Nivestym

1 INDICATIONS AND USAGE NIVESTYM is a leukocyte growth factor 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. ( 1.1 ) • Reduce the time to neutrophil recovery and the duration of fever, following induction or consolidation chemotherapy treatment of patients with acute myeloid leukemia (AML). ( 1.2 ) • Reduce the duration of neutropenia and neutropenia-related clinical sequelae‚ e.g.‚ febrile neutropenia, in patients with nonmyeloid malignancies undergoing myeloablative chemotherapy followed by bone marrow transplantation (BMT). ( 1.3 ) • Mobilize autologous hematopoietic progenitor cells into the peripheral blood for collection by leukapheresis. ( 1.4 ) • Reduce the incidence and duration of sequelae of severe neutropenia (e.g.‚ fever‚ infections‚ oropharyngeal ulcers) in symptomatic patients with congenital neutropenia‚ cyclic neutropenia‚ or idiopathic neutropenia. ( 1.5 ) 1.1 Patients with Cancer Receiving Myelosuppressive Chemotherapy NIVESTYM 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 [see Clinical Studies (14.1) ] . 1.2 Patients with Acute Myeloid Leukemia Receiving Induction or Consolidation Chemotherapy NIVESTYM is indicated for reducing the time to neutrophil recovery and the duration of fever, following induction or consolidation chemotherapy treatment of patients with acute myeloid leukemia (AML) [see Clinical Studies (14.2) ] . 1.3 Patients with Cancer Undergoing Bone Marrow Transplantation NIVESTYM is indicated to reduce the duration of neutropenia and neutropenia-related clinical sequelae‚ e.g.‚ febrile neutropenia, in patients with nonmyeloid malignancies undergoing myeloablative chemotherapy followed by bone marrow transplantation [see Clinical Studies (14.3) ]. 1.4 Patients Undergoing Autologous Peripheral Blood Progenitor Cell Collection and Therapy NIVESTYM is indicated for the mobilization of autologous hematopoietic progenitor cells into the peripheral blood for collection by leukapheresis [see Clinical Studies (14.4) ] . 1.5 Patients with Severe Chronic Neutropenia NIVESTYM is indicated for chronic administration to reduce the incidence and duration of sequelae of neutropenia (e.g.‚ fever‚ infections‚ oropharyngeal ulcers) in symptomatic patients with congenital neutropenia‚ cyclic neutropenia‚ or idiopathic neutropenia [see Clinical Studies (14.5) ] .

