Neupogen (Filgrastim)

NEUPOGEN®

Amgen

Filgrastim

Granulocyte Colony Stimulating Factor – Hematopoietic Agent

Action And Clinical Pharmacology: Filgrastim is a human granulocyte colony stimulating factor (G-CSF) produced by recombinant DNA technology. G-CSF regulates the production of neutrophils within the bone marrow; endogenous G-CSF is a glycoprotein produced by monocytes, fibroblasts, and endothelial cells. G-CSF is a colony stimulating factor which has been shown to have minimal direct in vivo or in vitro effects on the production of other hematopoietic cell types. Filgrastim is the name for recombinant methionyl human granulocyte colony stimulating factor (r-metHuG-CSF).

Filgrastim is a 175 amino acid protein manufactured by recombinant DNA technology. Filgrastim is produced by E. coli bacteria into which has been inserted the human granulocyte colony stimulating factor gene. Filgrastim has a molecular weight of 18 800 daltons. The protein has an amino acid sequence that is identical to the natural sequence predicted from human DNA sequence analysis, except for the addition of an N-terminal methionine necessary for expression in E. coli. Because filgrastim is produced in E. coli, the product is non-glycosylated and thus differs from G-CSF isolated from a human cell.

Pre-clinical Studies: The results of all pre-clinical studies indicate that the pharmacologic effects are consistent with its role as a specific regulator of neutrophil production and function.

Colony Stimulating Factors: Colony stimulating factors are glycoproteins which act on hematopoietic cells by binding to 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 with selectivity for the neutrophil lineage. G-CSF is not species specific and has been shown to primarily affect neutrophil progenitor proliferation, differentiation, and selected end-cell functional activation (including enhanced phagocytic ability, priming of the cellular metabolism associated with respiratory burst, antibody dependent killing, and the increased expression of some functions associated with cell surface antigens).

Pharmacologic Effects of Filgrastim: In Phase I studies involving 96 patients with various non-myeloid malignancies, filgrastim administration resulted in a dose-dependent increase in neutrophil counts over the dose range of 1 to 70 g/kg/day. This increase in neutrophil counts was observed whether filgrastim was administered i.v. (1 to 70 g/kg twice daily), s.c. (1 to 3 g/kg once daily), or by continuous s.c. infusion (3 to 11 g/kg/day). With discontinuation of filgrastim therapy, neutrophil counts returned to baseline, in most cases within 4 days. Isolated neutrophils displayed normal phagocytic (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 in most patients receiving filgrastim, however, the percentage of monocytes in the differential count remained within the normal range. In all studies to date, absolute counts of both eosinophils and basophils did not change and were within the normal range following administration of filgrastim. Increases in lymphocyte counts following filgrastim administration have been reported in some normal subjects and cancer patients.

White blood cell differentials obtained during clinical trials have demonstrated a shift towards granulocyte progenitor cells (left shift), including the appearance of promyelocytes and myeloblasts, usually during neutrophil recovery following the chemotherapy-induced nadir. In addition, increased granulocyte granulation, as well as hypersegmented neutrophils have been observed. Such changes were transient, and were not associated with clinical sequelae nor were they necessarily associated with infection.

Pharmacokinetics: Absorption and clearance of filgrastim follows first-order pharmacokinetic modeling without apparent concentration dependence. A positive linear correlation occurred between the parenteral dose and both the serum concentration and area under the concentration-time curves. Continuous i.v. infusion of 20 g/kg of filgrastim over 24 hours resulted in mean and median serum concentrations of approximately 48 and 56 ng/mL, respectively.

S.C. administration of 3.45 g/kg and 11.5 g/kg resulted in maximum serum concentrations of 4 and 49 ng/mL, respectively, within 2 to 8 hours. The volume of distribution averaged 150 mL/kg in normal subjects and cancer patients. The elimination half-life, in both normal subjects and cancer patients, was approximately 3.5 hours. Clearance rates of filgrastim were approximately 0.5 to 0.7 mL/min/kg. Single parenteral doses or daily i.v. doses, over a 14 day period, resulted in comparable half-lives. The half-lives were similar for i.v. administration (231 minutes, following filgrastim doses of 34.5 g/kg) and for s.c. administration (210 minutes, following filgrastim doses of 3.45 g/kg). Continuous 24-hour i.v. infusions of 20 g/kg over an 11 to 20 day period produced steady-state serum concentrations of filgrastim with no evidence of drug accumulation over the time period investigated.

Clinical Experience: Response to Filgrastim: Cancer Patients Receiving Myelosuppressive Chemotherapy: Filgrastim has been shown to be safe and effective in accelerating the recovery of neutrophil counts following a variety of chemotherapy regimens for a number of cancer types. In a Phase III clinical trial in small cell lung cancer, patients received s.c. administration of filgrastim (4 to 8 g/kg/day, days 4 to 17) or placebo. In this study, the benefits of filgrastim therapy were shown to be prevention of infection as manifested by febrile neutropenia, decreased hospitalization, and decreased antibiotic usage.

In the Phase III, randomized, double-blind placebo-controlled trial conducted in patients with small cell lung cancer, patients were randomized to receive filgrastim (n=101) or placebo (n=110). Of the 211 patients enrolled, 207 patients were evaluable for safety (filgrastim, n=98; placebo, n=109) and 199 patients were evaluable for efficacy (filgrastim, n=95; placebo, n=104). Filgrastim was started on day 4, after patients received standard dose chemotherapy with cyclophosphamide, doxorubicin and etoposide.

The incidence of febrile neutropenia during Cycle I was significantly reduced by 51% in the filgrastim group as compared to the placebo group (28% versus 57%, respectively)
The absolute neutrophil nadir (severity) and duration of severe neutropenia [days with absolute neutrophil count (ANC).

