Neutrophil support for patients with cancer receiving myelosuppressive chemotherapy

Appropriate dosing of NEUPOGEN in recovery of neutrophil counts in myelosuppressive regimens Neutrophil support for patients with cancer receiving myelosuppressive chemotherapy Indication NEUPOGEN is indicated to decrease the incidence of infection as manifested by febrile neutropenia in patients with nonmyeloid malignancies receiving myelosuppressive anti-cancer drugs associated with a significant incidence of severe neutropenia with fever. Please see Important Safety Information on page 2 and full Prescribing Information. 1

NEUPOGEN Important Safety Information NEUPOGEN stimulates neutrophil production Contraindication NEUPOGEN is contraindicated in patients with a history of serious allergic reactions to human granulocyte colony-stimulating factors, such as filgrastim or pegfilgrastim. Splenic Rupture Splenic rupture, including fatal cases, has been reported following the administration of NEUPOGEN. Evaluate patients who report left upper abdominal or shoulder pain for an enlarged spleen or splenic rupture. Acute Respiratory Distress Syndrome Acute respiratory distress syndrome (ARDS) has been reported in patients receiving NEUPOGEN. Evaluate patients who develop fever and lung infiltrates or respiratory distress for ARDS. Discontinue NEUPOGEN in patients with ARDS. Serious Allergic Reactions Serious allergic reactions, including anaphylaxis, have been reported in patients receiving NEUPOGEN. The majority of reported events occurred upon initial exposure. Provide symptomatic treatment for allergic reactions. Allergic reactions, including anaphylaxis, in patients receiving NEUPOGEN can recur within days after the discontinuation of initial anti-allergic treatment. Permanently discontinue NEUPOGEN in patients with serious allergic reactions. Sickle Cell Disorders Sickle cell crisis, in some cases fatal, has been reported with the use of NEUPOGEN in patients with sickle cell trait or sickle cell disease. Capillary Leak Syndrome Capillary leak syndrome (CLS) has been reported after G-CSF administration, including NEUPOGEN, and is characterized by hypotension, hypoalbuminemia, edema, and hemoconcentration. Episodes vary in frequency, severity, and may be life-threatening if treatment is delayed. Patients who develop symptoms of capillary leak syndrome should be closely monitored and receive standard symptomatic treatment, which may include the need for intensive care. Thrombocytopenia Thrombocytopenia has been reported in patients receiving NEUPOGEN. Monitor platelet counts. Leukocytosis White blood cell counts of 100,000/mm 3 were observed in about 2% of patients with cancer receiving myelosuppressive chemotherapy who received NEUPOGEN at dosages > 5 mcg/kg/day. It is recommended to monitor CBCs at least twice weekly, and adjust NEUPOGEN dosing as clinically indicated to help mitigate risk of leukocytosis. Dosages of NEUPOGEN that increase the absolute neutrophil count (ANC) beyond 10 000/mm 3 may not result in any additional clinical benefit. Discontinuation of NEUPOGEN therapy usually resulted in a 50% decrease in circulating neutrophils within 1 to 2 days with a return to pretreatment levels in 1 to 7 days. Cutaneous Vasculitis Cutaneous vasculitis has been reported in patients treated with NEUPOGEN. In most cases the severity of cutaneous vasculitis was moderate or severe. Most of the reports involved patients with severe chronic neutropenia (SCN) receiving long-term NEUPOGEN therapy. Hold NEUPOGEN therapy in patients with cutaneous vasculitis. NEUPOGEN may be started at a reduced dose when the symptoms resolve and the absolute neutrophil count (ANC) has