CLINICAL EVIDENCE

Study Design Efficacy Safety

Confirmed biosimilarity of ZARXIO to NEUPOGEN® (filgrastim)1,2

Biosimilarity was confirmed by the PIONEER study and a PK/PD study that demonstrated equivalence with regard to ANC* and CD34+ cell counts1,2

PIONEER was a randomized, double-blind, comparative study of efficacy and safety between ZARXIO and NEUPOGEN® in 218 breast cancer patients treated with myelosuppressive chemotherapy.2†

  • Study duration: 24 weeks1
  • All patients received 6 cycles (3 weeks per cycle) of TAC‡ combination chemotherapy administered on Day 1 of each cycle2
    • Starting on Day 2 of each chemotherapy cycle, ZARXIO or NEUPOGEN® was administered daily and continued until the ANC recovered to 10 x 109/L after the nadir or up to a maximum of 14 days (whichever occurred first)
  • The study included 4 arms in total2
    • 2 arms received treatment with either ZARXIO or NEUPOGEN® across all cycles
    • 2 arms started with either ZARXIO or NEUPOGEN® in Cycle 1, then alternated treatment in each subsequent cycle

Study design

PIONEER Study design

*ANC is absolute neutrophil count.2
†A total of 218 patients were randomized in the study of which 204 were included in the primary prophylaxis (PP) population for the primary analysis. A total of 34 patients did not complete the study as planned or discontinued study treatment prematurely. The PP patients were on average 49.0 years old with an overall range between 23 and 76 years. The median duration since breast cancer diagnosis was 2.0 months (range from 0 to 171 months) and the majority of patients had stage II cancer (51.4%) or stage III cancer (41.6%). A total of 163 patients (76.2%) had an ECOG status of 0 and 51 patients (23.8%) had an ECOG status of 1.1
‡TAC combination chemotherapy includes docetaxel, doxorubicin, and cyclophosphamide.2

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Efficacy

Primary endpoint for equivalence (in Cycle 1): mean duration of severe neutropenia (DSN)1,4§

Primary endpoint Cycle 1

§Defined as the number of consecutive days with severe neutropenia (ANC less than 0.5 x 109/L) in Cycle 1.1
IIANCOVA with treatment, disease status, and baseline ANC level.4

Biosimilarity demonstrated through the totality of evidence5

Secondary endpoints Cycle 1

#Defined as oral temperature ≥38.3°C while having an ANC <0.5 x 109/L (both measured on the same day).1,2
**ANC recovery was defined as the time in days from ANC nadir until the patient's ANC increases to ≥2 x 109/L after the nadir in Cycle 1.1,2
††Defined as the patient's lowest ANC in Cycle 1.1,2
‡‡Defined as oral temperature ≥38.3°C.1,2

ANC profiles of ZARXIO and NEUPOGEN®2

Depth of nadir Cycle 1

§§The nadir occurred around Days 7 and 8. There were no marked differences in the mean ANC between ZARXIO and NEUPOGEN® up to Day 10. Following Day 10, when in most patients the ANC had recovered by reaching at least 10 x 109/L, the number of patients with measurements decreased markedly as the ANC recovered in more and more patients.2

No antibodies against rhG-CSF were detected throughout the PIONEER study for either ZARXIO or NEUPOGEN®.2

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Safety

Cardinal adverse events (between-group comparison)4

Cycle 1 by treatment

||||Includes arthralgia, back pain, bone pain, musculoskeletal chest pain, musculoskeletal pain, myalgia, pain, pain in extremity, or spinal pain.
¶¶Includes injection site erythema, extravasation, hematoma, pain, or pruritus.

Treatment-emergent adverse events (TEAEs) >5% in Cycle 11

TEAEs >5% in Cycle 1

The overall safety profile of ZARXIO was similar across all 6 cycles with continuous treatment.4

Prescribing Information adverse reactions6

The following most common adverse reactions listed in the ZARXIO Prescribing Information are based on the reference biologic.