Thus, treatment with filgrastim resulted in a clinically and statistically significant reduction in the incidence of infection, as manifested by febrile neutropenia, as well as the severity and duration of severe neutropenia following chemotherapy.

In-patient hospitalization and antibiotic use were evaluated as secondary endpoints (clinical sequelae) to neutropenia. The incidence of febrile neutropenia with hospitalization during Cycle 1 was significantly reduced by 50% in the filgrastim group compared to the placebo group (26% versus 55%).

Administration of filgrastim resulted in an earlier ANC nadir following chemotherapy than was experienced by patients receiving placebo (day 10 versus day 12). Filgrastim was well tolerated when given s.c. daily at doses of 4 to 8 g/kg for up to 14 consecutive days following each cycle of chemotherapy (see Adverse Effects).

In 36 patients receiving M-VAC (methotrexate, vinblastine, doxorubicin, and cisplatin) for treatment of transitional cell carcinoma of the urothelium, both the severity (p=0.0001) and the duration of granulocytopenia.

In 45 patients treated with melphalan for a variety of advanced malignancies, patients were treated with filgrastim at several doses and using 3 routes of administration (s.c. bolus, i.v. and s.c. infusion). This was a dose finding study without controls. A dose-dependent effect on maximum ANC was demonstrated in this study [p=0.004 (nonparametric test of ordered responses)]. Descriptive analysis showed that the period of severe neutropenia.

The effect of filgrastim has also been studied in 12 patients receiving chemotherapy (doxorubicin, ifosfamide with Mesna, and etoposide) for small cell lung cancer. Chemotherapy cycles without filgrastim were alternated with cycles in which filgrastim was administered following chemotherapy. There was a statistically significant reduction in the duration of both severe (ANC
Cancer Patients Receiving Myeloablative Chemotherapy followed by Bone Marrow Transplantation: In 2 separate randomized, controlled trials, patients with Hodgkin’s and non-Hodgkin’s lymphoma were treated with myeloablative chemotherapy and autologous bone marrow transplantation (ABMT). In one study (n=54), filgrastim was administered at doses of 10 or 30 g/kg/day; a third treatment group in this study received no filgrastim. A statistically significant reduction in the median number of days of severe neutropenia.

In the second study (n=44, 43 patients evaluable), filgrastim was administered at doses of 10 or 20 g/kg/day; a third treatment group in this study received no filgrastim. A statistically significant reduction in the median number of days of severe neutropenia occurred in the filgrastim-treated group versus the control group (21.5 days in the control group and 10 days in both treatment groups.

In a randomized, placebo-controlled trial, 70 patients with myeloid and nonmyeloid malignancies were treated with myeloablative therapy and allogeneic bone marrow transplant followed by 300 g/mday of filgrastim. A statistically significant reduction in the median number of days of severe neutropenia occurred in the treated group versus the control group (19 days in the control group and 15 days in the treatment group.

In three nonrandomized studies (n=119), patients received ABMT and treatment with filgrastim. One study (n=45) involved patients with breast cancer and malignant melanoma. A second study (n=39) involved patients with Hodgkin’s disease. The third study (n=35) involved patients with non- Hodgkin’s lymphoma, acute lymphoblastic leukemia (ALL), and germ cell tumor. In these studies, the recovery of the ANC to ³0.5´10L ranged from a median of 11.5 to 13 days.

Cancer Patients Undergoing Peripheral Blood Progenitor Cell (PBPC) Collection and Therapy: Use of filgrastim either alone, or after chemotherapy, mobilizes hematopoietic progenitor cells into the peripheral blood. These autologous peripheral blood progenitor cells may be harvested and infused after high dose chemotherapy, either in place of, or in addition to bone marrow transplantation. Infusion of peripheral blood progenitor cells accelerates the rate of neutrophil and platelet recovery reducing the risk of hemorrhagic complications and the need for platelet transfusions.

Filgrastim Mobilized PBPC Collection: In 4 studies (n=126), patients with NHL, HD, ALL, and breast cancer received filgrastim for 6 to 7 days to mobilize hematopoietic progenitor cells into the circulating blood pool where they were collected by 3 aphereses on days 5, 6, and 7 (except for 13 patients in 1 study who where pheresed on days 4, 6, and 8). In 2 studies, the tested doses and schedules of filgrastim resulted in a greater number of PBPC in the pheresis product compared to the baseline leukapheresis product.

Filgrastim Mobilized PBPC Therapy Followed by Filgrastim: In a randomized study of patients with HD or NHL undergoing myeloablative chemotherapy, 27 patients received filgrastim mobilized PBPC followed by filgrastim and 31 patients received ABMT plus filgrastim. Patients randomized to the filgrastim mobilized PBPC group compared to the ABMT group had significantly fewer median days of platelet transfusions, (6 vs 10 days, p 20´10L, (16 vs 23 days, p=0.02), a significantly shorter median time to recovery of a sustained ANC ³0.5´10L (11 vs 14 days, p=0.005), and a significantly shorter duration of hospitalization (17 vs 23 days, p=0.002).

Overall, therapy with filgrastim mobilized peripheral blood progenitor cells provided rapid and sustained hematologic recovery. Long-term (limited to 100 days) follow up hematology data from patients treated with PBPCT alone or in combination with bone marrow, was compared to historical data from patients treated with ABMT alone (1 study only). This retrospective analysis indicated that engraftment is durable.

Patients with Severe Chronic Neutropenia: In the Phase III trial in patients with severe chronic neutropenia (SCN), patients with diagnoses of congenital, cyclic and idiopathic neutropenia were evaluated. Untreated patients had a median absolute neutrophil count (ANC) of 0.210´10L. Filgrastim therapy was adjusted to maintain the median ANC between 1.5´10L and 10´10L. A complete response was seen in 88% of patients (defined as a median ANC ³1.5´10L over 5 months of filgrastim therapy). Overall, complete response to filgrastim was observed in 1 to 2 weeks. The median ANC after 5 months of filgrastim therapy for all patients was 7.46´10L (range 0.03 to 30.88´10L). In general, patients with congenital neutropenia responded to filgrastim therapy with a lower median ANC than patients with idiopathic or cyclic neutropenia.

