1NEUPOGEN® (Filgrastim)DESCRIPTIONFilgrastim is a human granulocyte colony stimulating factor (G-CSF)‚ produced byrecombinant DNA technology. NEUPOGEN® is the Amgen Inc. trademark forFilgrastim‚ which has been selected as the name for recombinant methionyl humangranulocyte colony stimulating factor (r-metHuG-CSF).NEUPOGEN is a 175 amino acid protein manufactured by recombinant DNAtechnology.1 NEUPOGEN is produced by Escherichia coli (E coli) bacteria into whichhas been inserted the human granulocyte colony stimulating factor gene. NEUPOGENhas a molecular weight of 18‚800 daltons. The protein has an amino acid sequence that isidentical to the natural sequence predicted from human DNA sequence analysis‚ except forthe addition of an N-terminal methionine necessary for expression in E coli. BecauseNEUPOGEN is produced in E coli‚ the product is nonglycosylated and thus differs fromG-CSF isolated from a human cell.NEUPOGEN is a sterile‚ clear‚ colorless‚ preservative-free liquid for parenteraladministration. Each single-use vial of NEUPOGEN contains 300 mcg/mL of Filgrastimat a specific activity of 1.0 ± 0.6 x 108 U/mg‚ (as measured by a cell mitogenesis assay).The product is formulated in a 10 mM sodium acetate buffer at pH 4.0‚ containing 5%sorbitol‚ and 0.004% Tween® 80. The quantitative composition (per mL) ofNEUPOGEN is:Filgrastim300 mcgAcetate0.59 mgSorbitol50.0 mgTween® 800.004%Sodium0.035 mgWater for Injection USP q.s. ad1.0 mL
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`AMGEN INC.
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`2CLINICAL PHARMACOLOGYColony Stimulating FactorsColony stimulating factors are glycoproteins which act on hematopoietic cells by bindingto specific cell surface receptors and stimulating proliferation‚ differentiation commitment‚and some end-cell functional activation.Endogenous G-CSF is a lineage specific colony stimulating factor which is produced bymonocytes‚ fibroblasts, and endothelial cells. G-CSF regulates the production ofneutrophils within the bone marrow and affects neutrophil progenitor proliferation‚2‚3differentiation,2‚4 and selected end-cell functional activation (including enhancedphagocytic ability‚5 priming of the cellular metabolism associated with respiratory burst‚6antibody dependent killing,7 and the increased expression of some functions associatedwith cell surface antigens8). G-CSF is not species specific and has been shown to haveminimal direct in vivo or in vitro effects on the production of hematopoietic cell typesother than the neutrophil lineage.Preclinical ExperienceFilgrastim was administered to monkeys‚ dogs‚ hamsters‚ rats‚ and mice as part of apreclinical toxicology program which included single-dose acute‚ repeated-dose subacute‚subchronic‚ and chronic studies. Single-dose administration of Filgrastim by the oral‚intravenous (IV)‚ subcutaneous (SC)‚ or intraperitoneal (IP) routes resulted in nosignificant toxicity in mice‚ rats‚ hamsters‚ or monkeys. Although no deaths wereobserved in mice‚ rats‚ or monkeys at dose levels up to 3450 mcg/kg or in hamsters usingsingle doses up to approximately 860 mcg/kg‚ deaths were observed in a subchronic (13-week) study in monkeys. In this study‚ evidence of neurological symptoms was seen inmonkeys treated with doses of Filgrastim greater than 1150 mcg/kg/day for up to 18 days.Deaths were seen in five of the eight treated animals and were associated with 15- to 28-fold increases in peripheral leukocyte counts‚ and neutrophil-infiltrated hemorrhagic fociwere seen in both the cerebrum and cerebellum. In contrast‚ no monkeys died following13 weeks of daily IV administration of Filgrastim at a dose level of 115 mcg/kg. In anensuing 52-week study‚ one 115 mcg/kg dose female monkey died after 18 weeks of dailyIV administration