decreased. Potential Effect on Malignant Cells The possibility that NEUPOGEN acts as a growth factor for any tumor type, including myeloid malignancies and myelodysplasia, cannot be excluded. Simultaneous Use with Chemotherapy and Radiation Therapy Not Recommended The safety and efficacy of NEUPOGEN given simultaneously with cytotoxic chemotherapy have not been established. Do not use NEUPOGEN in the period 24 hours before or after the administration of cytotoxic chemotherapy. The safety and efficacy of NEUPOGEN have not been evaluated in patients receiving concurrent radiation therapy. Avoid the simultaneous use of NEUPOGEN with chemotherapy and radiation therapy. Nuclear Imaging Increased hematopoietic activity of the bone marrow in response to growth factor therapy has been associated with transient, positive bone-imaging changes. This should be considered when interpreting bone-imaging results. The most common adverse reactions ( 5% difference in incidence, compared to placebo) are pyrexia, pain, rash, cough, and dyspnea. Neutrophils are a type of granulocyte, which are important infection-fighting white blood cells produced in the bone marrow 1 Febrile neutropenia, the development of fever and associated infection due to a low number of neutrophils, is a medical emergency that can occur in patients with cancer receiving myelosuppressive chemotherapy 1,2 1 2 3 NEUPOGEN binds to cell surface receptors on hematopoietic cells in the bone marrow. 3 NEUPOGEN stimulates neutrophil progenitor cell proliferation and differentiation. 3-5 NEUPOGEN requires daily dosing because of its short elimination half-life NEUPOGEN molecules are cleared predominantly via filtration in the kidneys. 7 In addition, NEUPOGEN is cleared by binding to neutrophils already in circulation. 7 NEUPOGEN speeds up neutrophil maturation, leading to an increased number of mature neutrophils released into the circulation. 5,6 The elimination half-life of NEUPOGEN is approximately 3.5 hours. Therefore, NEUPOGEN requires daily dosing. NEUPOGEN should not be administered in the period 24 hours before through 24 hours after the administration of chemotherapy. 3 NEUPOGEN stimulates neutrophil proliferation, which helps reduce the risk of infection in patients with nonmyeloid malignancies receiving myelosuppressive anticancer drugs associated with a significant incidence of severe neutropenia with fever. Please see full Prescribing Information. 2 3

NEUPOGEN stimulates proliferation and decreases maturation time of neutrophils Effect of NEUPOGEN on neutrophil proliferation and maturation 4,5,8,9 NEUPOGEN decreased the severity and duration of chemotherapy-induced neutropenia The timing and depth of neutrophil nadirs vary based on patient factors and the type of chemotherapy administered 10,11 With endogenous granulocyte colony-stimulating factor (G-CSF) MITOTIC PHASE POSTMITOTIC PHASE Myeloblast Promyelocyte Myelocyte Metamyelocyte Band cell Mature segmented cell A longer duration of severe neutropenia (absolute neutrophil count [ANC] < 0.5 10 9 /L) is directly related to an increased risk of febrile neutropenia 12 Chemotherapy-induced neutrophil nadir was less severe with 10 days of NEUPOGEN support 13 3 to 9 days 5 to 7 days With exogenous G-CSF (NEUPOGEN) Circulating neutrophils Log ANC ( 10 9 /L) in Cycle 1 100.0 10.0 1.0 0.5 0.10 Grade 4 neutropenia* Chemotherapy administered NEUPOGEN or placebo administered NEUPOGEN Placebo MITOTIC PHASE Myeloblast Promyelocyte Myelocyte POSTMITOTIC PHASE Metamyelocyte Band cell Mature segmented cell 0.01 0 4 8 12 16 20 24 Day *Grade 4 neutropenia = ANC < 0.5 10 9 /L. Circulating neutrophils Adapted from Crawford J, et al. N Engl J Med. 1991. 