1.1 Patients with Cancer Receiving Myelosuppressive Chemotherapy

ZARXIO 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

ZARXIO 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

ZARXIO 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

ZARXIO 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

ZARXIO 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)].

2.1 Dosage in Patients with Cancer Receiving Myelosuppressive Chemotherapy or Induction and/or Consolidation Chemotherapy for AML

The recommended starting dosage of ZARXIO 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 ZARXIO 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 ZARXIO if the ANC increases beyond 10‚000/mm3[see Warnings and Precautions (5.10)].

Administer ZARXIO at least 24 hours after cytotoxic chemotherapy. Do not administer ZARXIO 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 ZARXIO therapy. Therefore, to ensure a sustained therapeutic response‚ administer ZARXIO daily for up to 2 weeks or until the ANC has reached 10‚000/mm3 following the expected chemotherapy-induced neutrophil nadir. The duration of ZARXIO 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 ZARXIO 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 ZARXIO 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 ZARXIO against the neutrophil response (see Table 1).

2.3 Dosage in Patients Undergoing Autologous Peripheral Blood Progenitor Cell Collection and Therapy

The recommended dosage of ZARXIO for the mobilization of autologous peripheral blood progenitor cells (PBPC) is 10 mcg/kg/day given by subcutaneous injection. Administer ZARXIO for at least 4 days before the first leukapheresis procedure and continue until the last leukapheresis. Although the optimal duration of ZARXIO administration and leukapheresis schedule have not been established‚ administration of filgrastim for 6 to 7 days with leukaphereses on days 5‚ 6‚ and 7 was found to be safe and effective [see Clinical Studies (14.4)]. Monitor neutrophil counts after 4 days of ZARXIO‚ and discontinue ZARXIO if the white blood cell (WBC) count rises to greater than 100‚000/mm3.

2.4 Dosage in Patients with Severe Chronic Neutropenia

Prior to starting ZARXIO in patients with suspected chronic neutropenia, confirm the diagnosis of severe chronic neutropenia (SCN) by evaluating serial CBCs with differential and platelet counts‚ and evaluating bone marrow morphology and karyotype. The use of ZARXIO prior to confirmation of a correct diagnosis of SCN may impair diagnostic efforts and may thus impair or delay evaluation and treatment of an underlying condition‚ other than SCN‚ causing the neutropenia.

The recommended starting dosage in patients with Congenital Neutropenia is 6 mcg/kg as a twice daily subcutaneous injection and the recommended starting dosage in patients with Idiopathic or Cyclic Neutropenia is 5 mcg/kg as a single daily subcutaneous injection.

Dosage Adjustments in Patients with Severe Chronic Neutropenia

Chronic daily administration is required to maintain clinical benefit. Individualize the dosage based on the patient’s clinical course as well as ANC. In the SCN postmarketing surveillance study, the reported median daily doses of filgrastim were: 6 mcg/kg (congenital neutropenia), 2.1 mcg/kg (cyclic neutropenia), and 1.2 mcg/kg (idiopathic neutropenia). In rare instances, patients with congenital neutropenia have required doses of filgrastim greater than or equal to 100 mcg/kg/day.

Monitor CBCs for Dosage Adjustments

During the initial 4 weeks of ZARXIO therapy and during the 2 weeks following any dosage adjustment‚ monitor CBCs with differential and platelet counts. Once a patient is clinically stable‚ monitor CBCs with differential and platelet counts monthly during the first year of treatment. Thereafter, if the patient is clinically stable, less frequent routine monitoring is recommended.

2.5 Important Administration Instructions

Patient self-administration and administration by a caregiver may benefit from training by a healthcare professional. Training should aim to demonstrate to those patients and caregivers how to measure the dose using the prefilled syringe, and the focus should be on ensuring that a patient or caregiver can successfully perform all of the steps in the Instructions for Use of ZARXIO prefilled syringe with BD UltraSafe Passive® Needle Guard. If a patient or caregiver is not able to demonstrate that they can measure the dose and administer the product successfully, you should consider whether the patient is an appropriate candidate for self-administration of ZARXIO [see Instructions for Use].

ZARXIO prefilled syringe with BD UltraSafe Passive® Needle Guard is not designed to allow for direct administration of doses of less than 0.3 mL (180 mcg). The spring-mechanism of the needle guard apparatus affixed to the prefilled syringe interferes with the visibility of the graduation markings on the syringe barrel corresponding to 0.1 mL and 0.2 mL. The visibility of these markings is necessary to accurately measure doses of ZARXIO less than 0.3 mL (180 mcg) for direct administration to patients. Thus, the direct administration to patients requiring doses of less than 0.3 mL (180 mcg) is not recommended due to the potential for dosing errors.