of Filgrastim. Death was attributed to cardiopulmonary insufficiency.In subacute‚ repeated-dose studies‚ changes observed were attributable to the expectedpharmacological actions of Filgrastim (ie‚ dose-dependent increases in white cell counts‚increased circulating segmented neutrophils‚ and increased myeloid:erythroid ratio in bonemarrow). In all species‚ histopathologic examination of the liver and spleen revealedevidence of ongoing extramedullary granulopoiesis; increased spleen weights were seen inall species and appeared to be dose-related. A dose-dependent increase in serum alkaline
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`3phosphatase was observed in rats‚ and may reflect increased activity of osteoblasts andosteoclasts. Changes in serum chemistry values were reversible following discontinuationof treatment.In rats treated at doses of 1150 mcg/kg/day for 4 weeks (5 of 32 animals) and for 13weeks at doses of 100 mcg/kg/day (4 of 32 animals) and 500 mcg/kg/day (6 of 32animals)‚ articular swelling of the hind legs was observed. Some degree of hind legdysfunction was also observed; however‚ symptoms reversed following cessation ofdosing. In rats‚ osteoclasis and osteoanagenesis were found in the femur‚ humerus‚coccyx‚ and hind legs (where they were accompanied by synovitis) after IV treatment for4 weeks (115 to 1150 mcg/kg/day)‚ and in the sternum after IV treatment for 13 weeks(115 to 575 mcg/kg/day). These effects reversed to normal within 4 to 5 weeks followingcessation of treatment.In the 52-week chronic‚ repeated-dose studies performed in rats (IP injection up to 57.5mcg/kg/day)‚ and cynomolgus monkeys (IV injection of up to 115 mcg/kg/day)‚ changesobserved were similar to those noted in the subacute studies. Expected pharmacologicalactions of Filgrastim included dose-dependent increases in white cell counts‚ increasedcirculating segmented neutrophils and alkaline phosphatase levels‚ and increasedmyeloid:erythroid ratios in the bone marrow. Decreases in platelet counts were also notedin primates. In no animals tested were hemorrhagic complications observed. Ratsdisplayed dose-related swelling of the hind limb‚ accompanied by some degree of hindlimb dysfunction; osteopathy was noted microscopically. Enlarged spleens (both species)and livers (monkeys)‚ reflective of ongoing extramedullary granulopoiesis‚ as well asmyeloid hyperplasia of the bone marrow‚ were observed in a dose-dependent manner.Pharmacologic Effects of NEUPOGENIn phase 1 studies involving 96 patients with various nonmyeloid malignancies‚NEUPOGEN administration resulted in a dose-dependent increase in circulatingneutrophil counts over the dose range of 1 to 70 mcg/kg/day.9-11 This increase inneutrophil counts was observed whether NEUPOGEN was administered IV (1 to 70mcg/kg twice daily)‚9 SC (1 to 3 mcg/kg once daily)‚11 or by continuous SC infusion (3 to11 mcg/kg/day).10 With discontinuation of NEUPOGEN therapy‚ neutrophil countsreturned to baseline‚ in most cases within 4 days. Isolated neutrophils displayed normalphagocytic (measured by zymosan-stimulated chemoluminescence) and chemotactic[measured by migration under agarose using N-formyl-methionyl-leucyl-phenylalanine(fMLP) as the chemotaxin] activity in vitro.The absolute monocyte count was reported to increase in a dose-dependent manner inmost patients receiving NEUPOGEN‚ however‚ the percentage of monocytes in thedifferential count remained within the normal range. In all studies to date‚ absolute countsof both eosinophils and basophils did not change and were within the normal rangefollowing administration of NEUPOGEN. Increases in lymphocyte counts following