13 Data from a multicenter, randomized, double-blind, placebo-controlled trial that included 199 patients with small-cell lung cancer receiving up to 6 cycles of chemotherapy with cyclophosphamide, doxorubicin, and etoposide. Patients were randomly assigned to receive either placebo or NEUPOGEN 24 hours postchemotherapy (beginning on day 4 and continuing through day 17 of a 21-day cycle, unless the postnadir neutrophil count after day 12 exceeded 10 10 9 /L, in which case growth factor was discontinued for the remainder of the cycle). The primary endpoint was infection as manifested by fever with neutropenia (temperature 38.2 C, with an absolute neutrophil count < 1.0 x 10 9 /L). 13 Select secondary endpoints from Crawford J, et al. 13 Endpoint Placebo NEUPOGEN Decrease P Value 3 to 9 days 1 day Median duration of grade 4 neutropenia in first cycle Median duration of fever with neutropenia in first cycle 6 days 3 days 50% <.001 5 days 4 days NS IMPORTANT SAFETY INFORMATION 4 Contraindication NEUPOGEN is contraindicated in patients with a history of serious allergic reactions to human granulocyte colony-stimulating factors, such as filgrastim or pegfilgrastim. Please see additional Important Safety Information on page 2. 5

Less-than-labeled doses of NEUPOGEN were associated with a greater incidence of febrile neutropenia NEUPOGEN used for 7 days decreased the rate of febrile neutropenia by 65% compared with dosing of < 7 days 14 Incidence of Febrile Neutropenia in Patients Receiving Secondary Prophylaxis, % 20 15 10 5 0 17% < 7 Days (Mean = 4.7 Days) Days Receiving NEUPOGEN 65% Reduction Adapted from Scott SD, et al. J Manag Care Pharm. 2003. Data obtained through review of patient medical records for the Oncology Practice Pattern Study at 12 sites between 1991 and 1999. Study included patients (n = 170) with intermediate-grade non-hodgkin s lymphoma treated with first-line CHOP-21 chemotherapy and receiving primary or secondary prophylaxis* with NEUPOGEN. Filgrastim was administered for 7 days in most cycles (Group 2 received 7 days of filgrastim in 579 cycles, and Group 1 received < 7 days of filgrastim in 73 cycles). Seven days was chosen as the cutoff based on the empirical frequency distribution of the days of prophylactic NEUPOGEN treatment. It was also supported by an abstract by Meza et al, in which the lower bound for the mean number of days of NEUPOGEN therapy required for 95% of the population to achieve ANC recovery (mean minus 2 times the standard deviation) was approximately 7 days. 12,14 6% 7 Days (Mean = 10.1 Days) NEUPOGEN reduced febrile neutropenia consistently across 3 studies when dosed appropriately and for the proper duration NEUPOGEN reduced febrile neutropenia in patients receiving myelosuppressive chemotherapy 13,15,16 Incidence of Febrile Neutropenia, % 100 80 60 40 20 0 76% 47% Reduction NEUPOGEN PI (N = 210) P <.001 40% 53% Trillet-Lenoir (N = 130) P <.002 51% Reduction 26% 44% Placebo NEUPOGEN Pettengell (N = 80) Adapted from NEUPOGEN PI; Trillet-Lenoir, et al, Eur J Cancer, 1993; Pettengell, et al, Blood, 1992. Two randomized, placebo-controlled, double-blind, multicenter phase 3 trials in patients with small-cell lung cancer (SCLC) receiving myelosuppressive chemotherapy and one randomized, open-label, parallel-controlled, single-center trial in patients with NHL receiving myelosuppressive chemotherapy. 3,13,15,16 In SCLC studies, NEUPOGEN was initiated 24 hours after chemotherapy and administered daily until the postnadir ANC was greater than 10 10 9 /L or for a maximum of 14 days. 3,13,15 In the NHL study, NEUPOGEN was administered for 13 weeks, except on days preceding and during treatment with doxorubicin, cyclophosphamide, or etoposide, and discontinued at week 13 or when the ANC reached 20 10 9 /L, whichever came first. 