ZARXIO is supplied in single-dose prefilled syringes (for subcutaneous use) [see Dosage Forms and Strengths (3)]. Prior to use‚ remove the prefilled syringe from the refrigerator and allow ZARXIO to reach room temperature for a minimum of 30 minutes and a maximum of 4 days. Discard any prefilled syringe left at room temperature for greater than 4 days. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration (the solution is clear and colorless to slightly yellowish). Do not administer ZARXIO if particulates or discoloration are observed.

Discard unused portion of ZARXIO in prefilled syringes. Do not save unused drug for later administration.

Subcutaneous Injection

Inject ZARXIO subcutaneously in the outer area of upper arms, abdomen, thighs, or upper outer areas of the buttock. If patients or caregivers are to administer ZARXIO, instruct them in appropriate injection technique and ask them to follow the subcutaneous injection procedures in the Instructions for Use for the prefilled syringe [see Patient Counseling Information (17)].

Training by the healthcare provider should aim to demonstrate to those patients and caregivers how to measure the dose of ZARXIO, and the focus should be on ensuring that a patient or caregiver can successfully perform all the steps in the Instructions for Use for the prefilled syringe. If a patient or caregiver is not able to demonstrate that they can measure the dose and administer the product successfully, you should consider whether the patient is an appropriate candidate for self-administration of ZARXIO.

If the patient or caregiver misses a dose of ZARXIO, instruct them to contact their healthcare provider.

Administration Instructions for the Prefilled Syringe

Persons with latex allergies should not administer the ZARXIO prefilled syringe, because the needle cap contains natural rubber latex (derived from latex).

Dilution

If required for intravenous administration, ZARXIO may be diluted in 5% Dextrose Injection, USP to concentrations between 5 mcg/mL and 15 mcg/mL. ZARXIO diluted to concentrations from 5 mcg/mL to 15 mcg/mL should be protected from adsorption to plastic materials by the addition of Albumin (Human) to a final concentration of 2 mg/mL. When diluted in 5% Dextrose Injection, USP, or 5% Dextrose plus Albumin (Human)‚ ZARXIO is compatible with glass, polyvinylchloride, polyolefin, and polypropylene.

Do not dilute with saline at any time, because the product may precipitate.

Diluted ZARXIO solution can be stored at room temperature for up to 24 hours. This 24-hour time period includes the time during room temperature storage of the infusion solution and the duration of the infusion.

5.1 Splenic Rupture

Splenic rupture, including fatal cases, has been reported following the administration of filgrastim products. Evaluate patients who report left upper abdominal or shoulder pain for an enlarged spleen or splenic rupture.

5.2 Acute Respiratory Distress Syndrome

Acute respiratory distress syndrome (ARDS) has been reported in patients receiving filgrastim products. Evaluate patients who develop fever and lung infiltrates or respiratory distress for ARDS. Discontinue ZARXIO in patients with ARDS.

5.3 Serious Allergic Reactions

Serious allergic reactions, including anaphylaxis, have been reported in patients receiving filgrastim products. The majority of reported events occurred upon initial exposure. Provide symptomatic treatment for allergic reactions. Allergic reactions, including anaphylaxis, in patients receiving filgrastim products can recur within days after the discontinuation of initial anti-allergic treatment. Permanently discontinue ZARXIO in patients with serious allergic reactions. ZARXIO is contraindicated in patients with a history of serious allergic reactions to human granulocyte colony-stimulating factors such as filgrastim products or pegfilgrastim products.

5.4 Sickle Cell Disorders

Severe and sometimes fatal sickle cell crises can occur in patients with sickle cell disorders receiving filgrastim products. Discontinue ZARXIO if sickle cell crisis occurs.

5.5 Glomerulonephritis

Glomerulonephritis has occurred in patients receiving filgrastim products. The diagnoses were based upon azotemia, hematuria (microscopic and macroscopic), proteinuria, and renal biopsy. Generally, events of glomerulonephritis resolved after dose-reduction or discontinuation of filgrastim products. If glomerulonephritis is suspected, evaluate for cause. If causality is likely, consider dose-reduction or interruption of ZARXIO.

5.6 Alveolar Hemorrhage and Hemoptysis

Alveolar hemorrhage manifesting as pulmonary infiltrates and hemoptysis requiring hospitalization have been reported in healthy donors treated with filgrastim products undergoing peripheral blood progenitor cell (PBPC) collection mobilization. Hemoptysis resolved with discontinuation of filgrastim products. The use of ZARXIO for PBPC mobilization in healthy donors is not an approved indication.

5.7 Capillary Leak Syndrome

Capillary leak syndrome (CLS) has been reported after G-CSF administration, including filgrastim products, 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 a need for intensive care.

5.8 Myelodysplastic Syndrome (MDS) and Acute Myeloid Leukemia (AML)

Patients with Severe Chronic Neutropenia

Confirm the diagnosis of SCN before initiating ZARXIO therapy.