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`4NEUPOGEN administration have been reported in some normal subjects and cancerpatients.White blood cell (WBC) differentials obtained during clinical trials have demonstrated ashift towards earlier granulocyte progenitor cells (left shift)‚ including the appearance ofpromyelocytes and myeloblasts‚ usually during neutrophil recovery following thechemotherapy-induced nadir. In addition‚ Dohle bodies‚ increased granulocytegranulation‚ as well as hypersegmented neutrophils have been observed. Such changeswere transient‚ and were not associated with clinical sequelae nor were they necessarilyassociated with infection.PharmacokineticsAbsorption and clearance of NEUPOGEN follows first-order pharmacokinetic modelingwithout apparent concentration dependence. A positive linear correlation occurredbetween the parenteral dose and both the serum concentration and area under theconcentration-time curves. Continuous IV infusion of 20 mcg/kg of NEUPOGEN over 24hours resulted in mean and median serum concentrations of approximately 48 and 56ng/mL‚ respectively. Subcutaneous administration of 3.45 mcg/kg and 11.5 mcg/kgresulted in maximum serum concentrations of 4 and 49 ng/mL‚ respectively‚ within 2 to 8hours. The volume of distribution averaged 150 mL/kg in both normal subjects andcancer patients. The elimination half-life‚ in both normal subjects and cancer patients‚ wasapproximately 3.5 hours. Clearance rates of NEUPOGEN were approximately 0.5 to 0.7mL/minute/kg. Single parenteral doses or daily IV doses‚ over a 14-day period‚ resultedin comparable half-lives. The half-lives were similar for IV administration (231 minutes‚following doses of 34.5 mcg/kg) and for SC administration (210 minutes‚ followingNEUPOGEN doses of 3.45 mcg/kg). Continuous 24-hour IV infusions of 20 mcg/kgover an 11- to 20-day period produced steady-state serum concentrations of NEUPOGENwith no evidence of drug accumulation over the time period investigated.CLINICAL EXPERIENCECancer Patients Receiving Myelosuppressive ChemotherapyNEUPOGEN has been shown to be safe and effective in accelerating the recovery ofneutrophil counts following a variety of chemotherapy regimens. In a phase 3 clinical trialin small cell lung cancer‚ patients received SC administration of NEUPOGEN (4 to 8mcg/kg/day‚ days 4 to 17) or placebo. In this study‚ the benefits of NEUPOGEN therapywere shown to be prevention of infection as manifested by febrile neutropenia‚ decreasedhospitalization‚ and decreased IV antibiotic usage. No difference in survival or diseaseprogression was demonstrated.In the phase 3‚ randomized‚ double-blind‚ placebo-controlled trial conducted in patients
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`5with small cell lung cancer‚ patients were randomized to receive NEUPOGEN (n = 99) orplacebo (n = 111) starting on day 4‚ after receiving standard dose chemotherapy withcyclophosphamide‚ doxorubicin‚ and etoposide. A total of 210 patients were evaluatedfor efficacy and 207 evaluated for safety. Treatment with NEUPOGEN resulted in aclinically and statistically significant reduction in the incidence of infection‚ as manifestedby febrile neutropenia; the incidence of at least one infection over all cycles ofchemotherapy was 76% (84/111) for placebo-treated patients‚ versus 40% (40/99) forNEUPOGEN-treated patients (p < 0.001). The following secondary analyses were alsoperformed. The requirements for in-patient hospitalization and antibiotic use were alsosignificantly decreased during the first cycle of chemotherapy; incidence of hospitalizationwas 69% (77/111) for placebo-treated patients in cycle 1‚ versus 52% (51/99) forNEUPOGEN-treated patients (p = 0.032). The incidence of IV antibiotic usage was 60%(67/111) for placebo-treated patients in cycle 1‚ versus 38% (38/99) for NEUPOGEN-treated patients (p = 0.003). The incidence‚ severity‚ and duration of severe