2 DOSAGE AND ADMINISTRATION • Patients with cancer receiving myelosuppressive chemotherapy or induction and/or consolidation chemotherapy for AML. o Recommended starting dose is 5 mcg/kg/day subcutaneous injection, short intravenous infusion (15 to 30 minutes), or continuous intravenous infusion. See Full Prescribing Information for recommended dosage adjustments and timing of administration. ( 2.1 ) • Patients with cancer undergoing bone marrow transplantation. o 10 mcg/kg/day given as an intravenous infusion no longer than 24 hours. See Full Prescribing Information for recommended dosage adjustments and timing of administration. ( 2.2 ) • Patients undergoing autologous peripheral blood progenitor cell collection and therapy. o 10 mcg/kg/day subcutaneous injection. ( 2.3 ) o Administer for at least 4 days before first leukapheresis procedure and continue until last leukapheresis. ( 2.3 ) • Patients with congenital neutropenia. o Recommended starting dose is 6 mcg/kg subcutaneous injection twice daily. ( 2.4 ) • Patients with cyclic or idiopathic neutropenia. o Recommended starting dose is 5 mcg/kg subcutaneous injection daily. ( 2.4 ) • Direct administration of less than 0.3 mL (180 mcg) using NIVESTYM prefilled syringe is not recommended due to potential for dosing errors. ( 2.5 ) 2.1 Dosage in Patients with Cancer Receiving Myelosuppressive Chemotherapy or Induction and/or Consolidation Chemotherapy for AML The recommended starting dosage of NIVESTYM is 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 complete blood count (CBC) and platelet count before instituting NIVESTYM 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 the absolute neutrophil count (ANC) nadir. Recommend stopping NIVESTYM if the ANC increases beyond 10‚000/mm 3 [see Warnings and Precautions (5.10) ] . Administer NIVESTYM at least 24 hours after cytotoxic chemotherapy. Do not administer NIVESTYM within the 24-hour period prior to chemotherapy [see Warnings and Precautions (5.13) ] . A transient increase in neutrophil count is typically seen 1 to 2 days after initiation of NIVESTYM therapy. Therefore, to ensure a sustained therapeutic response‚ administer NIVESTYM daily for up to 2 weeks or until the ANC has reached 10‚000/mm 3 following the expected chemotherapy-induced neutrophil nadir. The duration of NIVESTYM therapy needed to attenuate chemotherapy-induced neutropenia may be dependent on the myelosuppressive potential of the chemotherapy regimen employed. 2.2 Dosage in Patients with Cancer Undergoing Bone Marrow Transplantation The recommended dosage of NIVESTYM following bone marrow transplantation (BMT) is 10 mcg/kg/day given as an intravenous infusion no longer than 24 hours. Administer the first dose of NIVESTYM at least 24 hours after cytotoxic chemotherapy and at least 24 hours after bone marrow infusion. Monitor CBCs and platelet counts frequently following marrow transplantation. During the period of neutrophil recovery‚ titrate the daily dosage of NIVESTYM against the neutrophil response (see Table 1 ). Table 1. Recommended Dosage Adjustments During Neutrophil Recovery in Patients with Cancer Following BMT Absolute Neutrophil Count NIVESTYM Dosage Adjustment When ANC greater than 1,000/mm 3 for 3 consecutive days Reduce to 5 mcg/kg/day If ANC decreases to less than 1,000/mm 3 at any time during the 5 mcg/kg/day administration‚ increase NIVESTYM to 10 mcg/kg/day‚ and then follow the above steps. Then, if ANC remains greater than 1,000/mm 3 for 3 more consecutive days Discontinue NIVESTYM Then, if ANC decreases to less than 1,000/mm 3 Resume at 5 mcg/kg/day 2.3 Dosage in Patients Undergoing Autologous Peripheral Blood Progenitor Cell Collection and Therapy The recommended dosage of NIVESTYM for t …

3 DOSAGE FORMS AND STRENGTHS Vial • Injection: 300 mcg/mL in a single-dose vial ( 3 ) • Injection: 480 mcg/1.6 mL (300 mcg/mL) in a single-dose vial ( 3 ) Prefilled Syringe • Injection: 300 mcg/0.5 mL in a single-dose prefilled syringe ( 3 ) • Injection: 480 mcg/0.8 mL in a single-dose prefilled syringe ( 3 ) NIVESTYM is a clear, colorless solution available as: Vial: • Injection: 300 mcg/mL in a single-dose vial • Injection: 480 mcg/1.6 mL (300 mcg/mL) in a single-dose vial Prefilled Syringe: • Injection: 300 mcg/0.5 mL in a single-dose prefilled syringe • Injection: 480 mcg/0.8 mL in a single-dose prefilled syringe

4 CONTRAINDICATIONS NIVESTYM is contraindicated in patients with a history of serious allergic reactions to human granulocyte colony-stimulating factors such as filgrastim products or pegfilgrastim products [see Warnings and Precautions (5.3) ] . Patients with a history of serious allergic reactions to human granulocyte colony-stimulating factors such as filgrastim products or pegfilgrastim products. ( 4 )