MDS and AML have been reported to occur in the natural history of congenital neutropenia without cytokine therapy. Cytogenetic abnormalities, transformation to MDS, and AML have also been observed in patients treated with filgrastim products for SCN. Based on available data including a postmarketing surveillance study, the risk of developing MDS and AML appears to be confined to the subset of patients with congenital neutropenia. Abnormal cytogenetics and MDS have been associated with the eventual development of myeloid leukemia. The effect of filgrastim products on the development of abnormal cytogenetics and the effect of continued filgrastim products administration in patients with abnormal cytogenetics or MDS are unknown. Monitor patients for signs and symptoms of MDS/AML in these settings. If a patient with SCN develops abnormal cytogenetics or myelodysplasia‚ the risks and benefits of continuing ZARXIO should be carefully considered.

Patients with Breast and Lung Cancer

MDS and AML have been associated with the use of filgrastim products in conjunction with chemotherapy and/or radiotherapy in patients with breast and lung cancer. Monitor patients for signs and symptoms of MDS/AML in these settings.

5.9 Thrombocytopenia

Thrombocytopenia has been reported in patients receiving filgrastim products. Monitor platelet counts.

5.10 Leukocytosis

Patients with Cancer Receiving Myelosuppressive Chemotherapy

White blood cell counts of 100‚000/mm3 or greater were observed in approximately 2% of patients receiving filgrastim at dosages above 5 mcg/kg/day. In patients with cancer receiving ZARXIO as an adjunct to myelosuppressive chemotherapy‚ to avoid the potential risks of excessive leukocytosis‚ it is recommended that ZARXIO therapy be discontinued if the ANC surpasses 10‚000/mm3 after the chemotherapy-induced ANC nadir has occurred. Monitor CBCs at least twice weekly during therapy. Dosages of ZARXIO that increase the ANC beyond 10‚000/mm3 may not result in any additional clinical benefit. In patients with cancer receiving myelosuppressive chemotherapy‚ discontinuation of filgrastim 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.

Peripheral Blood Progenitor Cell Collection and Therapy

During the period of administration of ZARXIO for PBPC mobilization in patients with cancer, discontinue ZARXIO if the leukocyte count rises to > 100,000/mm3.

5.11 Cutaneous Vasculitis

Cutaneous vasculitis has been reported in patients treated with filgrastim products. In most cases‚ the severity of cutaneous vasculitis was moderate or severe. Most of the reports involved patients with SCN receiving long-term filgrastim therapy. Hold ZARXIO therapy in patients with cutaneous vasculitis. ZARXIO may be started at a reduced dose when the symptoms resolve and the ANC has decreased.

5.12 Potential Effect on Malignant Cells

ZARXIO is a growth factor that primarily stimulates neutrophils. The granulocyte colony-stimulating factor (G‑CSF) receptor through which ZARXIO acts has also been found on tumor cell lines. The possibility that ZARXIO acts as a growth factor for any tumor type cannot be excluded. The safety of filgrastim products in chronic myeloid leukemia (CML) and myelodysplasia has not been established.

When ZARXIO is used to mobilize PBPC‚ tumor cells may be released from the marrow and subsequently collected in the leukapheresis product. The effect of reinfusion of tumor cells has not been well studied‚ and the limited data available are inconclusive.

5.13 Simultaneous Use with Chemotherapy and Radiation Therapy Not Recommended

The safety and efficacy of ZARXIO 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 ZARXIO in the period 24 hours before through 24 hours after the administration of cytotoxic chemotherapy [see Dosage and Administration (2.2)].

The safety and efficacy of ZARXIO have not been evaluated in patients receiving concurrent radiation therapy. Avoid the simultaneous use of ZARXIO with chemotherapy and radiation therapy.

5.14 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.

5.15 Aortitis

Aortitis has been reported in patients receiving filgrastim products. It may occur as early as the first week after start of therapy. Manifestations may include generalized signs and symptoms such as fever, abdominal pain, malaise, back pain, and increased inflammatory markers (e.g., c-reactive protein and white blood cell count). Consider aortitis in patients who develop these signs and symptoms without known etiology. Discontinue ZARXIO if aortitis is suspected.

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/m2 (Study 1), 240 mcg/m2 (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.

Adverse events with ≥ 5% higher incidence in filgrastim patients compared to placebo and associated with the sequelae of the underlying malignancy or cytotoxic chemotherapy delivered included anemia, constipation, diarrhea, oral pain, vomiting, asthenia, malaise, edema peripheral, hemoglobin decreased, decreased appetite, oropharyngeal pain, and alopecia.