neutropenia[absolute neutrophil count (ANC) < 500/mm3] following chemotherapy were allsignificantly reduced. The incidence of severe neutropenia in cycle 1 was 84% (83/99) forpatients receiving NEUPOGEN versus 96% (106/110) for patients receiving placebo (p =0.004). Over all cycles‚ patients randomized to NEUPOGEN had a 57% (286/500 cycles)rate of severe neutropenia versus 77% (416/543 cycles) for patients randomized toplacebo. The median duration of severe neutropenia in cycle 1 was reduced from 6 days(range 0 to 10 days) for patients receiving placebo to 2 days (range 0 to 9 days) forpatients receiving NEUPOGEN (p < 0.001). The mean duration of neutropenia in cycle 1was 5.64 ± 2.27 days for patients receiving placebo versus 2.44 ± 1.90 days for patientsreceiving NEUPOGEN. Over all cycles‚ the median duration of neutropenia was 3 daysfor patients randomized to placebo versus 1 day for patients randomized to NEUPOGEN.The median severity of neutropenia (as measured by ANC nadir) was 72/mm3 (range0/mm3 to 7912/mm3) in cycle 1 for patients receiving NEUPOGEN versus 38/mm3 (range0/mm3 to 9520/mm3) for patients receiving placebo (p = 0.012). The mean severity ofneutropenia in cycle 1 was 496/mm3 ± 1382/mm3 for patients receiving NEUPOGENversus 204/mm3 ± 953/mm3 for patients receiving placebo. Over all cycles‚ the ANC nadirfor patients randomized to NEUPOGEN was 403/mm3‚ versus 161/mm3 for patientsrandomized to placebo. Administration of NEUPOGEN resulted in an earlier ANC nadirfollowing chemotherapy than was experienced by patients receiving placebo (day 10 vsday 12). NEUPOGEN was well tolerated when given SC daily at doses of 4 to 8 mcg/kgfor up to 14 consecutive days following each cycle of chemotherapy (see ADVERSEREACTIONS).Several other phase 1/2 studies‚ which did not directly measure the incidence of infection‚but which did measure increases in neutrophils‚ support the efficacy of NEUPOGEN. Theregimens are presented to provide some background on the clinical experience withNEUPOGEN. No claim regarding the safety or efficacy of the chemotherapy regimens ismade. The effects of NEUPOGEN on tumor growth or on the anti-tumor activity of the
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`6chemotherapy were not assessed. The doses of NEUPOGEN used in these studies areconsiderably greater than those found to be effective in the phase 3 study described above.Such phase 1/2 studies are summarized in the following table.Type ofMalignancyRegimenChemotherapyDoseNo.Pts.TrialPhaseNEUPOGEN DailyDosageaSmall CellLung CancerCyclophosphamide1 g/m2/day21034-8 mcg/kg SCDoxorubicin50 mg/m2/daydays 4-17Etoposide120 mg/m2/day x 3q 21 daysSmall CellLung Cancer11Ifosfamide5 g/m2/day121/25.75-46 mcg/kg IVDoxorubicin50 mg/m2/daydays 4-17Etoposide120 mg/m2/day x 3Mesna8 g/m2/dayq 21 daysUrothelialCancer12Methotrexate30 mg/m2/day x 2401/23.45-69 mcg/kg IVVinblastine3 mg/m2/day x 2days 4-11Doxorubicin30 mg/m2/dayCisplatin70 mg/m2/dayq 28 daysVariousNonmyeloidMalignancies13Cyclophosphamide2.5 g/m2/day x 2181/223-69 mcg/kgb IVEtoposide500 mg/m2/day x 3days 8-28Cisplatin50 mg/m2/day x 3q 28 daysBreast/OvarianCancer14Doxorubicinc75 mg/m221211.5 mcg/kg IV100 mg/m2days 2-9125 mg/m25.75 mcg/kg IV150 mg/m2days 10-12q 14 daysNeuroblastomaCyclophosphamide150 mg/m2 x 71225.45-17.25 mcg/kg SCDoxorubicin35 mg/m2days 6-19Cisplatin90 mg/m2q 28 days(cycles 1‚3‚5) daNEUPOGEN doses were those that accelerated neutrophil production. Doses which provided no additionalacceleration beyond that achieved at the next lower dose are not reported.bLowest dose(s) tested in the study.cPatients received doxorubicin at either 75‚ 100‚ 125‚ or 150 mg/m2.dCycles 2‚6 = cyclophosphamide 150 mg/m2 x 7 and etoposide 280 mg/m2 x 3.Cycle 4 = cisplatin 90 mg/m2 x 1 and etoposide 280 mg/m2 x 3.
