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Confirmed Biosimilarity▾  |  PK/PD Switch Study▾  |  Confirmatory Trials▾

The efficacy and safety profile you've come to expect

ZIEXTENZO demonstrated biosimilarity to its reference product via a rigorous preclinical and
clinical program.1-3

ZIEXTENZO offers the same efficacy and safety profile as Neulasta® (pegfilgrastim)1,2,4

PK/PD

  • ZIEXTENZO demonstrated PK and PD similarity vs Neulasta® US and Neulasta® EU4
  • The 90% CIs of these parameters were within the predefined equivalence margins of 0.80-1.254
ZIEXTENZO compares similarly to Neulasta in PK/PD, Safety, Immunogenicity, and MOA.

Safety

  • The safety profile of ZIEXTENZO matched that of Neulasta® US and Neulasta® EU1,2a
  • The overall incidence of TEAEs was similar as well1,2
ZIEXTENZO compares similarly to Neulasta in PK/PD, Safety, Immunogenicity, and MOA.

Immunogenicity

  • Incidence of ADAs was low and similar to Neulasta® US and Neulasta® EU1,2b
ZIEXTENZO compares similarly to Neulasta in PK/PD, Safety, Immunogenicity, and MOA.

MOA

  • ZIEXTENZO is a recombinant G-CSF that acts on hematopoietic cells by binding to specific cell surface receptors, identical to Neulasta®5,6
ZIEXTENZO compares similarly to Neulasta in PK/PD, Safety, Immunogenicity, and MOA.

aNo clinically meaningful differences were observed regarding safety and local tolerance among the treatment groups.4
bADAs had no impact on PK, PD, or safety.4

Biosimilarity confirmed through totality of evidence7

Bio Chart

ZIEXTENZO went through extensive preclinical characterization to Neulasta®9

  • State-of-the-art technology comparing key structural and functional attributes, including primary structure, higher order structure, pegylation, purity, aggregates, bioactivity, and receptor binding7
  • >40 different methodologies used to analyze >100 different specifications to demonstrate sameness10-12

 

Efficacy shown in ZIEXTENZO vs Neulasta® PK/PD crossover study in healthy subjects4

  • The primary objectives of the study were met: PK and PD similarity were demonstrated between ZIEXTENZO and Neulasta® US and between ZIEXTENZO and Neulasta® EU4

The LA-EP06-104 study was designed to demonstrate similarity between ZIEXTENZO and Neulasta®4

LA- EP06- 104 Study Design comparing ZIEXTENZO, Neulasta Us, and Neulasta EU over 3 treatment periods.

The LA-EP06-104 study proved bioequivalency to Neulasta®4

Mean (SD) pegfilgrastim serum concentration-time profiles overall (full analysis set for PK)

LA-EP06-104 Bioequivalency to Neulasta

ZIEXTENZO: The only biosimilar pegfilgrastim with 2 confirmatory phase 3 trials1,2,13-15

Table comparing ZIEXTENZO to Neulasta in PROTECT -1 and PROTECT – 2.

PROTECT-1 and PROTECT-2 were global, prospective, randomized, multicenter, double-blind, head-to-head, phase 3 confirmatory trials designed to demonstrate the efficacy and safety equivalence of ZIEXTENZO to Neulasta®* in patients with breast cancer receiving myelosuppressive chemotherapy (PROTECT-1, N=316; PROTECT-2, N=308).1,2

See the convenient dosing and administration

*Neulasta® EU and Neulasta® US were the reference pegfilgrastim in PROTECT-1 and PROTECT-2, respectively.1,2

ADA=anti-drug antibody; ANC=absolute neutrophil count; AUC0-inf=area under the serum concentration time curve measured from the time of dosing to infinity; AUC0-last=area under the serum concentration time curve measured from the time of dosing to the last measurable concentration; AUEC0-last=area under the effect curve measured from the time of dosing to the last measurable concentration; CI=confidence interval; Cmax=maximum observed serum concentration; Emax=maximum effect attributable to the Investigational Medicinal Product; G-CSF=granulocyte colony-stimulating factor; MOA=mechanism of action; PD=pharmacodynamic; PK=pharmacokinetic; SD=standard deviation; TEAE=treatment-emergent adverse event.

Neulasta is a registered trademark of Amgen Inc.