Adverse Reactions in Patients with Acute Myeloid Leukemia

Adverse reaction data below are from a randomized, double-blind, placebo-controlled study in patients with AML (Study 4) who received an induction chemotherapy regimen of intravenous daunorubicin days 1, 2, and 3; cytosine arabinoside days 1 to 7; and etoposide days 1 to 5 and up to 3 additional courses of therapy (induction 2, and consolidation 1, 2) of intravenous daunorubicin, cytosine arabinoside, and etoposide. The safety population included 518 patients randomized to receive either 5 mcg/kg/day filgrastim (n=257) or placebo (n=261). The median age was 54 (range 16 to 89) years and 54% were male.

Adverse reactions with ≥ 2% higher incidence in filgrastim patients compared to placebo included epistaxis, back pain, pain in extremity, erythema, and rash maculo-papular.

Adverse events with ≥ 2% higher incidence in filgrastim patients compared to placebo and associated with the sequelae of the underlying malignancy or cytotoxic chemotherapy included diarrhea, constipation, and transfusion reaction.

Adverse Reactions in Patients with Cancer Undergoing Bone Marrow Transplantation

The following adverse reaction data are from one randomized, no treatment-controlled study in patients with acute lymphoblastic leukemia or lymphoblastic lymphoma receiving high-dose chemotherapy (cyclophosphamide or cytarabine, and melphalan) and total body irradiation (Study 5) and one randomized, no treatment-controlled study in patients with Hodgkin’s disease (HD) and NHL undergoing high-dose chemotherapy and autologous bone marrow transplantation (Study 6). Patients receiving autologous bone marrow transplantation only were included in the analysis. A total of 100 patients received either 30 mcg/kg/day as a 4-hour infusion (Study 5) or 10 mcg/kg/day or 30 mcg/kg/day as a 24-hour infusion (Study 6) filgrastim (n=72), no treatment control or placebo (n=28). The median age was 30 (range 15 to 57) years, 57% were male.

Adverse reactions with ≥ 5% higher incidence in filgrastim patients compared to patients receiving no filgrastim included rash and hypersensitivity.

Adverse reactions in patients receiving intensive chemotherapy followed by autologous BMT with ≥ 5% higher incidence in filgrastim patients compared to patients receiving no filgrastim included thrombocytopenia, anemia, hypertension, sepsis, bronchitis, and insomnia.

Adverse Reactions in Patients with Cancer Undergoing Autologous Peripheral Blood Progenitor Cell Collection

The adverse reaction data in Table 3 are from a series of 7 trials in patients with cancer undergoing mobilization of autologous peripheral blood progenitor cells for collection by leukapheresis. Patients (n=166) in all these trials underwent a similar mobilization/collection regimen: filgrastim was administered for 6 to 8 days‚ in most cases the apheresis procedure occurred on days 5‚ 6, and 7. The dosage of filgrastim ranged between 5 to 30 mcg/kg/day and was administered subcutaneously by injection or continuous infusion. The median age was 39 (range 15 to 67) years, and 48% were male.

Adverse Reactions in Patients with Severe Chronic Neutropenia

The following adverse reaction data were identified in a randomized, controlled study in patients with SCN receiving filgrastim (Study 7). 123 patients were randomized to a 4-month observation period followed by subcutaneous filgrastim treatment or immediate subcutaneous filgrastim treatment. The median age was 12 years (range 7 months to 76 years) and 46% were male. The dosage of filgrastim was determined by the category of neutropenia.

Initial dosage of filgrastim:

•

Idiopathic neutropenia: 3.6 mcg/kg/day

•

Cyclic neutropenia: 6 mcg/kg/day

•

Congenital neutropenia: 6 mcg/kg/day divided 2 times per day

The dosage was increased incrementally to 12 mcg/kg/day divided 2 times per day if there was no response. Adverse reactions with ≥ 5% higher incidence in filgrastim patients compared to patients receiving no filgrastim included arthralgia, bone pain, back pain, muscle spasms, musculoskeletal pain, pain in extremity, splenomegaly, anemia, upper respiratory tract infection, and urinary tract infection (upper respiratory tract infection and urinary tract infection were higher in the filgrastim arm, total infection related events were lower in filgrastim-treated patients), epistaxis, chest pain, diarrhea, hypoesthesia, and alopecia.

6.2 Immunogenicity

As with all therapeutic proteins, there is a potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors, including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies in the studies described below with the incidence of antibodies in other studies or to other filgrastim products may be misleading.

The incidence of antibody development in patients receiving filgrastim products has not been adequately determined. While available data suggest that a small proportion of patients developed binding antibodies to filgrastim products, the nature and specificity of these antibodies has not been adequately studied. In clinical studies using filgrastim, the incidence of antibodies binding to filgrastim was 3% (11/333). In these 11 patients, no evidence of a neutralizing response was observed using a cell based bioassay.

Cytopenias resulting from an antibody response to exogenous growth factors have been reported on rare occasions in patients treated with other recombinant growth factors.