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`7Patients With Acute Myeloid Leukemia Receiving Induction or ConsolidationChemotherapyIn a randomized, double-blind‚ placebo-controlled‚ multi-center‚ phase 3 clinical trial‚ 521patients (median age 54‚ range 16 to 89 years) were treated for de novo acute myeloidleukemia (AML). Following a standard induction chemotherapy regimen comprisingdaunorubicin, cytosine arabinoside, and etoposide17 (DAV 3+7+5), patients receivedeither NEUPOGEN at 5 mcg/kg/day or placebo, SC, from 24 hours after the last dose ofchemotherapy until neutrophil recovery (ANC 1000/mm3 for 3 consecutive days or10,000/mm3 for 1 day) or for a maximum of 35 days.Treatment with NEUPOGEN significantly reduced the median time to ANC recovery andthe median duration of fever, antibiotic use, and hospitalization following inductionchemotherapy. In the NEUPOGEN-treated group‚ the median time from initiation ofchemotherapy to ANC recovery (ANC ‡ 500/mm3) was 20 days (vs 25 days in the controlgroup, p = 0.0001), the median duration of fever was reduced by 1.5 days (p = 0.009),and there were statistically significant reductions in the durations of IV antibiotic use andhospitalization. During consolidation therapy (DAV 2+5+5), patients treated withNEUPOGEN also experienced significant reductions in the incidence of severeneutropenia, time to neutrophil recovery, the incidence and duration of fever, and in thedurations of IV antibiotic use and hospitalization. Patients treated with a further course ofstandard (DAV 2+5+5) or high-dose cytosine arabinoside consolidation also experiencedsignificant reductions in the duration of neutropenia.There were no statistically significant differences between NEUPOGEN and placebogroups in complete remission rate (69% NEUPOGEN vs 68% placebo, p = 0.77), disease-free survival [median 342 days NEUPOGEN (n = 178), 322 days placebo (n = 177), p =0.99], time to progression of all randomized patients (median 165 days NEUPOGEN, 186days placebo, p = 0.87), or overall survival (median 380 days NEUPOGEN, 425 daysplacebo, p = 0.83).Cancer Patients Receiving Bone Marrow TransplantIn two separate randomized‚ controlled trials‚ patients with Hodgkin’s disease (HD) andnon-Hodgkin’s lymphoma (NHL) were treated with myeloablative chemotherapy andautologous bone marrow transplantation (ABMT). In one study (n = 54)‚ NEUPOGENwas administered at doses of 10 or 30 mcg/kg/day; a third treatment group in this studyreceived no NEUPOGEN. A statistically significant reduction in the median number ofdays of severe neutropenia (ANC < 500/mm3) occurred in the NEUPOGEN-treated groupversus the control group [23 days in the control group‚ 11 days in the 10 mcg/kg/daygroup‚ and 14 days in the 30 mcg/kg/day group‚ (11 days in the combined treatmentgroups‚ p = 0.004)]. In the second study (n = 44‚ 43 patients evaluable)‚ NEUPOGENwas administered at doses of 10 or 20 mcg/kg/day; a third treatment group in this studyreceived no NEUPOGEN. A statistically significant reduction in the median number of
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`8days of severe neutropenia occurred in the NEUPOGEN-treated group versus the controlgroup (21.5 days in the control group and 10 days in both treatment groups‚ p < 0.001).The number of days of febrile neutropenia was also reduced significantly in this study[13.5 days in the control group‚ 5 days in the 10 mcg/kg/day group‚ and 5.5 days in the 20mcg/kg/day group‚ (5 days in the combined treatment groups‚ p < 0.0001)]. Reductionsin the number of days of hospitalization and antibiotic use were also seen‚ although thesereductions were not statistically significant. There were no effects on red blood cell orplatelet levels.In a randomized‚ placebo-controlled trial‚ 70 patients with myeloid and nonmyeloidmalignancies were treated with myeloablative therapy and allogeneic bone marrowtransplant followed by 300 mcg/m2/day of a Filgrastim product. A statistically significantreduction in the median number of days of severe neutropenia occurred in the treatedgroup versus the control group (19 days in the control group and 15 days in the treatmentgroup‚ p < 0.001) and time to recovery of ANC to ‡ 500/mm3 (21 days in the controlgroup and 16 days in the treatment group‚ p < 0.001).In three nonrandomized studies (n = 119)‚ patients received ABMT and treatment withNEUPOGEN. One study (n = 45) involved patients with breast