6 ADVERSE REACTIONS The following serious adverse reactions are discussed in greater detail in other sections of the labeling: • Splenic Rupture [see Warnings and Precautions (5.1) ] • Acute Respiratory Distress Syndrome [see Warnings and Precautions (5.2) ] • Serious Allergic Reactions [see Warnings and Precautions (5.3) ] • Sickle Cell Disorders [see Warnings and Precautions (5.4) ] • Glomerulonephritis [see Warnings and Precautions (5.5) ] • Alveolar Hemorrhage and Hemoptysis [see Warnings and Precautions (5.6) ] • Capillary Leak Syndrome [see Warnings and Precautions (5.7) ] • Myelodysplastic Syndrome [see Warnings and Precautions (5.8) ] • Acute Myeloid Leukemia [see Warnings and Precautions (5.8) ] • Thrombocytopenia [see Warnings and Precautions (5.9) ] • Leukocytosis [see Warnings and Precautions (5.10) ] • Cutaneous Vasculitis [see Warnings and Precautions (5.11) ] • Aortitis [see Warnings and Precautions (5.15) ] Most common adverse reactions in patients: • With nonmyeloid malignancies receiving myelosuppressive anti-cancer drugs (≥ 5% difference in incidence compared to placebo) are pyrexia, pain, rash, cough, and dyspnea. ( 6.1 ) • With AML (≥ 2% difference in incidence) are pain, epistaxis and rash. ( 6.1 ) • With nonmyeloid malignancies undergoing myeloablative chemotherapy followed by BMT (≥ 5% difference in incidence) is rash. ( 6.1 ) • Undergoing peripheral blood progenitor cell mobilization and collection (≥ 5% incidence) are bone pain, pyrexia and headache. ( 6.1 ) • With severe chronic neutropenia (SCN) (≥ 5% difference in incidence) are pain, anemia, epistaxis, diarrhea, hypoesthesia and alopecia. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Pfizer Inc at 1-800-438-1985 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. Adverse Reactions in Patients with Cancer Receiving Myelosuppressive Chemotherapy The following adverse reaction data in Table 2 are from three randomized, placebo-controlled studies in patients with: • small cell lung cancer receiving standard dose chemotherapy with cyclophosphamide‚ doxorubicin‚ and etoposide (Study 1) • small cell lung cancer receiving ifosfamide, doxorubicin‚ and etoposide (Study 2), and • non-Hodgkin's lymphoma (NHL) receiving doxorubicin, cyclophosphamide, vindesine, bleomycin, methylprednisolone, and methotrexate ("ACVBP") or mitoxantrone, ifosfamide, mitoguazone, teniposide, methotrexate, folinic acid, methylprednisolone, and methotrexate ("VIM3") (Study 3). A total of 451 patients were randomized to receive subcutaneous filgrastim 230 mcg/m 2 (Study 1), 240 mcg/m 2 (Study 2) or 4 or 5 mcg/kg/day (Study 3) (n = 294) or placebo (n = 157). The patients in these studies were median age 61 (range 29 to 78) years and 64% were male. The ethnicity was 95% Caucasian, 4% African American, and 1% Asian. Table 2. Adverse Reactions in Patients with Cancer Receiving Myelosuppressive Chemotherapy (With ≥ 5% Higher Incidence in Filgrastim Compared to Placebo) System Organ Class Preferred Term Filgrastim (N = 294) Placebo (N = 157) Blood and lymphatic system disorders Thrombocytopenia 38% 29% Gastrointestinal disorders Nausea 43% 32% General disorders and administration site conditions Pyrexia 48% 29% Chest pain 13% 6% Pain 12% 6% Fatigue 20% 10% Musculoskeletal and connective tissue disorders Back pain 15% 8% Arthralgia 9% 2% Bone pain 11% 6% Pain in extremity Percent difference (Filgrastim – Placebo) was 4%. 7% 3% Nervous system disorders Dizziness 14% 3% Respiratory, thoracic and mediastinal disorders Cough 14% 8% Dyspnea 13% 8% Skin and subcutaneous tissue disorders Rash 14% 5% Investigations Blood lactate dehydrogenase increased 6% 1% Blood alkaline phosphatase incre …