Dosing requirements were generally higher for patients with congenital neutropenia (2.3 to 40 g/kg/day) than for patients with idiopathic (0.6 to 11.5 g/kg/day) or cyclic (0.5 to 6 g/kg/day) neutropenia.

Overall, daily treatment with filgrastim resulted in clinically and statistically significant reductions in the incidence and duration of fever, infection, and oropharyngeal ulcers. As a result, there also were decreases in requirements for antibiotic use and hospitalization. Additionally, patients treated with filgrastim reported fewer episodes of diarrhea, nausea, fatigue and sore throat. These clinical findings may translate into improvements in the quality of life in these patients.

Patients with HIV Infection: Filgrastim has been shown to be safe and effective in preventing and treating neutropenia in patients with HIV infection. In a randomized, controlled, multicenter trial of 258 patients, a statistically significant reduction was observed in the incidence of grade 4 neutropenia.

In this randomized study, 85 patients had a total of 128 new or worsening bacterial infections, during the 168 day study period. Of these, a total of 26 events were graded as severe bacterial infections (WHO toxicity grade 3 or higher). The incidence of bacterial infections was decreased by 31% (p=0.07, p=0.03 [adjusted for number of prior opportunistic infections and baseline CD4 count]) and the incidence of severe bacterial infections was decreased by 54% (p=0.005, p=0.002 [adjusted]) in filgrastim-treated patients when compared with untreated patients. In addition, the total number of hospitalizations or prolonged hospitalizations due to a bacterial infection for all groups in this study, was 24 events in 21 patients, for a total duration of 392 days. Days of hospitalization for bacterial infection were decreased by 45% (p=0.05, p=0.03 [adjusted]). A 28% decrease in the number of days of IV antibacterial medications was seen in filgrastim-treated patients (p=0.17, p=0.08 [adjusted]).

In three open-label nonrandomized clinical studies, the response to filgrastim (ANC >2 000 cells/L) was observed in a median of 2 to 9 days with either daily or intermittent dosing (see Dosage). Filgrastim therapy was titrated to maintain ANCs between 2 000 and 10 000 cells/L.

In the randomized controlled trial, there was a 12% increase in the number of days patients were able to receive full or high-dose myelosuppressive medications. In a multicentre, non-comparative study of 200 patients, filgrastim allowed more than 80% of patients to increase or maintain dosing of ganciclovir, zidovudine, trimethoprim/sulfamethoxazole and pyrimethamine, or to add one or more medications to their therapy. The number of these four medications received per patient increased by approximately 20% during filgrastim therapy.

In an open-label study to evaluate neutrophil function by in vitro chemiluminescence measurement, filgrastim-treated patients had increased oxidase-myeloperoxidase activity and potentially greater microbial killing capacity.

In the randomized controlled study, 13 deaths (5%) were reported on-study. There were 13 additional deaths within 30 days of study completion. The leading causes of death were HIV-associated complications and AIDS progression. There were no other patterns observed for cause of death. In three uncontrolled studies, 16 of the 32 deaths were reported as AIDS progression, the other 16 deaths were attributed to HIV-associated complications. In these clinical studies, all deaths were reported by the investigator as not related or unlikely to be related to filgrastim.

In clinical trials, changes in HIV viral load were evaluated by a quantitative HIV-1 RNA RT- Polymerase Chain Reaction (PCR) analyses and by measurement of HIV-1 p24 antigen levels. These studies did not show any evidence of increased HIV replication associated with filgrastim administration.

Indications And Clinical Uses: Cancer Patients Receiving Myelosuppressive Chemotherapy: To decrease the incidence of infection, as manifested by febrile neutropenia, in patients with nonmyeloid malignancies receiving myelosuppressive antineoplastic drugs.

A complete blood count and platelet count should be obtained prior to chemotherapy, and twice per week (see Precautions, Laboratory Monitoring) during filgrastim therapy to avoid leukocytosis and to monitor the neutrophil count. In Phase III clinical studies, filgrastim therapy was discontinued when the absolute neutrophil count (ANC) was >10´10L after expected chemotherapy-induced nadir.

Cancer Patients Receiving Myeloablative Chemotherapy followed by Bone Marrow Transplantation: To reduce the duration of neutropenia and neutropenia-related clinical sequelae, e.g., febrile neutropenia, in patients undergoing myeloablative therapy followed by bone marrow transplantation.

A complete blood count and platelet count should be obtained at a minimum of 3 times per week following marrow infusion to monitor marrow reconstitution (see Precautions, Laboratory Monitoring).

Cancer Patients Undergoing Peripheral Blood Progenitor Cell (PBPC) Collection and Therapy: For the mobilization of autologous peripheral blood progenitor cells in order to accelerate hematopoietic recovery by infusion of such cells, supported by filgrastim, after myelosuppressive or myeloablative chemotherapy (see Pharmacology, Clinical Experience).

Patients with Severe Chronic Neutropenia: For chronic administration to increase neutrophil counts and to reduce the incidence and duration of infection in patients with a diagnosis of congenital, cyclic or idiopathic neutropenia (see Pharmacology, Clinical Experience).

Patients with HIV Infection: Filgrastim is indicated in patients with HIV infection for the prevention and treatment of neutropenia, to maintain a normal ANC (e.g., between 2 000 and 10 000 cells/L). Filgrastim therapy reduces the clinical sequelae associated with neutropenia (e.g., bacterial infections) and increases the ability to deliver myelosuppressive medications used for the treatment of HIV and its associated complications (see Pharmacology, Clinical Experience). It is recommended that complete blood counts and platelet counts be monitored at regular intervals (e.g., initially twice weekly for 2 weeks, once weekly for an additional 2 weeks, then once monthly thereafter, or as clinically indicated) during filgrastim therapy (see Precautions, Laboratory Monitoring).