cancer and malignantmelanoma. A second study (n = 39) involved patients with HD. The third study (n = 35)involved patients with NHL‚ acute lymphoblastic leukemia (ALL)‚ and germ cell tumor.In these studies‚ the recovery of the ANC to ‡ 500/mm3 ranged from a median of 11.5 to13 days.None of the conditioning regimens used in the ABMT studies included radiation therapy.While these studies were not designed to compare survival‚ this information was collectedand evaluated. The overall survival and disease progression of patients receivingNEUPOGEN in these studies were similar to those observed in the respective controlgroups and to historical data.Peripheral Blood Progenitor Cell Collection and Therapy in Cancer PatientsAll patients in the Amgen-sponsored trials received a similar mobilization/collectionregimen: NEUPOGEN was administered for 6 to 7 days‚ with an apheresis procedure ondays 5‚ 6, and 7 (except for a limited number of patients receiving apheresis on days 4‚ 6,and 8). In a non-Amgen-sponsored study‚ patients underwent mobilization to a targetnumber of mononuclear cells (MNC)‚ with apheresis starting on day 5. There are no dataon the mobilization of peripheral blood progenitor cells (PBPC) after days 4 to 5 that arenot confounded by leukapheresis.Mobilization: Mobilization of PBPC was studied in 50 heavily pretreated patients(median number of prior cycles = 9.5) with NHL‚ HD, or ALL (Amgen study 1). CFU-
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`9GM was used as the marker for engraftable PBPC. The median CFU-GM level on eachday of mobilization was determined from the data available (CFU-GM assays were notobtained on all patients on each day of mobilization). These data are presented below.The data from Amgen study 1 were supported by data from Amgen study 2 in which 22pretreated breast cancer patients (median number of prior cycles = 3) were studied. Boththe CFU-GM and CD34+ cells reached a maximum on day 5 at > 10-fold over baseline andthen remained elevated with leukapheresis.Progenitor Cell Levels in Peripheral Blood by Mobilization DayOverall Study 1CFU-GM/mLStudy 2CFU-GM/mLStudy 2CD34+ (x 104/mL)No.SamplesMedian(25%-75%)No.SamplesMedian(25%-75%)No.SamplesMedian(25%-75%)Day 11118(13-62)2042(15-151)200.13(0.02-0.66)Day 2722(3-61)n/an/an/an/aDay 310138(39-364)n/an/an/an/aDay 418365(158-864)18576(108-1819)172.11(0.58-3.93)Day 536781(391-1608)21960(72-1677)223.16(1.08-6.11)Day 646505(199-1397)22756(70-3486)222.67(1.09-4.40)Day 737333(111-938)22597(118-2009)212.64(0.78-4.22)Day 815383(94-815)1251(10-746)121.61(0.38-4.31)n/a = not availableIn three studies of patients with prior exposure to chemotherapy‚ the median CFU-GMyield in the leukapheresis product ranged from 20.9 to 32.7 x 104/kg body weight (n =105). In two of these studies where CD34+ yields in the leukapheresis product were alsodetermined‚ the median CD34+ yields were 3.11 and 2.80 x 106/kg, respectively (n = 56).In an additional study of 18 chemotherapy-naive patients‚ the median CFU-GM yield was123.4 x 104/kg.Engraftment: Engraftment following NEUPOGEN-mobilized PBPC is summarized for101 patients in the table below. In all studies a Cox regression model showed that thetotal number of CFU-GM and/or CD34+ cells collected was a significant predictor of timeto platelet recovery.
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`10In a randomized unblinded study of patients with HD or NHL undergoing myeloablativechemotherapy (Amgen study 3)‚ 27 patients received NEUPOGEN-mobilized PBPCfollowed by NEUPOGEN and 31 patients received ABMT followed by NEUPOGEN.Patients randomized to the NEUPOGEN-mobilized PBPC group compared to the ABMTgroup had significantly fewer days of platelet transfusions (median 6 vs 10 days)‚ asignificantly shorter time to a sustained platelet count > 20‚000/mm3 (median 16 vs 23days)‚ a significantly shorter time to recovery of a sustained ANC ‡ 500/mm3 (median 11vs 14 days)‚ significantly fewer days of red blood cell transfusions (median 2 vs 3 days)and a significantly shorter duration of posttransplant hospitalization.Amgen-sponsoredStudy 1N = 13Amgen-sponsoredStudy 2N = 22Amgen-sponsoredStudy 3N = 27Non-Amgen-sponsoredStudyN = 39Median PBPC/kg Collected MNCCD34+CFU-GM9.5 x 108n/a63.9 x 1049.5 x 1083.1 x 10625.3 x 1048.1 x 1082.8 x 10632.6 x 10410.3 x 1086.2 x 106n/aDays to ANC ‡ 500/mm3 MedianRange98-10108-15119-38107-40Days to Plt. ‡ 20‚000/mm3 