16 P =.04 48% Reduction 23% *Prophylaxis was defined as NEUPOGEN started within 5 days of chemotherapy administration. 14 Therapeutic dosing of NEUPOGEN helps reduce the incidence of febrile neutropenia. Study Tumor Type Primary Endpoint(s) Selected Secondary Endpoints Crawford et al 13 SCLC Fever with neutropenia Duration and severity of neutropenia; incidence of antibiotic use Trillet-Lenoir et al 15 SCLC Fever with neutropenia Duration and severity of neutropenia; use of antibiotics Pettengell et al 16 NHL Fever with neutropenia; neutropenia; cytoxic dose intensity Duration and severity of neutropenia; incidence of documented infection; use of antibiotics 6 IMPORTANT SAFETY INFORMATION Splenic Rupture Splenic rupture, including fatal cases, has been reported following the administration of NEUPOGEN. Evaluate patients who report left upper abdominal or shoulder pain for an enlarged spleen or splenic rupture. Please see additional Important Safety Information on page 2. 7

Dose NEUPOGEN based on weight, and with proper scheduling and administration, to help reduce the risk of febrile neutropenia Recommended dosage and administration provide neutrophil support for patients with cancer receiving myelosuppressive chemotherapy 3 Starting dosage of 5 mcg/kg/day administered as a single daily injection by subcutaneous injection by short intravenous infusion (15 to 30 minutes) or by continuous intravenous infusion Obtain a CBC and platelet count before instituting therapy and monitor twice weekly during therapy Consider dose escalation in increments of 5 mcg/kg for each chemotherapy cycle according to the duration and severity of ANC nadir Recommend stopping NEUPOGEN if ANC increases > 10 000/mm 3 Administer 24 hours after cytotoxic chemotherapy; do not administer within the 24-hour period prior to chemotherapy Administer daily for up to 2 weeks or until the ANC has reached 10 000/mm 3 following the expected chemotherapy-induced neutrophil nadir IMPORTANT SAFETY INFORMATION Acute Respiratory Distress Syndrome Acute respiratory distress syndrome (ARDS) has been reported in patients receiving NEUPOGEN. Evaluate patients who develop fever and lung infiltrates or respiratory distress for ARDS. Discontinue NEUPOGEN in patients with ARDS. Please see additional Important Safety Information on page 2. References 1. National Cancer Institute. Dictionary of Cancer Terms. Available at: http://www.cancer.gov/dictionary. Accessed June 1, 2015. 2. Caggiano V, Weiss RV, Rickert TS, Linde-Zwirble WT. Incidence, cost, and mortality of neutropenia hospitalization associated with chemotherapy. Cancer. 2005;103:1916-1924. 3. NEUPOGEN (filgrastim) prescribing information, Amgen. 4. Jandl JH. Granulocytes. In: Blood: Textbook of Hematology. 2nd ed. Boston, MA: Little Brown & Co; 1996:615-649. 5. Dexter TM. Granulocyte colony stimulating factor: from laboratory bench to clinical use. Eur J Cancer. 1994;30A(suppl 3):S15-S19. 6. Dale DC. Physiology, Function, and Role of the Neutrophil in Host Defense. Thousand Oaks, CA: Amgen, Inc; 1994:1-32. 7. Yang BB, Kido A, Shibata A. Serum pegfilgrastim concentrations during recovery of absolute neutrophil count in patients with cancer receiving pegfilgrastim after chemotherapy. Pharmacotherapy. 2007;27:1387-1393. 8. Núñez C, Brady G (Testa NG, Lord BI, Dexter TM, eds). Neutrophils and macrophages. In: Hematopoietic Lineages in Health and Disease. New York, NY: Marcel Dekker; 1997:49-55. 9. Kim SK, Demetri GD. Hematol Oncol Clin North Am. 1996;10:377-395. 10. McEvoy G. AHFS Drug Information 2012. Bethesda, MD: American Society of Health-System Pharmacists; 2012. 