Contra-Indications: Patients with known hypersensitivity to E. coli derived products or to any constituent of the product.

Precautions: General: Simultaneous Use with Chemotherapy: The safety and efficacy of filgrastim given simultaneously with cytotoxic chemotherapy have not been established. Because of the potential sensitivity of rapidly dividing myeloid cells to cytotoxic chemotherapy, do not use filgrastim in the period 24 hours before through 24 hours after the administration of cytotoxic chemotherapy (see Dosage).

The efficacy of filgrastim has not been evaluated in patients receiving chemotherapy associated with delayed myelosuppression (e.g., nitrosoureas) or with mitomycin C or with myelosuppressive doses of antimetabolites such as 5-fluorouracil or cytosine arabinoside.

The safety and efficacy of filgrastim have not been evaluated in patients receiving concurrent radiation therapy. Simultaneous use of filgrastim with chemotherapy and radiation therapy should be avoided.

Growth Factor Potential: Filgrastim is a growth factor that primarily stimulates production of neutrophils. However, the possibility that filgrastim can act as a growth factor for certain tumor types, particularly myeloid malignancies, cannot be excluded. Therefore, because of the possibility of tumor growth, precaution should be exercised in using this drug in patients with myelodysplasia or in any malignancy with myeloid characteristics.

Tumor cells may be collected in the leukapheresis product, following PBPC mobilization by filgrastim. The clinical significance and the effect of reinfusion of tumor cells with the leukapheresis product is still unknown and the possible contribution of clonogenic tumor cells to an eventual relapse has not been determined.

Acute myeloid leukemia (AML) has been reported to occur in the natural history of severe chronic neutropenia without cytokine therapy. It is not known what, if any, additional risk may be imposed by filgrastim therapy.

Cancer Patients Receiving Myelosuppressive Chemotherapy: Leukocytosis: In all studies, including Phase I/II dose ranging studies, white blood cell counts of 100´10L or greater were observed in approximately 2% of patients receiving filgrastim at doses above 5 and up to 115 g/kg/day. There were no reports of adverse events associated with this degree of leukocytosis. In order to avoid the potential complications of excessive leukocytosis, a complete blood count (CBC) is recommended twice per week during filgrastim therapy (see Laboratory Monitoring).

Premature Discontinuation of Filgrastim Therapy: A transient increase in neutrophil counts is typically seen 1 to 2 days after initiation of filgrastim therapy. However, for a sustained therapeutic response, filgrastim therapy should be continued following chemotherapy until the post nadir ANC reaches 10´10L. Therefore, the premature discontinuation of filgrastim therapy, prior to the time of recovery from the expected neutrophil nadir, is generally not recommended (see Dosage).

Patients with Severe Chronic Neutropenia: Diagnosis of Congenital, Cyclic or Idiopathic Neutropenia: Care should be taken to confirm the diagnosis of congenital, cyclic or idiopathic neutropenia, which may be difficult to distinguish from myelodysplasia, before initiating filgrastim therapy. The safety and efficacy of filgrastim in the treatment of neutropenia or pancytopenia due to other hematopoietic disorders (e.g., myelodysplastic disorders or myeloid leukemia) have not been established.

It is, therefore, essential that serial complete blood counts with differential and platelet counts, and an evaluation of bone marrow morphology and karyotype, be performed prior to initiation of filgrastim therapy.

Acute myeloid leukemia (AML) or abnormal cytogenetics have been reported to occur in the natural history of severe chronic neutropenia without cytokine therapy. Abnormal cytogenetics have been associated with the eventual development of myeloid leukemia. The effect of continued filgrastim administration in patients with abnormal cytogenetics is unknown. If a patient with severe chronic neutropenia (SCN) develops abnormal cytogenetics, the risks and benefits of continuing filgrastim should be carefully considered (see Adverse Effects).

Chronic Administration: The safety and efficacy of chronic daily administration of filgrastim in patients with SCN have been established in Phase I/II clinical trials of 74 patients treated for up to 4.5 years, and in a Phase III trial of 123 patients treated for up to 3.5 years.

Although the relationship to filgrastim is unclear, osteoporosis has been reported in approximately 7% of patients receiving filgrastim therapy for up to 4.5 years in clinical trials in patients with SCN. Patients with SCN, particularly those with congenital neutropenia and those with underlying osteoperotic bone disease, should be monitored for the possible occurrence of bone density changes while on long-term filgrastim therapy. Other infrequently observed adverse events included exacerbation of some preexisting skin disorders (e.g., psoriasis), cutaneous vasculitis (leukocytoclastic), alopecia, hematuria/proteinuria, thrombocytopenia (platelets less than 50´10L).

Patients with HIV Infection: Risks Associated with Increased Doses of Myelosuppressive Medications: Treatment with filgrastim alone does not preclude thrombocytopenia and anemia due to myelosuppressive medications. As a result of the potential to receive higher doses or a greater number of these medications with filgrastim therapy, the patient may be at higher risk of developing thrombocytopenia (see Adverse Effects) and anemia. Regular monitoring of blood counts is recommended.

Infections Causing Myelosuppression: Neutropenia may be due to bone marrow infiltrating opportunistic infections such as M. avium complex or malignancies such as lymphoma. In patients with known bone marrow infiltrating infection or malignancy, consideration should be given to appropriate therapy for treatment of the underlying condition, in addition to administration of filgrastim for treatment of neutropenia.

Other: The response to filgrastim may be diminished in patients with reduced neutrophil precursors such as those previously treated with extensive dose chemotherapy or radiotherapy.