MedianRange107-1612.510-30168-5215.57-63n/a = not availableThree of the 101 patients (3%) did not achieve the criteria for engraftment as defined by aplatelet count ‡ 20‚000/mm3 by day 28. In clinical trials of NEUPOGEN for themobilization of PBPC‚ NEUPOGEN was administered to patients at 5 to 24 mcg/kg/dayafter reinfusion of the collected cells until a sustainable ANC ( ‡ 500/mm3) was reached.The rate of engraftment of these cells in the absence of NEUPOGEN posttransplantationhas not been studied.Patients With Severe Chronic NeutropeniaSevere chronic neutropenia (SCN) (idiopathic‚ cyclic‚ and congenital) is characterized bya selective decrease in the number of circulating neutrophils and an enhanced susceptibilityto bacterial infections.The daily administration of NEUPOGEN has been shown to be safe and effective incausing a sustained increase in the neutrophil count and a decrease in infectious morbidity
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`11in children and adults with the clinical syndrome of SCN.15 In the phase 3 trial‚summarized in the following table‚ daily treatment with NEUPOGEN resulted insignificant beneficial changes in the incidence and duration of infection‚ fever‚ antibioticuse‚ and oropharyngeal ulcers. In this trial‚ 120 patients with a median age of 12 years(range 1 to 76 years) were treated.Overall Significant Changes in Clinical Endpoints Median Incidencea(Events) or Duration (Days) per 28-day PeriodControlPatientsbNEUPOGEN-treatedPatientsp-valueIncidence of Infection0.500.20< 0.001Incidence of Fever0.250.20< 0.001Duration of Fever0.630.200.005Incidence ofOropharyngeal Ulcers0.260.00< 0.001Incidence of Antibiotic Use0.490.20< 0.001aIncidence values were calculated for each patient‚ and are defined as the total number of eventsexperienced divided by the number of 28-day periods of exposure (on-study). Median incidencevalues were then reported for each patient group.bControl patients were observed for a 4-month period.The incidence for each of these five clinical parameters was lower in the NEUPOGEN armcompared to the control arm for cohorts in each of the three major diagnostic categories.All three diagnostic groups showed favorable trends in favor of treatment. An analysis ofvariance showed no significant interaction between treatment and diagnosis‚ suggestingthat efficacy did not differ substantially in the different diseases. Although NEUPOGENsubstantially reduced neutropenia in all patient groups‚ in patients with cyclic neutropenia‚cycling persisted but the period of neutropenia was shortened to 1 day.As a result of the lower incidence and duration of infections‚ there was also a lowernumber of episodes of hospitalization [28 hospitalizations in 62 patients in the treatedgroup vs 44 hospitalizations in 60 patients in the control group over a 4-month period (p =0.0034)]. Patients treated with NEUPOGEN also reported a lower number of episodes ofdiarrhea‚ nausea‚ fatigue‚ and sore throat.In the phase 3 trial‚ untreated patients had a median ANC of 210/mm3 (range 0 to
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`121550/mm3). NEUPOGEN therapy was adjusted to maintain the median ANC between1500 and 10‚000/mm3. Overall‚ the response to NEUPOGEN was observed in 1 to 2weeks. The median ANC after 5 months of NEUPOGEN therapy for all patients was7460/mm3 (range 30 to 30‚880/mm3). NEUPOGEN dosing requirements were generallyhigher for patients with congenital neutropenia (2.3 to 40 mcg/kg/day) than for patientswith idiopathic (0.6 to 11.5 mcg/kg/day) or cyclic (0.5 to 6 mcg/kg/day) neutropenia.INDICATIONS AND USAGECancer Patients Receiving Myelosuppressive ChemotherapyNEUPOGEN is indicated to decrease the incidence of infection‚ as manifested by febrileneutropenia‚ in patients with nonmyeloid malignancies receiving myelosuppressive anti-cancer drugs associated with a significant incidence of severe neutropenia with fever (seeCLINICAL EXPERIENCE). A complete blood count (CBC) and platelet count shouldbe obtained prior to chemotherapy‚ and twice per week (see LABORATORYMONITORING) during NEUPOGEN therapy to avoid leukocytosis and to monitor theneutrophil count. In phase 3 clinical studies‚ NEUPOGEN therapy was discontinuedwhen the ANC was ‡ 10‚000/mm3 after the expected chemotherapy-induced nadir.Patients With Acute Myeloid Leukemia Receiving Induction or ConsolidationChemotherapyNEUPOGEN is indicated for reducing the time to neutrophil