ADVERSE REACTIONS

  • Most common adverse reactions in patients:
  • With nonmyeloid malignancies receiving myelosuppressive anti-cancer drugs (≥ 5% difference in incidence compared to placebo) are thrombocytopenia, nausea, pyrexia, chest pain, pain, fatigue, back pain, arthralgia, bone pain, pain in extremity, dizziness, cough, dyspnea, rash, blood lactate dehydrogenase increased and blood alkaline phosphatase increased
  • With AML (≥ 2% difference in incidence) are epistaxis, back pain, pain in extremity, erythema, and rash maculo-papular
  • With nonmyeloid malignancies undergoing myeloablative chemotherapy followed by BMT (≥ 5% difference in incidence) are rash and hypersensitivity
  • Undergoing peripheral blood progenitor cell mobilization and collection (≥ 5% incidence) are bone pain, pyrexia, blood alkaline phosphatase increased and headache
  • With severe chronic neutropenia (SCN) (≥ 5% difference in incidence) are arthralgia, bone pain, back pain, muscle spasms, musculoskeletal pain, pain in extremity, splenomegaly, anemia, upper respiratory tract infection, urinary tract infection, epistaxis, chest pain, diarrhea, hypoesthesia, and alopecia

CONTRAINDICATIONS6

  • Patients with a history of serious allergic reactions to human granulocyte colony-stimulating factors such as filgrastim or pegfilgrastim products

WARNINGS AND PRECAUTIONS6

  • Fatal splenic rupture: Evaluate patients who report left upper abdominal or shoulder pain for an enlarged spleen or splenic rupture
  • Acute respiratory distress syndrome (ARDS): Evaluate patients who develop fever and lung infiltrates or respiratory distress for ARDS. Discontinue ZARXIO in patients with ARDS
  • Serious allergic reactions, including anaphylaxis: Permanently discontinue ZARXIO in patients with serious allergic reactions
  • Fatal sickle cell crises: Have occurred
  • Glomerulonephritis: Evaluate and consider dose-reduction or interruption of ZARXIO if causality is likely

USE IN SPECIFIC POPULATIONS6

  • ZARXIO should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus
  • It is not known whether filgrastim products are excreted in human milk

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References: 1. Data on file. Sandoz Inc. Princeton, NJ. 2. Blackwell K, Semiglazov V, Krasnozhon D, et al. Comparison of EP2006, a filgrastim biosimilar, to the reference: a phase III, randomized, double-blind clinical study in the prevention of severe neutropenia in patients with breast cancer receiving myelosuppressive chemotherapy. Ann Oncol. 2015;26:1948-1953. http://annonc.oxfordjournals.org/content/26/9/1948.full.pdf. Accessed May 3, 2017. 3. Blackwell K, Semiglazov V, Krasnozhon D, et al. Comparison of EP2006, a filgrastim biosimilar, to the reference: a phase III, randomized, double-blind clinical study in the prevention of severe neutropenia in patients with breast cancer receiving myelosuppressive chemotherapy [supplementary data]. Ann Oncol. 2015;26(9):1948-1953. http://annonc.oxfordjournals.org/content/early/2015/06/28/annonc.mdv281/suppl/DC1. Accessed May 3, 2017. 4. US Food and Drug Administration. Presentations for the January 7, 2015 Meeting of the Oncologic Drugs Advisory Committee. https://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/OncologicDrugsAdvisoryCommittee/UCM431118.pdf. Published January 7, 2015. Accessed May 3, 2017. 5. US Department of Health and Human Services. Scientific considerations in demonstrating biosimilarity to a reference product. Washington, DC: US Dept of Health and Human Services; April 2015. 6. ZARXIO Prescribing Information. Sandoz Inc. August 2019.


ZARXIO is a registered trademark of Novartis AG.
NEUPOGEN is a registered trademark of Amgen Inc.

