Nivestym

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 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)]

  .
  )
• •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 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)]

  .
  )
• •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 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)].
  )
• •Mobilize autologous hematopoietic progenitor cells into the peripheral blood for collection by leukapheresis. (
  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)]

  .
  )
• •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 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)]

  .
  )

• •Patients with cancer receiving myelosuppressive chemotherapy or induction and/or consolidation chemotherapy for AML.
  • oRecommended 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 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/mm³

    [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/mm³following 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.
    )
• •Patients with cancer undergoing bone marrow transplantation.
  • o10 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 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/mm3for 3 consecutive days	Reduce to 5 mcg/kg/dayIf ANC decreases to less than 1,000/mm3at 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/mm3for 3 more consecutive days	Discontinue NIVESTYM
    Then, if ANC decreases to less than 1,000/mm3	Resume at 5 mcg/kg/day
    )
• •Patients undergoing autologous peripheral blood progenitor cell collection and therapy.
  • o10 mcg/kg/day subcutaneous injection. (
    2.3 Dosage in Patients Undergoing Autologous Peripheral Blood Progenitor Cell Collection and Therapy

    The recommended dosage of NIVESTYM for the mobilization of autologous peripheral blood progenitor cells (PBPC) is 10 mcg/kg/day given by subcutaneous injection. Administer NIVESTYM for at least 4 days before the first leukapheresis procedure and continue until the last leukapheresis. Although the optimal duration of NIVESTYM 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 NIVESTYM‚ and discontinue NIVESTYM if the white blood cell (WBC) count rises to greater than 100‚000/mm³.
    )
  • oAdminister for at least 4 days before first leukapheresis procedure and continue until last leukapheresis. (
    2.3 Dosage in Patients Undergoing Autologous Peripheral Blood Progenitor Cell Collection and Therapy

    The recommended dosage of NIVESTYM for the mobilization of autologous peripheral blood progenitor cells (PBPC) is 10 mcg/kg/day given by subcutaneous injection. Administer NIVESTYM for at least 4 days before the first leukapheresis procedure and continue until the last leukapheresis. Although the optimal duration of NIVESTYM 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 NIVESTYM‚ and discontinue NIVESTYM if the white blood cell (WBC) count rises to greater than 100‚000/mm³.
    )
• •Patients with congenital neutropenia.
  • oRecommended starting dose is 6 mcg/kg subcutaneous injection twice daily. (
    2.4 Dosage in Patients with Severe Chronic Neutropenia

    Prior to starting NIVESTYM 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 NIVESTYM 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 NIVESTYM 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.
    )
• •Patients with cyclic or idiopathic neutropenia.
  • oRecommended starting dose is 5 mcg/kg subcutaneous injection daily. (
    2.4 Dosage in Patients with Severe Chronic Neutropenia

    Prior to starting NIVESTYM 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 NIVESTYM 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 NIVESTYM 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.
    )
• •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 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 NIVESTYM prefilled syringe with BD UltraSafe Plus™ 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 NIVESTYM

  [see Instructions for Use]

  .

  NIVESTYM prefilled syringe with BD UltraSafe Plus™ 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 NIVESTYM less than 0.3 mL (180 mcg) for direct administration. 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. For direct administration of doses less than 0.3 mL (180 mcg) use NIVESTYM single-dose vial.

  NIVESTYM is supplied in single-dose vials (for subcutaneous use or intravenous infusion) and single-dose prefilled syringes (for subcutaneous use)

  [see Dosage Forms and Strengths (3)]

  . Prior to use‚ remove the vial or prefilled syringe from the refrigerator and allow NIVESTYM to reach room temperature for a minimum of 30 minutes. If not used immediately, the vial or prefilled syringe may be stored at room temperature [between 20°C to 25°C (68°F to 77°F)] for up to 24 hours. Discard any vial or prefilled syringe left at room temperature for greater than 24 hours. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit (the solution is clear and colorless). Do not administer NIVESTYM if particulates or discoloration are observed.

  Discard unused portion of NIVESTYM in vials or prefilled syringes; do not re-enter the vial. Do not save unused drug for later administration.