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary Available data from published studies, including several observational studies of pregnancy outcomes in women exposed to filgrastim products and those who were unexposed, have not established an association with filgrastim products use during pregnancy and major birth defects, miscarriage, or adverse maternal or fetal outcomes (see Data ) . Reports in the scientific literature have described transplacental passage of filgrastim in pregnant women when administered ≤ 30 hours prior to preterm delivery (≤ 30 weeks gestation). In animal reproduction studies, effects of filgrastim on prenatal development have been studied in rats and rabbits. No malformations were observed in either species. No maternal or fetal effects were observed in pregnant rats at doses up to 58 times the human doses. Filgrastim has been shown to have adverse effects in pregnant rabbits at doses 2 to 10 times higher than the human doses (see Data ) . The estimated background risk of major birth defects and miscarriage for the indicated populations is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risks of major birth defects and miscarriage in clinically recognized pregnancies is 2–4% and 15–20%, respectively. Data Human data Several observational studies based on the Severe Chronic Neutropenia International Registry (SCNIR) described pregnancy outcomes in women with severe chronic neutropenia (SCN) who were exposed to filgrastim products during pregnancy and women with SCN who were unexposed. No major differences were seen between treated and untreated women with respect to pregnancy outcome (including miscarriage and preterm labor), newborn complications (including birth weight) and infections. Methodological limitations of these studies, include small sample size, and lack of generalizability due to the underlying maternal condition. Animal data Effects of filgrastim on prenatal development have been studied in rats and rabbits. No malformations were observed in either species. Filgrastim has been shown to have adverse effects in pregnant rabbits at doses 2 to 10 times higher than the human doses. In pregnant rabbits showing signs of maternal toxicity, reduced embryo-fetal survival (at 20 and 80 mcg/kg/day) and increased abortions (at 80 mcg/kg/day) were observed. In pregnant rats, no maternal or fetal effects were observed at doses up to 575 mcg/kg/day, which is approximately 58 times higher than the human dose of 10 mcg/kg/day. Offspring of rats administered filgrastim during the peri-natal and lactation periods exhibited a delay in external differentiation and growth retardation (≥ 20 mcg/kg/day) and slightly reduced survival rate (100 mcg/kg/day). 8.2 Lactation Risk Summary There is published literature documenting transfer of filgrastim into human milk. There are a few case reports describing the use of filgrastim in breastfeeding mothers with no adverse effects noted in the infants. There are no data on the effects of filgrastim products on milk production. Other filgrastim products are secreted poorly into breast milk, and filgrastim products are not absorbed orally by neonates. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for NIVESTYM and any potential adverse effects on the breastfed child from NIVESTYM or from the underlying maternal condition. 8.4 Pediatric Use NIVESTYM prefilled syringe with BD UltraSafe PlusTM Passive Needle Guard may not accurately measure volumes less than 0.3 mL due to the needle spring mechanism design. Therefore, the direct administration of a volume less than 0.3 mL using NIVESTYM prefilled syringe is not recommended due to the potential for dosing errors. For direct administration of doses less than 0.3 mL (180 mcg) use NIVESTYM single-dose vial. In patients with cancer receiving myelosuppr …

12.1 Mechanism of Action 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 that is produced by monocytes‚ fibroblasts, and endothelial cells. G-CSF regulates the production of neutrophils within the bone marrow and affects neutrophil progenitor proliferation‚ differentiation, and selected end-cell functions (including enhanced phagocytic ability‚ priming of the cellular metabolism associated with respiratory burst‚ antibody-dependent killing, and the increased expression of some cell surface antigens). G-CSF is not species-specific and has been shown to have minimal direct in vivo or in vitro effects on the production or activity of hematopoietic cell types other than the neutrophil lineage.