In studies of filgrastim administration following chemotherapy, most reported side effects were consistent with those usually seen as a result of cytotoxic chemotherapy (see Adverse Effects). As a result of the potential of receiving higher doses of chemotherapy (i.e., full doses on the prescribed schedule), the patient may be at greater risk of thrombocytopenia, anemia, and nonhematological consequences of increased chemotherapy doses (please refer to the prescribing information of the specific chemotherapy agents used). Regular monitoring of the hematocrit and platelet count is recommended.

In septic patients receiving filgrastim, the physician should be alert to the theoretical possibility of adult respiratory distress syndrome, due to the possible influx of neutrophils at the site of inflammation.

Cardiac events (myocardial infarctions, arrhythmias) have been reported in 11 of 375 cancer patients receiving filgrastim in clinical studies; the relationship to filgrastim therapy is unknown. However, patients with preexisting cardiac conditions receiving filgrastim should be monitored closely.

Information for the Patient: In those situations in which the physician determines that the patient can safely and effectively self-administer filgrastim, the patient should be instructed as to the proper dosage and administration. Patients should also be instructed that filgrastim should be refrigerated, but not allowed to freeze. The most common adverse experience occurring with filgrastim therapy is bone pain. Patients should also be instructed about the rare possibility of an allergic-type reaction, possibly manifested as shortness of breath, faintness, or rash. If any of these symptoms occur, patients should contact their physician immediately (see Adverse Effects). If home use is prescribed, patients should be thoroughly instructed in the importance of proper disposal and cautioned against the reuse of needles, syringes, or drug product. A puncture-resistant container for the disposal of used syringes and needles should be available to the patient. The full container should be disposed of according to the directions provided by the physician.

Laboratory Monitoring: Cancer Patients Receiving Myelosuppressive Chemotherapy: A CBC and platelet count should be obtained prior to chemotherapy, and at regular intervals (twice per week) during filgrastim therapy. Following cytotoxic chemotherapy, the neutrophil nadir occurred earlier during cycles when filgrastim was administered, and white blood cell differentials demonstrated a left shift, including the appearance of promyelocytes and myeloblasts. In addition, the duration of severe neutropenia was reduced, and was followed by an accelerated recovery in the neutrophil counts. Therefore, regular monitoring of white blood cell counts, particularly at the time of the recovery from the post chemotherapy nadir, is recommended in order to avoid excessive leukocytosis.

Cancer Patients Receiving Myeloablative Chemotherapy followed by Bone Marrow Transplantation: A CBC and platelet count should be obtained at regular intervals (3 times/week during filgrastim therapy) following marrow infusion.

Cancer Patients Undergoing Peripheral Blood Progenitor Cell (PBPC) Collection and Therapy: After 4 days of filgrastim treatment for PBPC mobilization, neutrophil counts should be monitored. Monitoring of platelet and red blood cell counts is recommended during the leukapheresis period. Frequent complete blood counts and platelet counts are recommended (at least 3 times/week) following PBPC reinfusion.

Patients with Severe Chronic Neutropenia: During the initial 4 weeks of filgrastim therapy, and for 2 weeks following any dose adjustment, a complete blood count (CBC) with differential and platelet determination should be performed twice weekly. Once a patient is clinically stable, a CBC with differential and platelet determination should be performed monthly.

In clinical trials, the following laboratory results were observed: Cyclic fluctuations in the neutrophil counts were frequently observed in patients with congenital or idiopathic neutropenia after initiation of filgrastim therapy.

Platelet counts were generally at the upper limits of normal prior to filgrastim therapy. With filgrastim therapy, platelet counts decreased but generally remained within normal limits (see Adverse Effects).

Early myeloid forms were noted in the peripheral blood in most patients, including the appearance of metamyelocytes and myelocytes. Promyelocytes and myeloblasts were noted in some patients.

Relative increases were occasionally noted in the number of circulating eosinophils and basophils. No consistent increases were observed with filgrastim therapy.

As in other trials, increases were observed in serum uric acid, lactic dehydrogenase, and serum alkaline phosphatase.

Patients with HIV Infection: A CBC and platelet count should be obtained prior to starting filgrastim therapy and at regular intervals (e.g., initially twice weekly for 2 weeks, once weekly for an additional 2 weeks, then once monthly thereafter, or as clinically indicated) during filgrastim therapy. Some patients may respond very rapidly and with a considerable increase in neutrophil count to the initial doses of filgrastim. It is recommended that blood samples be drawn for ANC measurement prior to any scheduled dosing with filgrastim.

Drug Interactions: Interactions of filgrastim with other cytokines, including hematopoietic growth factors, have been observed in animal studies. The safety, efficacy, and possible interactions of filgrastim used in combination with other cytokines have not been characterized in clinical trials. Drugs which may potentiate the release of neutrophils, such as lithium, should be used with caution.

Carcinogenesis, Mutagenesis, Impairment of Fertility: The carcinogenic potential of filgrastim has not been studied. Filgrastim failed to induce bacterial gene mutations in either the presence or absence of a drug metabolizing enzyme system. Filgrastim had no observed effect on the fertility of male or female rats, or on gestation at doses up to 500 g/kg.

Pregnancy: Filgrastim has been shown to cause adverse effects in pregnant rabbits when given in doses 2 to 10 times the human dose.

In rabbits, increased abortion and embryolethality were observed in animals treated with filgrastim at 80 g/kg/day. Filgrastim administered to pregnant rabbits at doses of 80 g/kg/day during the period of organogenesis was associated with increased fetal resorption, genitourinary bleeding, developmental abnormalities, and decreased body weight, live births, and food consumption. External abnormalities were not observed in the fetuses of dams treated at 80 g/kg/day. Reproductive studies in pregnant rats have shown that filgrastim was not associated with lethal, teratogenic, or behavioral effects on fetuses when administered by daily i.v. injection during the period of organogenesis at dose levels up to 575 g/kg/day.