  Subcutaneous Injection

  Inject NIVESTYM subcutaneously in the outer area of upper arms, abdomen, thighs, or upper outer areas of the buttock. If patients or caregivers are to administer NIVESTYM, instruct them in appropriate injection technique and ask them to follow the subcutaneous injection procedures in the Instructions for Use for the vial or 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 NIVESTYM, and the focus should be on ensuring that a patient or caregiver can successfully perform all of the steps in the Instructions for Use for the vial or 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 NIVESTYM or whether the patient would benefit from a different NIVESTYM presentation. If a patient or caregiver experiences difficulty measuring the required dose, especially if it is other than the entire contents of the NIVESTYM prefilled syringe, use of the NIVESTYM vial may be considered.

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

  Administration Instructions for the Prefilled Syringe

  The NIVESTYM syringe plunger stopper and needle cover are not made with natural rubber latex.

  Administration Instructions for Dilution (Vial Only)

  If required for intravenous administration‚ NIVESTYM (vial only) may be diluted in 5% Dextrose Injection, USP from a concentration of 300 mcg/mL to 5 mcg/mL (do not dilute to a final concentration less than 5 mcg/mL). NIVESTYM 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)‚ NIVESTYM is compatible with glass bottles‚ polyvinyl chloride (PVC) and polyolefin intravenous bags‚ and polypropylene syringes.

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

  Diluted NIVESTYM 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.
  )

• •Injection: 300 mcg/mL in a single-dose vial (
  3 DOSAGE FORMS AND STRENGTHS

  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

  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
  )
• •Injection: 480 mcg/1.6 mL (300 mcg/mL) in a single-dose vial (
  3 DOSAGE FORMS AND STRENGTHS

  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

  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
  )

• •Injection: 300 mcg/0.5 mL in a single-dose prefilled syringe (
  3 DOSAGE FORMS AND STRENGTHS

  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

  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
  )
• •Injection: 480 mcg/0.8 mL in a single-dose prefilled syringe (
  3 DOSAGE FORMS AND STRENGTHS

  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

  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
  )

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

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.

• •Fatal splenic rupture: Evaluate patients who report left upper abdominal or shoulder pain for an enlarged spleen or splenic rupture. (
  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.
  )
• •Acute respiratory distress syndrome (ARDS): Evaluate patients who develop fever and lung infiltrates or respiratory distress for ARDS.
• •Discontinue NIVESTYM in patients with ARDS. (
  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 NIVESTYM in patients with ARDS.
  )
• •Serious allergic reactions, including anaphylaxis: Permanently discontinue NIVESTYM in patients with serious allergic reactions. (
  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 NIVESTYM in patients with serious allergic reactions. 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.
  )
• •Fatal sickle cell crises: Discontinue NIVESTYM if sickle cell crisis occurs. (
  5.4 Sickle Cell Disorders

  Severe and sometimes fatal sickle cell crises can occur in patients with sickle cell disorders receiving filgrastim products. Discontinue NIVESTYM if sickle cell crisis occurs.
  )
• •Glomerulonephritis: Evaluate and consider dose-reduction or interruption of NIVESTYM if causality is likely. (
  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 NIVESTYM.
  )
• •Myelodysplastic Syndrome (MDS) and Acute Myeloid Leukemia (AML): Monitor patients with breast and lung cancer using NIVESTYM in conjunction with chemotherapy and/or radiotherapy for signs and symptoms of MDS/AML. (
  5.8 Myelodysplastic Syndrome (MDS) and Acute Myeloid Leukemia (AML)

  Patients with Severe Chronic Neutropenia

  Confirm the diagnosis of SCN before initiating NIVESTYM 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 NIVESTYM 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.
  )
• •Thrombocytopenia: Monitor platelet counts. (
  5.9 Thrombocytopenia

  Thrombocytopenia has been reported in patients receiving filgrastim products. Monitor platelet counts.
  )
• •Aortitis: Aortitis has been reported in patients receiving NIVESTYM. Discontinue NIVESTYM if aortitis is suspected. (
  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 NIVESTYM if aortitis is suspected.
  )