11 DESCRIPTION Filgrastim-aafi is a 175 amino acid human granulocyte colony-stimulating factor (G-CSF) manufactured by recombinant DNA technology. NIVESTYM is produced by Escherichia coli ( E coli) bacteria into which has been inserted the human granulocyte colony-stimulating factor gene. NIVESTYM has a molecular weight of 18‚799 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 NIVESTYM is produced in E coli ‚ the product is non-glycosylated and thus differs from G-CSF isolated from a human cell. NIVESTYM is a sterile‚ clear‚ colorless‚ preservative-free liquid containing filgrastim-aafi injection for subcutaneous or intravenous use. The product is available in single-dose vials for subcutaneous or intravenous use and prefilled syringes for subcutaneous use. The single-dose vials contain either 300 mcg/mL or 480 mcg/1.6 mL of filgrastim-aafi. The single-dose prefilled syringes contain either 300 mcg/0.5 mL or 480 mcg/0.8 mL of filgrastim-aafi. The final pH range of the NIVESTYM drug product solution is 3.8 to 4.3. See Table 4 below for product composition of each single-dose vial or prefilled syringe. Table 4. Product Composition 300 mcg/mL Vial 480 mcg/1.6 mL Vial 300 mcg/0.5 mL Syringe 480 mcg/0.8 mL Syringe Filgrastim-aafi 300 mcg 480 mcg 300 mcg 480 mcg Acetate 0.59 mg 0.94 mg 0.295 mg 0.472 mg Polysorbate 80 0.04 mg 0.064 mg 0.02 mg 0.032 mg Sodium 0.035 mg 0.056 mg 0.0175 mg 0.028 mg Sorbitol 50 mg 80 mg 25 mg 40 mg Water for Injection USP q.s. ad quantity sufficient to make 1 mL 1.6 mL 0.5 mL 0.8 mL

10 OVERDOSAGE The maximum tolerated dose of filgrastim products has not been determined. In filgrastim clinical trials of patients with cancer receiving myelosuppressive chemotherapy‚ WBC counts > 100‚000/mm 3 have been reported in less than 5% of patients‚ but were not associated with any reported adverse clinical effects. Patients in the BMT studies received up to 138 mcg/kg/day without toxic effects‚ although there was a flattening of the dose response curve above daily doses of greater than 10 mcg/kg/day.

16 HOW SUPPLIED/STORAGE AND HANDLING NIVESTYM injection is a clear, colorless, preservative-free solution supplied as: Vials Single-dose vials containing 300 mcg/mL of filgrastim-aafi solution. Dispensing packs of 10 vials (NDC 0069-0293-10). Single-dose vials containing 480 mcg/1.6 mL (300 mcg/mL) of filgrastim-aafi solution. Dispensing packs of 10 vials (NDC 0069-0294-10). Prefilled Syringes Single-dose prefilled syringe with BD UltraSafe PlusTM Passive Needle Guard, containing 300 mcg/0.5 mL of filgrastim-aafi solution. • Pack of 1 prefilled syringe (NDC 0069-0291-01). • Pack of 10 prefilled syringes (NDC 0069-0291-10). Single-dose, prefilled syringe with BD UltraSafe PlusTM Passive Needle Guard, containing 480 mcg/0.8 mL of filgrastim-aafi solution. • Pack of 1 prefilled syringe (NDC 0069-0292-01). • Pack of 10 prefilled syringes (NDC 0069-0292-10). The NIVESTYM syringe plunger stopper and needle cover are not made with natural rubber latex [see Dosage and Administration (2.5) ] . Storage Store NIVESTYM in the refrigerator at 2°C to 8°C (36°F to 46°F) in the original carton to protect from light. Do not leave NIVESTYM in direct sunlight. Avoid freezing; if frozen, thaw in the refrigerator before administration. Discard NIVESTYM if frozen more than once. Avoid shaking. Transport via a pneumatic tube has not been studied.