recovery and the duration offever, following induction or consolidation chemotherapy treatment of adults with AML.Cancer Patients Receiving Bone Marrow TransplantNEUPOGEN is indicated to reduce the duration of neutropenia and neutropenia-relatedclinical sequelae‚ eg‚ febrile neutropenia‚ in patients with nonmyeloid malignanciesundergoing myeloablative chemotherapy followed by marrow transplantation (seeCLINICAL EXPERIENCE). It is recommended that CBCs and platelet counts beobtained at a minimum of three times per week (see LABORATORY MONITORING)following marrow infusion to monitor the recovery of marrow reconstitution.Patients Undergoing Peripheral Blood Progenitor Cell Collection and TherapyNEUPOGEN is indicated for the mobilization of hematopoietic progenitor cells into theperipheral blood for collection by leukapheresis. Mobilization allows for the collection ofincreased numbers of progenitor cells capable of engraftment compared with collection byleukapheresis without mobilization or bone marrow harvest. After myeloablativechemotherapy‚ the transplantation of an increased number of progenitor cells can lead tomore rapid engraftment‚ which may result in a decreased need for supportive care (see
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`13CLINICAL EXPERIENCE).Patients With Severe Chronic NeutropeniaNEUPOGEN is indicated for chronic administration to reduce the incidence and durationof sequelae of neutropenia (eg‚ fever‚ infections‚ oropharyngeal ulcers) in symptomaticpatients with congenital neutropenia‚ cyclic neutropenia‚ or idiopathic neutropenia (seeCLINICAL EXPERIENCE). It is essential that serial CBCs with differential and plateletcounts‚ and an evaluation of bone marrow morphology and karyotype be performed priorto initiation of NEUPOGEN therapy. The use of NEUPOGEN prior to confirmation ofSCN may impair diagnostic efforts and may thus impair or delay evaluation and treatmentof an underlying condition‚ other than SCN‚ causing the neutropenia.CONTRAINDICATIONSNEUPOGEN is contraindicated in patients with known hypersensitivity to E coli-derivedproteins‚ Filgrastim‚ or any component of the product.WARNINGSAllergic-type reactions occurring on initial or subsequent treatment have been reported in< 1 in 4000 patients treated with NEUPOGEN. These have generally been characterizedby systemic symptoms involving at least two body systems‚ most often skin (rash‚urticaria‚ facial edema)‚ respiratory (wheezing‚ dyspnea)‚ and cardiovascular(hypotension‚ tachycardia). Some reactions occurred on initial exposure. Reactionstended to occur within the first 30 minutes after administration and appeared to occurmore frequently in patients receiving NEUPOGEN IV. Rapid resolution of symptomsoccurred in most cases after administration of antihistamines‚ steroids‚ bronchodilators‚and/or epinephrine. Symptoms recurred in more than half the patients who wererechallenged.Patients With Severe Chronic NeutropeniaThe safety and efficacy of NEUPOGEN in the treatment of neutropenia due to otherhematopoietic disorders (eg‚ myelodysplastic disorders or myeloid leukemia) have notbeen established. Care should be taken to confirm the diagnosis of SCN before initiatingNEUPOGEN therapy.While 9 of 325 patients developed myelodysplasia or myeloid leukemia while receivingNEUPOGEN during clinical trials‚ AML or abnormal cytogenetics have been reported tooccur in the natural history of SCN without cytokine therapy.16 Abnormal cytogeneticshave been associated with the eventual development of myeloid leukemia. The effect ofNEUPOGEN on the development of abnormal cytogenetics and the effect of continuedNEUPOGEN administration in patients with abnormal cytogenetics are unknown. If a
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`14patient with SCN develops abnormal cytogenetics‚ the risks and benefits of continuingNEUPOGEN should be carefully considered (see ADVERSE REACTIONS).PRECAUTIONSGeneralSimultaneous Use With Chemotherapy and Radiation TherapyThe safety and efficacy of NEUPOGEN given simultaneously with cytotoxicchemotherapy have not been established. Because of the potential sensitivity of rapidlydividing myeloid cells to cytotoxic chemotherapy‚ do not use NEUPOGEN in the period24 hours before through 24 hours after the administration of cytotoxic chemotherapy (seeDOSAGE AND ADMINISTRATION).The efficacy of NEUPOGEN has not been evaluated in patients receiving chemothera