptients on either rm. In prentheses re the incidences of Grde 3 nd 4 dverse rections (Gemzr plus crbopltin versus crbopltin): AST or ALT elevtion (0 versus 1.2%), dyspne (3.4% versus 2.9%), febrile neutropeni (1.1% versus 0), hemorrhgic event (2.3% versus 1.1%), hypersensitivity rection (2.3% versus 2.9%), motor neuropthy (1.1% versus 0.6%), 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. 6.2 Post-Mrketing Experience The following dverse rections hve been identified during post-pprovl use of Gemzr. Becuse these rections re reported voluntrily from popultion of uncertin size, it is not lwys possible to relibly estimte their frequency or estblish cusl reltionship to drug exposure. These dverse rections hve occurred fter Gemzr single-gent use nd Gemzr 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 Gemzr. Crdiovsculr Congestive hert filure nd myocrdil infrction hve been reported very rrely with the use of Gemzr. 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 Gemzr lone or in combintion with other potentilly heptotoxic drugs. Heptic veno-occlusive disese hs been reported. 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 Gemzr dministered to ptients with vrious mlignncies. Some ptients experienced the onset of pulmonry symptoms up to 2 weeks fter the lst Gemzr 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 Gemzr. 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 Wrnings nd Precutions (5.8)]. 7 DRUG INTERACTIONS No specific drug interction studies hve been conducted. Informtion is vilble on the phrmcodynmics nd phrmcokinetics of Gemzr in combintion with cispltin, pclitxel, or crbopltin [see Clinicl Phrmcology (12.2 nd 12.3)]. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnncy Pregnncy Ctegory D. See Wrnings nd Precutions section. Gemzr cn cuse fetl hrm when dministered to pregnnt womn. Bsed on its mechnism of ction, Gemzr is expected to result in dverse reproductive effects. There re no dequte nd well-controlled studies of Gemzr in pregnnt women. 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. If this drug is used during pregnncy, or if the ptient becomes pregnnt while tking this drug, the ptient should be pprised of the potentil hzrd to the fetus [see Wrnings nd Precutions (5.6)]. 8.3 Nursing Mothers It is not known whether this drug is excreted in humn milk. Becuse mny drugs re excreted in humn milk nd becuse of the potentil for serious dverse rections in nursing infnts from Gemzr, decision should be mde whether to discontinue nursing or to discontinue the drug, tking into ccount the importnce of the drug to the mother. 8.4 Peditric Use
12 The sfety nd effectiveness of Gemzr in peditric ptients hs not been estblished. Gemzr 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 360 minutes three times weekly followed by one-week rest period. Gemzr 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 360 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. 8.5 Geritric Use Gemzr clernce is ffected by ge [see Clinicl Phrmcology (12.3)]. There is no evidence, however, tht unusul dose djustments [see Dosge nd Administrtion (2.1, 2.2, 2.3, nd 2.4)] 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. Grde 3/4 thrombocytopeni ws more common in the elderly. In the rndomized clinicl tril of Gemzr in combintion with crbopltin for recurrent ovrin cncer [see Clinicl Studies (14.1)], 125 women treted with Gemzr plus crbopltin were <65 yers nd 50 were 65 yers. Similr effectiveness ws observed between older nd younger women. There ws significntly higher Grde 3/4 neutropeni in women 65 yers of ge or older. Overll, there were no other substntil differences in toxicity profile of Gemzr plus crbopltin bsed on ge. 8.6 Renl Hemolytic Uremic Syndrome (HUS) nd/or renl filure hve been reported following one or more doses of Gemzr. Renl filure leding to deth or requiring dilysis, despite discontinution of therpy, hs been reported. The mjority of the cses of renl filure leding to deth were due to HUS [see Adverse Rections (6.1 nd 6.2)]. Gemzr should be used with cution in ptients with preexisting renl impirment s there is insufficient informtion from clinicl studies to llow cler dose recommendtion for these ptient popultions [see Wrnings nd Precutions (5.4)]. 8.7 Heptic Serious heptotoxicity, including liver filure nd deth, hs been reported in ptients receiving Gemzr lone or in combintion with other potentilly heptotoxic drugs [see Adverse Rections (6.1 nd 6.2)]. Gemzr should be used with cution in ptients with preexisting heptic insufficiency s there is insufficient informtion from clinicl studies to llow cler dose recommendtion for these ptient popultions. Administrtion of Gemzr in ptients with concurrent liver metstses or preexisting medicl history of heptitis, lcoholism, or liver cirrhosis my led to excerbtion of the underlying heptic insufficiency [see Wrnings nd Precutions (5.5)]. 8.8 Gender Gemzr clernce is ffected by gender [see Clinicl Phrmcology (12.3)]. In the single-gent sfety dtbse (N=979 ptients), however, there is no evidence tht unusul dose djustments [see Dosge nd Administrtion (2)] re necessry in women. In generl, in single-gent studies of Gemzr, 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 Grde 3/4 neutropeni nd thrombocytopeni. There ws greter tendency in women, especilly older women, not to proceed to the next cycle. 10 OVERDOSAGE There is no known ntidote for overdoses of Gemzr. Myelosuppression, presthesis, nd severe rsh were the principl toxicities seen when single dose s high s 5700 mg/m 2 ws dministered by intrvenous infusion over 30 minutes every 2 weeks to severl ptients in Phse 1 study. In the event of suspected overdose, the ptient should be monitored with pproprite blood counts nd should receive supportive therpy, s necessry. 11 DESCRIPTION Gemzr (gemcitbine for injection, USP) is nucleoside metbolic inhibitor tht exhibits ntitumor ctivity. Gemcitbine HCl is 2 -deoxy-2,2 -difluorocytidine monohydrochloride ( -isomer). The structurl formul is s follows:
13 The empiricl formul for gemcitbine HCl is C 9 H 11 F 2 N 3 O 4 HCl. It hs moleculr weight of 299.66. 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. The clinicl formultion is supplied in sterile form for intrvenous use only. Vils of Gemzr contin either 200 mg or 1 g of gemcitbine HCl (expressed s free bse) formulted with mnnitol (200 mg or 1 g, respectively) nd sodium cette (12.5 mg or 62.5 mg, respectively) s sterile lyophilized powder. Hydrochloric cid nd/or sodium hydroxide my hve been dded for ph djustment. 12 CLINICAL PHARMACOLOGY 12.1 Mechnism of Action 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) nucleosides. The cytotoxic effect of gemcitbine is ttributed to combintion of two ctions of the diphosphte nd the triphosphte nucleosides, 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 deoxynucleotides, 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. 12.2 Phrmcodynmics 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-H460 or NCI-H520 xenogrfts. Gemcitbine ws synergistic with cispltin in the Lewis lung murine xenogrft. Sequentil exposure to gemcitbine 4 hours before cispltin produced the gretest interction. 12.3 Phrmcokinetics Absorption nd Distribution The phrmcokinetics of gemcitbine were exmined in 353 ptients, 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 Gemzr dose vried from 500 to 3600 mg/m 2. The volume of distribution ws incresed with infusion length. Volume of distribution of gemcitbine ws 50 L/m 2 following infusions lsting <70 minutes. For long infusions, the volume of distribution rose to 370 L/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. Gemcitbine plsm protein binding is negligible. Metbolism Gemcitbine disposition ws studied in 5 ptients who received single 1000 mg/m 2 /30 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. 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 19.4 hours.