11. Saab YB, Sharaf L, Zeidan I, Bizri A. Cancer Ther. 2003;1:191-196. 12. Meza L, Baselga J, Holmes FA, et al, for the Pegfilgrastim Study Group. Abstract presented at: 38th Annual Meeting of the American Society of Clinical Oncology; May 18-21, 2002; Orlando, FL. 13. Crawford J, Ozer H, Stoller R, et al. N Engl J Med. 1991;325:164-170. 14. Scott SD, Chrischilles EA, Link BK, et al. J Manag Care Pharm. 2003;9(suppl 2):15-21. 15. Trillet-Lenoir V, Green J, Manegold C. Recombinant granulocyte colony stimulating factor reduces the infectious complications of cytotoxic chemotherapy. Eur J Cancer. 1993;29A:319-324. 16. Pettengell R, Gurney H, Radford JA, et al. Granulocyte colony-stimulating factor to prevent dose-limiting neutropenia in non-hodgkin s lymphoma: a randomized controlled trial. Blood. 1992;80;1430-1436. 8 9

Help reduce the risk of febrile neutropenia Use NEUPOGEN at the appropriate dose and duration NEUPOGEN helps stimulate neutrophil production NEUPOGEN helps decrease the severity and duration of chemotherapyinduced neutropenia for patients with cancer receiving myelosuppressive chemotherapy Dose NEUPOGEN based on weight and with proper scheduling and administration to help reduce the risk of febrile neutropenia Efficacy has been shown to be compromised when NEUPOGEN was dosed at less than the label-indicated dose The most common adverse reactions ( 5% difference in incidence, compared to placebo) are pyrexia, pain, rash, cough, and dyspnea Please see Important Safety Information on page 2 and full Prescribing Information. 2015 Amgen. All rights reserved. USA-002-106485 10

Weight-based dosing NEUPOGEN weight-based dosing Dosing information in patients receiving myelosuppressive chemotherapy 1 NEUPOGEN is available in single-dose vials and syringes Single-Dose Vials SingleJect Single-Dose Syringes Filgrastim Fill Volume Fill Volume 300 mcg 1.0 ml 0.5 ml 480 mcg 1.6 ml 0.8 ml Recommended dosing by patient weight The recommended starting dose of NEUPOGEN is 5 mcg/kg/day. Please see additional dosing and administration information on page 8 of the dosing brochure. Patient Weight Patient Weight NEUPOGEN Starting Dose (5 mcg/kg/day) 60 kg HCPs should draw the appropriate dose of NEUPOGEN from the 300-mcg vial for patients weighing 60 kg < 50 kg < 110 lb < 250 mcg 55 kg 121 lb 275 mcg 60 kg 132 lb 300 mcg > 60 to < 100 kg HCPs should draw the appropriate dose of NEUPOGEN from the 480-mcg vial for patients weighing > 60 kg to < 100 kg 65 kg 143 lb 325 mcg 70 kg 154 lb 350 mcg 75 kg 165 lb 375 mcg 80 kg 176 lb 400 mcg 85 kg 187 lb 425 mcg 90 kg 198 lb 450 mcg 95 kg 209 lb 475 mcg 100 kg HCPs should draw the appropriate dose of NEUPOGEN from two 300-mcg vials for patients weighing 100 kg 100 kg 220 lb 500 mcg 105 kg 231 lb 525 mcg 110 kg 242 lb 550 mcg Indication NEUPOGEN is indicated to decrease the incidence of infection as manifested by febrile neutropenia in patients with nonmyeloid malignancies receiving myelosuppressive anti-cancer drugs associated with a significant incidence of severe neutropenia with fever. Please see Important Safety Information on the next page and full Prescribing Information. 1. NEUPOGEN (filgrastim) prescribing information, Amgen. 1