6.3 Postmarketing Experience

The following adverse reactions have been identified during post-approval use of filgrastim products. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

•

splenic rupture and splenomegaly (enlarged spleen) [see Warnings and Precautions (5.1)]

•

acute respiratory distress syndrome [see Warnings and Precautions (5.2)]

•

anaphylaxis [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)]

•

leukocytosis [see Warnings and Precautions (5.10)]

•

cutaneous vasculitis [see Warnings and Precautions (5.11)]

•

Sweet’s syndrome (acute febrile neutrophilic dermatosis)

•

decreased bone density and osteoporosis in pediatric patients receiving chronic treatment with filgrastim products

•

myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) in patients with breast and lung cancer receiving chemotherapy and/or radiotherapy [see Warnings and Precautions (5.8)]

•

aortitis [see Warnings and Precautions (5.15)]

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 population 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 ZARXIO and any potential adverse effects on the breastfed child from ZARXIO or from the underlying maternal condition.

8.4 Pediatric Use

ZARXIO prefilled syringe with BD UltraSafe 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 (180 mcg) is not recommended due to the potential for dosing errors.

In patients with cancer receiving myelosuppressive chemotherapy‚ 15 pediatric patients median age 2.6 (range 1.2 to 9.4) years with neuroblastoma were treated with myelosuppressive chemotherapy (cyclophosphamide‚ cisplatin‚ doxorubicin‚ and etoposide) followed by subcutaneous filgrastim at doses of 5, 10, or 15 mcg/kg/day for 10 days (n=5/dose) (Study 8). The pharmacokinetics of filgrastim in pediatric patients after chemotherapy were similar to those in adults receiving the same weight-normalized doses, suggesting no age-related differences in the pharmacokinetics of filgrastim. In this population‚ filgrastim was well tolerated. There was one report of palpable splenomegaly and one report of hepatosplenomegaly 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.

The safety and effectiveness of filgrastim have been established in pediatric patients with SCN [see Clinical Studies (14.5)]. In a phase 3 study (Study 7) to assess the safety and efficacy of filgrastim in the treatment of SCN, 123 patients with a median age of 12 years (range 7 months to 76 years) were studied. Of the 123 patients, 12 were infants (7 months to 2 years of age), 49 were children (2 to 12 years of age), and 9 were adolescents (12 to 16 years of age). Additional information is available from a SCN postmarketing surveillance study, which includes long-term follow-up of patients in the clinical studies and information from additional patients who entered directly into the postmarketing surveillance study. Of the 731 patients in the surveillance study, 429 were pediatric patients < 18 years of age (range 0.9 to 17) [see Indications and Usage (1.5), Dosage and Administration (2.5), and Clinical Studies (14.5)].

Long-term follow-up data from the postmarketing surveillance study suggest that height and weight are not adversely affected in patients who received up to 5 years of filgrastim treatment. Limited data from patients who were followed in the phase 3 study for 1.5 years did not suggest alterations in sexual maturation or endocrine function.

Pediatric patients with congenital types of neutropenia (Kostmann’s syndrome, congenital agranulocytosis, or Schwachman-Diamond syndrome) have developed cytogenetic abnormalities and have undergone transformation to MDS and AML while receiving chronic filgrastim treatment. The relationship of these events to filgrastim administration is unknown [see Warnings and Precautions (5.8) and Adverse Reactions (6)].

8.5 Geriatric Use

Among 855 subjects enrolled in 3 randomized, placebo-controlled trials of filgrastim treated-patients receiving myelosuppressive chemotherapy, there were 232 subjects age 65 or older, and 22 subjects age 75 or older. No overall differences in safety or effectiveness were observed between these subjects and younger subjects. Clinical studies of filgrastim in other approved indications (i.e., BMT recipients, PBPC mobilization, and SCN) did not include sufficient numbers of subjects aged 65 and older to determine whether elderly subjects respond differently from younger subjects.

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.

12.2 Pharmacodynamics

In phase 1 studies involving 96 patients with various nonmyeloid malignancies‚ administration of filgrastim resulted in a dose-dependent increase in circulating neutrophil counts over the dose range of 1 to 70 mcg/kg/day. This increase in neutrophil counts was observed whether filgrastim was administered intravenous (1 to 70 mcg/kg twice daily)‚ subcutaneous (1 to 3 mcg/kg once daily)‚ or by continuous subcutaneous infusion (3 to 11 mcg/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 chemiluminescence) 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. 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 patients with cancer.

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

12.3 Pharmacokinetics

Filgrastim products exhibit nonlinear pharmacokinetics. Clearance is dependent on filgrastim product concentration and neutrophil count: G-CSF receptor-mediated clearance is saturated by high concentration of filgrastim products and is diminished by neutropenia. In addition, filgrastim products are cleared by the kidney.