In Segment III studies in rats, offspring of dams treated at greater than 20 g/kg/day exhibited a delay in external differentiation (detachment of auricles and descent of testes) and slight growth retardation, possibly due to lower body weight of females during rearing and nursing. Offspring of dams treated at 100 g/kg/day exhibited decreased body weights at birth, and a slightly reduced 4 day survival rate.

There are no adequate, well controlled studies in pregnant women, therefore, filgrastim is not recommended for use in pregnant women.

Lactation: It is not known whether filgrastim is excreted in human milk, therefore, filgrastim is not recommended for use in nursing women.

Children: Cancer Patients Receiving Myelosuppressive Chemotherapy: Twelve pediatric patients with neuroblastoma have received up to 6 cycles of cyclophosphamide, cisplatin, doxorubicin, and etoposide chemotherapy concurrently with filgrastim, in this population, filgrastim was well tolerated. There was one report of palpable splenomegaly associated with filgrastim therapy; however, the only consistently reported adverse event was musculoskeletal pain, which is no different from the experience in the adult population.

Patients with Severe Chronic Neutropenia: Serious long-term risks of daily treatment with filgrastim have been rarely observed in clinical trials. Potential effects of long-term treatment with this hematopoietic growth factor, such as alterations of growth and development, sexual maturation, or endocrine function, have not been observed.

The safety and efficacy in neonates and patients with autoimmune neutropenia of infancy have not been established.

Adverse Reactions: Cancer Patients Receiving Myelosuppressive Chemotherapy: In clinical trials involving over 350 patients receiving filgrastim following cytotoxic chemotherapy, most adverse experiences were the sequelae of the underlying malignancy or cytotoxic chemotherapy. In all Phase II and III trials, medullary bone pain, reported in 24% of patients, was the only consistently observed adverse reaction attributed to filgrastim therapy. This bone pain was generally reported to be of mild-to-moderate severity, and could be controlled in most patients with nonopioid analgesics; infrequently, bone pain was severe enough to require opioid analgesics. Bone pain was reported more frequently in patients treated with higher doses (20 to 100 g/kg/day) administered i.v., and less frequently in patients treated with lower s.c. doses (3 to 10 g/kg/day).

In the randomized, double-blind, placebo-controlled trial of filgrastim therapy following combination chemotherapy in patients (n=207) with small cell lung cancer, the adverse events in Table I were reported during blinded cycles of study medication (placebo or filgrastim at 4 to 8 g/kg/day). Events are reported as exposure adjusted since patients remained on double-blind filgrastim a median of 3 cycles versus 1 cycle for placebo.

In this study, there were no serious, life-threatening, or fatal adverse reactions attributed to filgrastim therapy. Specifically, there were no reports of flu-like symptoms, pleuritis, pericarditis, or other major systemic reactions.

Spontaneously reversible elevations in uric acid, lactate dehydrogenase, and alkaline phosphatase occurred in 27 to 58% of 98 patients receiving blinded filgrastim therapy following cytotoxic chemotherapy; increases were generally mild to moderate. Transient decreases in blood pressure.

Cancer Patients Receiving Myeloablative Chemotherapy followed by Bone Marrow Transplantation: In clinical trials, the reported adverse effects were those typically seen in patients receiving intensive chemotherapy followed by bone marrow transplantation. The most common events reported in both control and treatment groups included stomatitis and nausea and vomiting, generally of mild to moderate severity and were considered unrelated to filgrastim. In the randomized studies of BMT involving 167 patients who received study drug, the following events occurred more frequently in patients treated with filgrastim than in controls; nausea (10% vs. 4%), vomiting (7% vs. 3%), hypertension (4% vs. 0%), rash (12% vs. 10%), and peritonitis (2% vs. 0%). None of these events were reported by the investigator to be related to filgrastim. One event of erythema nodosum was reported moderate in severity and possibly related to filgrastim.

Cancer Patients Undergoing Peripheral Blood Progenitor Cell (PBPC) Collection and Therapy: Filgrastim: Mobilized PBPC Collection: In clinical trials, 126 patients have received filgrastim for mobilization of PBPC. During the mobilization period, adverse events related to filgrastim consisted primarily of mild to moderate musculoskeletal symptoms, reported in 44% of patients. These symptoms were predominantly events of medullary bone pain (38%). Headache was reported related to filgrastim in 7% of patients. Mild to moderate transient increases in alkaline phosphatase levels were reported related to filgrastim in 21% of the patients who had serum chemistries evaluated during the mobilization phase.

All patients had increases in neutrophil counts consistent with the biological effects of filgrastim. Two patients had a white blood cell count greater than 100´10L with white blood cell count increases during the mobilization period ranging from 16.7´10L to 138´10L above baseline. Eighty eight percent of patients had an increase in white blood cell count between 10´10L and 70´10L above baseline. No clinical sequelae were associated with any grade of leukocytosis.

Sixty five percent of patients had mild to moderate anemia and 97% of patients had decreases in platelet counts possibly related to the leukapheresis procedure. Only 5 patients had platelet counts
PBPC Transplantation followed by Filgrastim: During the period of filgrastim administration post PBPC transplant, filgrastim was administered to 110 patients as supportive therapy and adverse events were consistent with those expected after high dose chemotherapy. Mild to moderate musculoskeletal pain was the most frequently reported adverse event related to filgrastim, reported in 15% of patients.

Patients with Severe Chronic Neutropenia: Mild to moderate bone pain was reported in approximately 33% of patients in clinical trials. This symptom was usually readily controlled with mild analgesics. General musculoskeletal pain was also noted in higher frequency in patients treated with filgrastim. Palpable splenomegaly was observed in approximately 30% of patients. Abdominal or flank pain was seen infrequently and thrombocytopenia.