NEUPOGEN Important Safety Information Contraindication NEUPOGEN is contraindicated in patients with a history of serious allergic reactions to human granulocyte colony-stimulating factors, such as filgrastim or pegfilgrastim. Splenic Rupture Splenic rupture, including fatal cases, has been reported following the administration of NEUPOGEN. Evaluate patients who report left upper abdominal or shoulder pain for an enlarged spleen or splenic rupture. Acute Respiratory Distress Syndrome Acute respiratory distress syndrome (ARDS) has been reported in patients receiving NEUPOGEN. Evaluate patients who develop fever and lung infiltrates or respiratory distress for ARDS. Discontinue NEUPOGEN in patients with ARDS. Serious Allergic Reactions Serious allergic reactions, including anaphylaxis, have been reported in patients receiving NEUPOGEN. The majority of reported events occurred upon initial exposure. Provide symptomatic treatment for allergic reactions. Allergic reactions, including anaphylaxis, in patients receiving NEUPOGEN can recur within days after the discontinuation of initial anti-allergic treatment. Permanently discontinue NEUPOGEN in patients with serious allergic reactions. Sickle Cell Disorders Sickle cell crisis, in some cases fatal, has been reported with the use of NEUPOGEN in patients with sickle cell trait or sickle cell disease. Capillary Leak Syndrome Capillary leak syndrome (CLS) has been reported after G-CSF administration, including NEUPOGEN, and is characterized by hypotension, hypoalbuminemia, edema, and hemoconcentration. Episodes vary in frequency, severity, and may be life-threatening if treatment is delayed. Patients who develop symptoms of capillary leak syndrome should be closely monitored and receive standard symptomatic treatment, which may include the need for intensive care. Thrombocytopenia Thrombocytopenia has been reported in patients receiving NEUPOGEN. Monitor platelet counts. Leukocytosis White blood cell counts of 100,000/mm 3 were observed in about 2% of patients with cancer receiving myelosuppressive chemotherapy who received NEUPOGEN at dosages > 5 mcg/kg/day. It is recommended to monitor CBCs at least twice weekly, and adjust NEUPOGEN dosing as clinically indicated to help mitigate risk of leukocytosis. Dosages of NEUPOGEN that increase the absolute neutrophil count (ANC) beyond 10 000/mm 3 may not result in any additional clinical benefit. Discontinuation of NEUPOGEN therapy usually resulted in a 50% decrease in circulating neutrophils within 1 to 2 days with a return to pretreatment levels in 1 to 7 days. Cutaneous Vasculitis Cutaneous vasculitis has been reported in patients treated with NEUPOGEN. In most cases the severity of cutaneous vasculitis was moderate or severe. Most of the reports involved patients with severe chronic neutropenia (SCN) receiving long-term NEUPOGEN therapy. Hold NEUPOGEN therapy in patients with cutaneous vasculitis. NEUPOGEN may be started at a reduced dose when the symptoms resolve and the absolute neutrophil count (ANC) has decreased. Potential Effect on Malignant Cells The possibility that NEUPOGEN acts as a growth factor for any tumor type, including myeloid malignancies and myelodysplasia, cannot be excluded. Simultaneous Use with Chemotherapy and Radiation Therapy Not Recommended The safety and efficacy of NEUPOGEN given simultaneously with cytotoxic chemotherapy have not been established. Do not use NEUPOGEN in the period 24 hours before or after the administration of cytotoxic chemotherapy. The safety and efficacy of NEUPOGEN have not been evaluated in patients receiving concurrent radiation therapy. Avoid the simultaneous use of NEUPOGEN with chemotherapy and radiation therapy. Nuclear Imaging Increased hematopoietic activity of the bone marrow in response to growth factor therapy has been associated with transient, positive bone-imaging changes. This should be considered when interpreting bone-imaging results. The most common adverse reactions ( 5% difference in incidence, compared to placebo) are pyrexia, pain, rash, cough, and dyspnea. Please see full Prescribing Information. 2015 Amgen. All rights reserved. USA-002-106485 2