INDICATIONS

  • Patients with Cancer Receiving Myelosuppressive Chemotherapy: 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.
  • Patients with Acute Myeloid Leukemia Receiving Induction or Consolidation Chemotherapy: 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).
  • Patients with Cancer Undergoing Bone Marrow Transplantation: 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.
  • Patients Undergoing Autologous Peripheral Blood Progenitor Cell Collection and Therapy: for the mobilization of autologous hematopoietic progenitor cells into the peripheral blood for collection by leukapheresis.
  • Patients with Severe Chronic Neutropenia: 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.

IMPORTANT SAFETY INFORMATION

CONTRAINDICATIONS

  • ZARXIO is contraindicated in patients with a history of serious allergic reactions to human granulocyte colony-stimulating factors such as filgrastim or pegfilgrastim products.

WARNINGS AND PRECAUTIONS

  • Splenic rupture, including fatal cases, has been reported following the administration of filgrastim products. Patients who report left upper abdominal or shoulder pain should be evaluated.
  • Acute respiratory distress syndrome (ARDS) has been reported in patients receiving filgrastim products. Patients who develop fever and lung infiltrates or respiratory distress should be evaluated. Discontinue ZARXIO in patients with ARDS.
  • 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.
  • Sickle cell crisis, in some cases fatal, has been reported with the use of filgrastim products in patients with sickle cell trait or sickle cell disease.
  • 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.
  • 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. The use of ZARXIO for PBPC mobilization in healthy donors is not an approved indication.
  • 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 appropriate treatment.
  • Confirm the diagnosis of severe chronic neutropenia (SCN) before initiating ZARXIO therapy. Myelodysplastic syndrome (MDS) and acute myelogenous leukemia (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. 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 administration in patients with abnormal cytogenetics or MDS are unknown. If a patient with SCN develops abnormal cytogenetics or myelodysplasia‚ the risks and benefits of continuing ZARXIO should be carefully considered.
  • Thrombocytopenia has been reported in patients receiving filgrastim products. Monitor platelet counts.
  • 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.
    • Peripheral Blood Progenitor Cell (PBPC) 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.
  • 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.
  • 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. Available data is limited and inconclusive.
  • The safety and efficacy of ZARXIO given simultaneously with cytotoxic chemotherapy have not been established. Do not use ZARXIO in the period 24 hours before through 24 hours after the administration of cytotoxic chemotherapy. 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.
  • Increased hematopoietic activity of the bone marrow in response to growth factor therapy has been associated with transient positive bone-imaging changes on nuclear imaging.
  • 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.

ADVERSE REACTIONS

  • Most common adverse reactions in patients:
  • With nonmyeloid malignancies receiving myelosuppressive anti-cancer drugs (≥ 5% difference in incidence compared to placebo) are thrombocytopenia, nausea, pyrexia, chest pain, pain, fatigue, back pain, arthralgia, bone pain, pain in extremity, dizziness, cough, dyspnea, rash, blood lactate dehydrogenase increased and blood alkaline phosphatase increased
  • With AML (≥ 2% difference in incidence) are epistaxis, back pain, pain in extremity, erythema, and rash maculo-papular
  • With nonmyeloid malignancies undergoing myeloablative chemotherapy followed by BMT (≥ 5% difference in incidence) are rash and hypersensitivity
  • Undergoing peripheral blood progenitor cell mobilization and collection (≥ 5% incidence) are bone pain, pyrexia, blood alkaline phosphatase increased and headache
  • With severe chronic neutropenia (SCN) (≥ 5% difference in incidence) are arthralgia, bone pain, back pain, muscle spasms, musculoskeletal pain, pain in extremity, splenomegaly, anemia, upper respiratory tract infection, urinary tract infection, epistaxis, chest pain, diarrhea, hypoesthesia, and alopecia

Please see full Prescribing Information.

To report SUSPECTED ADVERSE REACTIONS, contact Sandoz Inc. at 1-800-525-8747 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

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