Eight patients from a subset of 94 who had normal cytogenetic evaluations at baseline were subsequently found to have abnormalities, including monosomy 7, on routine repeat evaluation conducted 18 to 52 months of filgrastim therapy. It is unknown whether the development of these findings is related to chronic daily filgrastim administration or reflects the natural history of SCN.

Other adverse events infrequently observed and possibly related to filgrastim therapy were: injection site reaction, headache, hepatomegaly, arthralgia, osteoporosis, rash, alopecia and hematuria/proteinuria.

Patients with HIV Infection: In the multicenter, randomized, controlled trial, 172 of 258 patients were treated with filgrastim. Filgrastim was generally well-tolerated. The most frequently reported treatment-related adverse events in the 24-week treatment period were skeletal pain (14.5%), headache (6.4%), back pain and myalgia (5.8% each), and increased alkaline phosphatase (5.2%).

There were no new or unexpected treatment-related events seen in filgrastim-treated patients. Adverse events observed in clinical trials were consistent with progression of HIV disease or events observed in other clinical settings.

There was no apparent increase or decrease in HIV replication and viral load as measured by quantitative reverse transcriptase polymerase chain reaction (RT-PCR). Although prior in vitro and in vivo studies have not shown any increase in viral load following use of filgrastim in HIV-infected patients, the randomized study was not powered to address this issue and possibility of an effect due to filgrastim on HIV replication cannot be entirely excluded.

As of 31 January 1996, an estimated 1.2 million patients worldwide have received filgrastim therapy across all indications. Of an estimated 150 000 HIV-infected patients receiving filgrastim to date, there have been 106 spontaneous adverse event reports received worldwide. No new adverse event patterns were identified in adults or children receiving filgrastim for neutropenia associated with HIV infection. Five deaths were reported in 106 postmarketing reports in patients receiving filgrastim for HIV infection. Three of five deaths were attributed to various manifestations of HIV disease progression. In the fourth case, the cause of death was not reported. In the fifth case, the physician reported that death in the context of ARDS occurred in the absence of fever and microbiological cause and was typical of bleomycin pulmonary toxicity; however, the physician reported that this may have been enhanced by filgrastim. It is notable, however, that randomized trials, and non-randomized trials demonstrated no increase in the known pulmonary toxicity of bleomycin when filgrastim was added to treatment.

In the randomized controlled study, the overall incidence of thrombocytopenia was 9.9% in the filgrastim-treated groups compared with 8.1% in the control group. Severe thrombocytopenia occurred in 7% of the filgrastim-treated patients and 3.5% of control patients in the controlled, randomized study. During this study, mean platelet count decreased at week 2 in the filgrastim-treated patients, but returned to baseline by week 3 and remained stable thereafter. In the post-marketing experience of HIV-infected patients which includes an estimated 150 000 patients worldwide, 10 of 106 spontaneous reports of adverse reactions were for thrombocytopenia. Of these, 3 cases were reported as serious.

Because adverse events of thrombocytopenia in HIV-infected individuals are multifactorial and may be attributed to the natural progression of HIV disease and associated infections, and because of the inconsistent occurrence of thrombocytopenia in a small number of patients in the aforementioned clinical trials, no definitive relationship between filgrastim therapy in HIV-infected patients and thrombocytopenia can be established.

In one study, 16 of 24 patients (66.7%) were reported to have splenomegaly during an observation period of 49 to 701 days. However, no baseline measurements of spleen size were made for comparison to on-study values. In three other uncontrolled clinical trials, only one of 297 patients (0.3%) had a report of splenomegaly. Since splenomegaly is a common clinical finding in 72% of patients with AIDS sometime during the course of their disease, it is likely that the observed splenomegaly was associated with HIV disease and not related to filgrastim.

Symptoms And Treatment Of Overdose: Symptoms and Treatment: The maximum tolerated dose of filgrastim has not been determined. In dose ranging studies, 5 of 16 patients given ³69 g/kg/day were withdrawn due to adverse experiences. In these and other clinical trials, only 2 of 253 patients on lower doses were withdrawn due to adverse events.

In filgrastim clinical trials of cancer patients receiving myelosuppressive chemotherapy, white blood cell counts >100´10L have been reported in less than 2% of patients and were not associated with any reported adverse clinical effects.

It is recommended, to avoid the potential risks of excessive leukocytosis, that filgrastim therapy should be discontinued if the ANC surpass 10´10L after the chemotherapy-induced ANC nadir has occurred.

In cancer patients receiving myelosuppressive chemotherapy, discontinuation of filgrastim therapy usually results in a 50% decrease in circulating neutrophils within 1 to 2 days, with a return to pretreatment levels in 1 to 7 days.

Dosage And Administration: Cancer Patients Receiving Myelosuppressive Chemotherapy: The recommended starting dose is 5 g/kg/day, administered as a single daily injection by s.c. bolus injection, by short i.v. infusion (15 to 30 minutes), or by continuous s.c. or continuous i.v. infusion. A CBC and platelet count should be obtained before instituting filgrastim therapy, and monitored twice weekly during therapy. Doses may be increased in increments of 5 g/kg for each chemotherapy cycle, according to the duration and severity of the ANC nadir. Therapy should be discontinued if the ANC surpasses 10´10L after the ANC nadir has occurred.

Filgrastim should be administered no earlier than 24 hours after the administration of cytotoxic chemotherapy. Filgrastim should not be administered in the period 24 hours before the administration of chemotherapy (see Precautions). Filgrastim should be administered daily for up to 2 weeks, until the ANC has reached 10´10L following the expected chemotherapy-induced neutrophil nadir. The duration of therapy needed to attenuate chemotherapy-induced neutropenia may be dependent on the myelosuppressive potential of the chemotherapy regimen employed. Filgrastim therapy should be discontinued if the ANC surpasses 10´10L after the expected chemotherapy-induced neutrophil nadir (see Precautions). In Phase III trials, efficacy was observed at doses of 4 to 8 g/kg/day.