Subcutaneous administration of 3.45 mcg/kg and 11.5 mcg/kg of filgrastim resulted in maximum serum concentrations of 4 and 49 ng/mL‚ respectively‚ within 2 to 8 hours. After intravenous administration, the volume of distribution averaged 150 mL/kg and the elimination half-life was approximately 3.5 hours in both normal subjects and subjects with cancer. Clearance rates of filgrastim were approximately 0.5 to 0.7 mL/minute/kg. Single parenteral doses or daily intravenous doses‚ over a 14-day period‚ resulted in comparable half-lives. The half-lives were similar for intravenous administration (231 minutes‚ following doses of 34.5 mcg/kg) and for subcutaneous administration (210 minutes‚ following filgrastim dosages of 3.45 mcg/kg). Continuous 24-hour intravenous infusions of 20 mcg/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. The absolute bioavailability of filgrastim after subcutaneous administration is 60% to 70%.

Specific Populations

Pediatric Patients

The pharmacokinetics of filgrastim in pediatric patients after chemotherapy are similar to those in adult patients receiving the same weight-normalized doses, suggesting no age-related differences in the pharmacokinetics of filgrastim products [see Use in Specific Populations (8.4)].

Renal Impairment

In a study with healthy volunteers, subjects with moderate renal impairment, and subjects with end stage renal disease (n=4 per group), higher serum concentrations were observed in subjects with end-stage renal disease. However, dose adjustment in patients with renal impairment is not necessary.

Hepatic Impairment

Pharmacokinetics and pharmacodynamics of filgrastim are similar between subjects with hepatic impairment and healthy subjects (n=12/group). The study included 10 subjects with mild hepatic impairment (Child-Pugh Class A) and 2 subjects with moderate hepatic impairment (Child-Pugh Class B). Therefore, dose adjustment for ZARXIO in patients with hepatic impairment is not necessary.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

The carcinogenic potential of filgrastim products 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 at doses up to 500 mcg/kg.

13.2 Animal Toxicology and Pharmacology

Filgrastim was administered to monkeys‚ dogs‚ hamsters‚ rats‚ and mice as part of a nonclinical toxicology program, which included studies up to 1-year duration.

In the repeated-dose studies‚ changes observed were attributable to the expected pharmacological actions of filgrastim (i.e.‚ dose-dependent increases in white blood cell counts‚ increased circulating segmented neutrophils‚ and increased myeloid: erythroid ratio in bone marrow). Histopathologic examination of the liver and spleen revealed evidence of ongoing extramedullary granulopoiesis, and dose-related increases in spleen weight were seen in all species. These changes all reversed after discontinuation of treatment.

14.1 Patients with Cancer Receiving Myelosuppressive Chemotherapy

The safety and efficacy of filgrastim to decrease the incidence of infection‚ as manifested by febrile neutropenia‚ in patients with nonmyeloid malignancies receiving myelosuppressive anti-cancer drugs were established in a randomized‚ double-blind‚ placebo-controlled trial conducted in patients with small cell lung cancer (Study 1).

In Study 1, patients received up to 6 cycles of intravenous chemotherapy including intravenous cyclophosphamide and doxorubicin on day 1; and etoposide on days 1, 2, and 3 of 21 day cycles. Patients were randomized to receive filgrastim (n=99) at a dose of 230 mcg/m2 (4 to 8 mcg/kg/day) or placebo (n=111). Study drug was administered subcutaneously daily beginning on day 4, for a maximum of 14 days. A total of 210 patients were evaluable for efficacy and 207 were evaluable for safety. The demographic and disease characteristics were balanced between arms with a median age of 62 (range 31 to 80) years; 64% males; 89% Caucasian; 72% extensive disease and 28% limited disease.

The main efficacy endpoint was the incidence of febrile neutropenia. Febrile neutropenia was defined as an ANC < 1,000/mm3 and temperature > 38.2°C. Treatment with filgrastim resulted in a clinically and statistically significant reduction in the incidence of infection‚ as manifested by febrile neutropenia, 40% for filgrastim-treated patients and 76% for placebo-treated patients (p < 0.001). There were also statistically significant reductions in the incidence and overall duration of infection manifested by febrile neutropenia; the incidence, severity and duration of severe neutropenia (ANC < 500/mm3); the incidence and overall duration of hospital admissions; and the number of reported days of antibiotic use.

14.2 Patients with Acute Myeloid Leukemia Receiving Induction or Consolidation Chemotherapy

The safety and efficacy of filgrastim to reduce the time to neutrophil recovery and the duration of fever, following induction or consolidation chemotherapy treatment of patients with acute myeloid leukemia (AML) was established in a randomized, double-blind‚ placebo-controlled‚ multi-center trial in patients with newly diagnosed, de novo AML (Study 4).