References: 1. Harbeck N, Lipatov O, Frolova M, et al. Randomized, double-blind study comparing proposed biosimilar LA-EP2006 with reference pegfilgrastim in breast cancer. Future Oncol. 2016;12(11):1359-1367. 2. Blackwell K, Donskih R, Jones MC, et al. A comparison of proposed biosimilar LA-EP2006 and reference pegfilgrastim for the prevention of neutropenia in patients with early-stage breast cancer receiving myelosuppressive adjuvant or neoadjuvant chemotherapy: pegfilgrastim randomized oncology (supportive care) trial to evaluate comparative treatment (PROTECT-2), a phase III, randomized, double-blind trial. Oncologist. 2016;21(7):789-794. 3. Data on file. Investigator's Brochure. Sandoz Inc. June 2018. 4. Data on file. Clinical Study Report of Study LA-EP06-104. Sandoz Inc. February 2019. 5. ZIEXTENZO Prescribing Information. Sandoz Inc. March 2021. 6. Neulasta Prescribing Information. Amgen Inc. March 2021. 7. US Department of Health and Human Services. Scientific Considerations in Demonstrating Biosimilarity to a Reference Product: Guidance for Industry. Washington, DC: US Dept of Health and Human Services; April 2015. 8. US Food and Drug Administration. Presented at: FDA Oncologic Drugs Advisory Committee Meeting; January 7, 2015. 9. Hoy SM. LA-EP2006: a pegfilgrastim biosimilar. BioDrugs. 2019;33(2):229-232. 10. McCamish M, Woollett G. The state of the art in the development of biosimilars. Clin Pharmacol Ther. 2012;91(3):405-417. 11. Vandekerckhove K, Seidl A, Gutka H, et al. Rational selection, criticality assessment, and tiering of quality attributes and test methods for analytical similarity evaluation of biosimilars. AAPS J. 2018;20(4):68. doi:10.1208/s12248-018-0230-9. 12. Data on file. Sandoz Inc. June 2023. 13. Fulphila Prescribing Information. Mylan GmbH. October 2021. 14. UDENYCA Prescribing Information. Coherus BioSciences Inc. March 2023. 15. Waller CF, Ranganna GM, Pennella EJ, et al. Randomized phase 3 efficacy and safety trial of proposed pergfilgrastim biosimilar MYL 1401H in the prophylactic treatment of chemotherapy-induced neutropenia. Ann Hematol. 2019;98(5):1217-1224.

IMPORTANT SAFETY INFORMATION FOR ZIEXTENZO

CONTRAINDICATIONS

ZIEXTENZO is contraindicated in patients with a history of serious allergic reactions to pegfilgrastim or filgrastim.

WARNINGS AND PRECAUTIONS

Splenic Rupture

  • Splenic rupture, including fatal cases, can occur following the administration of pegfilgrastim. Evaluate for an enlarged spleen or splenic rupture in patients who report left upper abdominal or shoulder pain after receiving ZIEXTENZO.

Acute Respiratory Distress Syndrome (ARDS)

  • ARDS can occur in patients receiving pegfilgrastim. Evaluate patients who develop fever and lung infiltrates or respiratory distress after receiving ZIEXTENZO, for ARDS. Discontinue ZIEXTENZO in patients with ARDS.

Serious Allergic Reactions

  • Serious allergic reactions, including anaphylaxis, can occur in patients receiving pegfilgrastim. The majority of events occurred upon initial exposure and can recur within days after the discontinuation of initial anti-allergic treatment. Permanently discontinue ZIEXTENZO in patients with serious allergic reactions. Do not administer ZIEXTENZO to patients with a history of serious allergic reactions to pegfilgrastim or filgrastim.

Use in Patients with Sickle Cell Disorders

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

Glomerulonephritis

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

Leukocytosis

  • White blood cell (WBC) counts of 100 x 109/L or greater have been observed in patients receiving pegfilgrastim. Monitoring of CBC during pegfilgrastim therapy is recommended.

Thrombocytopenia

  • Thrombocytopenia has been reported in patients receiving pegfilgrastim. Monitor platelet counts.

Capillary Leak Syndrome (CLS)

  • CLS has been reported after G-CSF administration, including pegfilgrastim, 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 CLS should be closely monitored and receive standard symptomatic treatment, which may include intensive care.

Potential for Tumor Growth Stimulatory Effects on Malignant Cells

  • The granulocyte colony-stimulating factor (G-CSF) receptor through which pegfilgrastim and filgrastim act has been found on tumor cell lines. The possibility that pegfilgrastim acts as a growth factor for any tumor type, including myeloid malignancies and myelodysplasia, diseases for which pegfilgrastim is not approved, cannot be excluded.

Myelodysplastic Syndrome (MDS) and Acute Myeloid Leukemia (AML) in Patients with Breast and Lung Cancer

  • MDS and AML have been associated with the use of pegfilgrastim 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.

Aortitis

  • Aortitis has been reported in patients receiving pegfilgrastim. 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 ZIEXTENZO if aortitis is suspected.

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.

ADVERSE REACTIONS

The most common adverse reactions are bone pain and pain in extremity.

Please see ZIEXTENZO full Prescribing Information.

IMPORTANT SAFETY INFORMATION FOR ZARXIO

CONTRAINDICATIONS

  • ZARXIO® (filgrastim-sndz) 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. Discontinue ZARXIO if sickle cell crisis occurs.
  • 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.
  • Myelodysplastic Syndrome (MDS) and Acute Myeloid Leukemia (AML):
    • Patients with Severe Chronic Neutropenia: 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. 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 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.
  • 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 for ZARXIO.

INDICATION FOR ZIEXTENZO

ZIEXTENZO is indicated to decrease the incidence of infection, as manifested by febrile neutropenia, in patients with non-myeloid malignancies receiving myelosuppressive anti-cancer drugs associated with a clinically significant incidence of febrile neutropenia.

INDICATIONS FOR ZARXIO

  • 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.

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.