Cancer Patients Receiving Myeloablative Chemotherapy followed by Bone Marrow Transplantation: The recommended dose following bone marrow transplant is 10 g/kg/day given as an i.v. infusion of 4 or 24 hours, or as a continuous 24-hour s.c. infusion. Filgrastim should be administered no earlier than 24 hours after the administration of cytotoxic chemotherapy and at least 24 hours after bone marrow infusion.

Cancer Patients Undergoing Peripheral Blood Progenitor Cell (PBPC) Collection and Therapy: The recommended dose of filgrastim for peripheral blood progenitor cell mobilization is 10 g/kg/day given as a single daily s.c. injection or a continuous 24 hour infusion. Filgrastim therapy should be given for at least 4 days before the first leukapheresis procedure, and should be continued through to the day of the last leukapheresis procedure. Collections should be commenced on day 5 and continued on consecutive days until the desired yield of haematopoietic progenitor cells is obtained. For peripheral blood progenitor cells mobilized with filgrastim, a schedule of leukapheresis collections on days 5, 6, and 7 of a 7 day treatment regimen has been found to be effective.

The target number of progenitor cells to be collected and reinfused is to be determined by the treating physician. The following should be considered: 1. A minimum or optimal number of progenitor cells in the leukapheresis product, needed for adequate haematopoietic reconstitution, has not been determined. However, studies indicate that the infusion of higher numbers of progenitor cells appears to be associated with a shorter time to neutrophil and platelet recovery, 2. Tests for quantifying the number of progenitor cells, measured as CD34+ or GM-CFU, are not standardized and variations may exist between laboratories, and 3. Factors other than filgrastim dosage, such as prior cytotoxic chemo-or radio-therapy, may affect the number and quality of progenitor cells mobilized and collected by leukapheresis.

The recommended dose of filgrastim following PBPC transplant is 5 g/kg/day given either s.c. or as an i.v. infusion. The first dose should be administered at least 24 hours after cytotoxic chemotherapy and at least 24 hours after PBPC infusion. The daily dose of filgrastim should be titrated according to the schedule provided above (Cancer patients receiving BMT).

Patients with HIV Infection: The recommended starting dose of filgrastim is 1 g/kg/day or 300 g 3 times/week by s.c. injection until a normal neutrophil count is reached and can be maintained (ANC ³2 000 cells/L). Dose adjustments may be necessary as determined by the patient’s ANC to maintain the ANC between 2 000 and 10 000 cells/L.

When reversal of neutropenia has been achieved, the minimal effective dose to maintain a normal neutrophil count should be established. An initial dose of 300 g 3 times/week by s.c. injection is recommended. A further dose adjustment may be necessary to maintain the ANC between 2 000 and 10 000 cells/L.

In clinical trials, the maximum filgrastim dose did not exceed 10 g/kg/day.

Patients with Severe Chronic Neutropenia: Starting Dose: Congenital Neutropenia: The recommended daily starting dose is 12 g/kg s.c. (single or divided dose).

Idiopathic or Cyclic Neutropenia: The recommended daily starting dose is 5 g/kg s.c. (single or divided dose).

Dose Adjustments: Filgrastim may be administered s.c. as a single daily injection to increase and sustain the absolute neutrophil count above 1.5´10L. Chronic daily administration is required to maintain an adequate neutrophil count. After 1 to 2 weeks of therapy, the initial dose may be doubled or halved. Subsequently, the dose may be individually adjusted not more than every 1 to 2 weeks to maintain the absolute neutrophil count between 1.5´10L and 10´10L. WBC/ANC monitoring should be done more frequently (e.g., every other day) if the ANC reaches values above 25´10L, and the dose reduced if the ANC remains greater than 25´10L for 1 week.

In clinical trials in patients with severe chronic neutropenia (SCN), 91% of patients who responded to filgrastim therapy responded at doses of less than or equal to 12 g/kg/day. Ninety-seven percent of patients responded at doses of less than or equal to 24 g/kg/day. Therefore, patients with SCN who do not respond to the recommended starting dose should be treated with up to 24 g/kg/day in order to determine if they will respond. In some cases, where higher doses were tried, an improvement in the ANC and the clinical condition was seen with a few patients only.

Dilution: If required, filgrastim may be diluted in 5% dextrose. Filgrastim diluted to a concentration between 5 and 15 g/mL should be protected from adsorption to plastic materials by the addition of Albumin (Human) at a concentration of 2 mg/mL. When diluted in 5% dextrose or 5% dextrose plus Albumin (Human), filgrastim is compatible with glass bottles, PVC and polyolefin i.v. bags and polypropylene syringes.

Dilution of filgrastim to a final concentration of less than 5 g/mL even in the presence of Albumin (Human) is not recommended at any time. Do not dilute with saline at any time: product may precipitate.

Stability and Storage: Store in the refrigerator at 2 to 8°C. Avoid vigorous shaking. Accidental exposure to room temperature (up to 30°C) or exposure to freezing temperatures does not adversely effect the stability of the product. Prior to injection Neupogen may be allowed to reach room temperature for a maximum of 24 hours. Any vial left at room temperature for greater than 24 hours should be discarded.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

Availability And Storage: Each mL of sterile, clear, colorless, preservative-free liquid for parenteral administration contains: filgrastim 0.30 mg (3´10units/mL) formulated in a 10 mM sodium acetate buffer at pH 4.0 with sorbitol 5% and 0.004% Tween 80. Single use, preservative-free vials of 1 mL (filgrastim 300 g) and 1.6 mL (filgrastim 480 g). Boxes of 10.

Use only one dose per vial; do not reenter the vial. Discard unused portions. Do not save unused drug for later administration.

NEUPOGEN® Amgen Filgrastim Granulocyte Colony Stimulating Factor – Hematopoietic Agent

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