In Study 4 the initial induction therapy consisted of intravenous daunorubicin days 1, 2, and 3; cytosine arabinoside days 1 to 7; and etoposide days 1 to 5. Patients were randomized to receive subcutaneous filgrastim (n=259) at a dose of 5 mcg/kg/day or placebo (n=262) from 24 hours after the last dose of chemotherapy until neutrophil recovery (ANC ≥1,000/mm3 for 3 consecutive days or ≥ 10,000/mm3 for 1 day) or for a maximum of 35 days. The demographic and disease characteristics were balanced between arms with a median age of 54 (range 16 to 89) years; 54% males; initial white blood cell count (65% <25,000 /mm3 and 27% > 100,000/mm3); 29% unfavorable cytogenetics.

The main efficacy endpoint was median duration of severe neutropenia defined as neutrophil count < 500/mm3. Treatment with filgrastim resulted in a clinically and statistically significant reduction in median number of days of severe neutropenia, filgrastim-treated patients 14 days, placebo-treated patients 19 days (p=0.0001: difference of 5 days (95% CI: -6.0, -4.0)). There was a reduction in the median duration of intravenous antibiotic use, filgrastim-treated patients: 15 days versus placebo-treated patients: 18.5 days; a reduction in the median duration of hospitalization, filgrastim-treated patients: 20 days versus placebo-treated patients: 25 days.

There were no statistically significant differences between the filgrastim and the placebo groups in complete remission rate (69% - filgrastim, 68% - placebo), median time to progression of all randomized patients (165 days - filgrastim, 186 days - placebo), or median overall survival (380 days - filgrastim, 425 days - placebo).

14.3 Patients with Cancer Undergoing Bone Marrow Transplantation

The safety and efficacy of filgrastim to reduce the duration of neutropenia in patients with nonmyeloid malignancies undergoing myeloablative chemotherapy followed by autologous bone marrow transplantation was evaluated in 2 randomized controlled trials of patients with lymphoma (Study 6 and Study 9). The safety and efficacy of filgrastim to reduce the duration of neutropenia in patients undergoing myeloablative chemotherapy followed by allogeneic bone marrow transplantation was evaluated in a randomized placebo-controlled trial (Study 10).

In Study 6, patients with Hodgkin’s disease received a preparative regimen of intravenous cyclophosphamide, etoposide, and BCNU (“CVP”), and patients with non-Hodgkin’s lymphoma received intravenous BCNU, etoposide, cytosine arabinoside and melphalan (“BEAM”). There were 54 patients randomized 1:1:1 to control, filgrastim 10 mcg/kg/day, and filgrastim 30 mcg/kg/day as a 24-hour continuous infusion starting 24-hours after bone marrow infusion for a maximum of 28 days. The median age was 33 (range 17 to 57) years; 56% males; 69% Hodgkin’s disease and 31% non-Hodgkin’s lymphoma.

The main efficacy endpoint was duration of severe neutropenia ANC < 500/mm3. A statistically significant reduction in the median number of days of severe neutropenia (ANC < 500/mm3) occurred in the filgrastim-treated groups versus the control group (23 days in the control group‚ 11 days in the 10 mcg/kg/day group‚ and 14 days in the 30 mcg/kg/day group [11 days in the combined treatment groups‚ p=0.004]).

In Study 9, patients with Hodgkin’s disease and non-Hodgkin’s lymphoma received a preparative regimen of intravenous cyclophosphamide, etoposide, and BCNU (“CVP”). There were 43 evaluable patients randomized to continuous subcutaneous infusion filgrastim 10 mcg/kg/day (n=19), filgrastim 30 mcg/kg/day (n=10) and no treatment (n=14) starting the day after marrow infusion for a maximum of 28 days. The median age was 33 (range 17 to 56) years; 67% males; 28% Hodgkin’s disease and 72% non-Hodgkin’s lymphoma.

The main efficacy endpoint was duration of severe neutropenia. There was statistically significant reduction in the median number of days of severe neutropenia (ANC < 500/mm3) in the filgrastim-treated groups versus the control group (21.5 days in the control group versus 10 days in the filgrastim-treated groups, p < 0.001). The number of days of febrile neutropenia was also reduced significantly in this study (13.5 days in the control group versus 5 days in the filgrastim-treated groups‚ p < 0.0001).

In Study 10, 70 patients scheduled to undergo bone marrow transplantation for multiple underlying conditions using multiple preparative regimens were randomized to receive filgrastim 300 mcg/m2/day (n=33) or placebo (n=37) days 5 through 28 after marrow infusion. The median age was 18 (range 1 to 45) years, 56% males. The underlying disease was: 67% hematologic malignancy, 24% aplastic anemia, 9% other. 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‚ p < 0.001) and time to recovery of ANC to ≥ 500/mm3 (21 days in the control group and 16 days in the treatment group‚ p < 0.001).

14.4 Patients Undergoing Autologous Peripheral Blood Progenitor Cell Collection and Therapy

The safety and efficacy of filgrastim to mobilize autologous peripheral blood progenitor cells for collection by leukapheresis was supported by the experience in uncontrolled trials, and a randomized trial comparing hematopoietic stem cell rescue using filgrastim-mobilized autologous peripheral blood progenitor cells to autologous bone marrow (Study 11). Patients in all these trials underwent a similar mobilization/collection regimen: filgrastim was administered for 6 to 7 days‚ in most cases the apheresis procedure occurred on days 5‚ 6, and 7. The dose of filgrastim ranged between 10 to 24 mcg/kg/day and was administered subcutaneously by injection or continuous intravenous infusion.

Engraftment was evaluated in 64 patients who underwent transplantation using filgrastim-mobilized autologous hematopoietic progenitor cells in uncontrolled trials. Two of the 64 patients (3%) did not achieve the criteria for engraftment as defined by a platelet count ≥ 20‚000/mm3 by day 28. In clinical trials of filgrastim for the mobilization of hematopoietic progenitor cells‚ filgrastim was administered to patients at doses between 5 to 24 mcg/kg/day after reinfusion of the collected cells until a sustainable ANC (≥ 500/mm3) was reached. The rate of engraftment of these cells in the absence of filgrastim post transplantation has not been studied.

Study 11 was a randomized, unblinded study of patients with Hodgkin’s disease or non-Hodgkin’s lymphoma undergoing myeloablative chemotherapy‚ 27 patients received filgrastim-mobilized autologous hematopoietic progenitor cells and 31 patients received autologous bone marrow. The preparative regimen was intravenous BCNU, etoposide, cytosine arabinoside and melphalan (“BEAM”). Patients received daily filgrastim 24 hours after stem cell infusion at a dose of 5 mcg/kg/day. The median age was 33 (range 1 to 59) years; 64% males; 57% Hodgkin’s disease and 43% non-Hodgkin’s lymphoma. The main efficacy endpoint was number of days of platelet transfusions. Patients randomized to filgrastim-mobilized autologous peripheral blood progenitor cells compared to autologous bone marrow had significantly fewer days of platelet transfusions (median 6 vs 10 days).

14.5 Patients with Severe Chronic Neutropenia

The safety and efficacy of filgrastim to reduce the incidence and duration of sequelae of neutropenia (that is fever‚ infections, oropharyngeal ulcers) in symptomatic adult and pediatric patients with congenital neutropenia‚ cyclic neutropenia‚ or idiopathic neutropenia was established in a randomized controlled trial conducted in patients with severe neutropenia (Study 7).

Patients eligible for Study 7 had a history of severe chronic neutropenia documented with an ANC < 500/mm3 on three occasions during a 6-month period, or in patients with cyclic neutropenia 5 consecutive days of ANC < 500/mm3 per cycle. In addition, patients must have experienced a clinically significant infection during the previous 12 months. Patients were randomized to a 4-month observation period followed by filgrastim treatment or immediate filgrastim treatment. The median age was 12 years (range 7 months to 76 years); 46% males; 34% idiopathic, 17% cyclic and 49% congenital neutropenia. Filgrastim was administered subcutaneously. The dose of filgrastim was determined by the category of neutropenia.

Initial dose of filgrastim:

•

Idiopathic neutropenia: 3.6 mcg/kg/day

•

Cyclic neutropenia: 6 mcg/kg/day

•

Congenital neutropenia: 6 mcg/kg/day divided 2 times per day

The dose was increased incrementally to 12 mcg/kg/day divided 2 times per day if there was no response.

The main efficacy endpoint was response to filgrastim treatment. ANC response from baseline (< 500/mm3) was defined as follows:

•

Complete response: median ANC > 1,500/mm3

•

Partial response: median ANC ≥ 500/mm3 and ≤ 1,500/mm3 with a minimum increase of 100%

•

No response: median ANC < 500/mm3

There were 112 of 123 patients who demonstrated a complete or partial response to filgrastim treatment.

Additional efficacy endpoints included a comparison between patients randomized to 4 months of observation and patients receiving filgrastim of the following parameters:

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incidence of infection

•

incidence of fever

•

duration of fever

•

incidence, duration, and severity of oropharyngeal ulcers

•

number of days of antibiotic use

The incidence for each of these 5 clinical parameters was lower in the filgrastim arm compared to the control arm for cohorts in each of the 3 major diagnostic categories. An analysis of variance showed no significant interaction between treatment and diagnosis‚ suggesting that efficacy did not differ substantially in the different diseases. Although filgrastim substantially reduced neutropenia in all patient groups‚ in patients with cyclic neutropenia‚ cycling persisted but the period of neutropenia was shortened to 1 day.