Nypozi Injection
FDA Label NDC 72374-102

NYPOZI 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)].

NYPOZI 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)].

NYPOZI 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)].

NYPOZI is indicated for the mobilization of autologous hematopoietic progenitor cells into the peripheral blood for collection by leukapheresis [see Clinical Studies (14.4)].

NYPOZI 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)].

NYPOZI is indicated to increase survival in patients acutely exposed to myelosuppressive doses of radiation [see Clinical Studies (14.6)].

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

Administer NYPOZI at least 24 hours after cytotoxic chemotherapy. Do not administer NYPOZI 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 filgrastim therapy. Therefore, to ensure a sustained therapeutic response‚ administer NYPOZI 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 NYPOZI therapy needed to attenuate chemotherapy-induced neutropenia may be dependent on the myelosuppressive potential of the chemotherapy regimen employed.

The recommended dosage of NYPOZI 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 NYPOZI 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 NYPOZI against the neutrophil response (see Table 1).

The recommended dosage of NYPOZI for the mobilization of autologous peripheral blood progenitor cells (PBPC) is 10 mcg/kg/day given by subcutaneous injection. Administer NYPOZI for at least 4 days before the first leukapheresis procedure and continue until the last leukapheresis. Although the optimal duration of NYPOZI 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 NYPOZI and discontinue NYPOZI if the white blood cell (WBC) count rises to greater than 100‚000/mm³.

Prior to starting NYPOZI 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 NYPOZI 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 NYPOZI 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.

Subcutaneous Injection

Inject NYPOZI subcutaneously in the outer area of upper arms, abdomen, thighs, or upper outer areas of the buttock. If patients or caregivers are to administer NYPOZI, 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 a healthcare professional 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 for the NYPOZI 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 NYPOZI.

NYPOZI 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 NYPOZI 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.

Dilution

If required for intravenous administration, NYPOZI may be diluted in 5% Dextrose Injection to a concentration of 15 mcg/mL. NYPOZI diluted 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 plus Albumin (Human), NYPOZI is compatible with polyvinylchloride and polyolefin.

Do not dilute with Sodium Chloride Injection at any time, because the product may precipitate.

Diluted NYPOZI solution can be stored at room temperature for up to 14 hours. This 14 hour time period includes the time during room temperature storage of the infusion solution and the duration of the infusion.

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

Patients with Severe Chronic Neutropenia

Confirm the diagnosis of SCN before initiating NYPOZI 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 NYPOZI 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.

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 NYPOZI as an adjunct to myelosuppressive chemotherapy‚ to avoid the potential risks of excessive leukocytosis‚ it is recommended that NYPOZI 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 NYPOZI 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 NYPOZI for PBPC mobilization in patients with cancer, discontinue NYPOZI if the leukocyte count rises to > 100,000/mm³.

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.

Table 2. Adverse Reactions in Patients with Cancer Receiving Myelosuppressive Chemotherapy (With ≥ 5% Higher Incidence in Filgrastim Compared to Placebo)

System Organ Class Preferred Term	Filgrastim (N = 294)	Placebo (N = 157)
Blood and lymphatic system disorders
Thrombocytopenia	38%	29%
Gastrointestinal disorders
Nausea	43%	32%
General disorders and administration site conditions
Pyrexia	48%	29%
Chest pain	13%	6%
Pain	12%	6%
Fatigue	20%	10%
Musculoskeletal and connective tissue disorders
Back pain	15%	8%
Arthralgia	9%	2%
Bone pain	11%	6%
Pain in extremity Percent difference (Filgrastim – Placebo) was 4%.	7%	3%
Nervous system disorders
Dizziness	14%	3%
Respiratory, thoracic and mediastinal disorders
Cough	14%	8%
Dyspnea	13%	8%
Skin and subcutaneous tissue disorders
Rash	14%	5%
Investigations
Blood lactate dehydrogenase increased	6%	1%
Blood alkaline phosphatase increased	6%	1%

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.

Table 3. Adverse Reactions in Patients with Cancer Undergoing Autologous PBPC in the Mobilization Phase (≥ 5% Incidence in Filgrastim Patients)

System Organ Class Preferred Term	Mobilization Phase (N = 166)
Musculoskeletal and connective tissue disorders
Bone pain	30%
General disorders and administration site conditions
Pyrexia	16%
Investigations
Blood alkaline phosphatase increased	11%
Nervous system disorders
Headache	10%

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.

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).

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

Specific Populations

Patients Acutely Exposed to Myelosuppressive Doses of Radiation

The pharmacokinetics of filgrastim products is not available in patients acutely exposed to myelosuppressive doses of radiation. Based on limited pharmacokinetics data in irradiated non-human primates, the area under the time-concentration curve (AUC), reflecting the exposure to filgrastim in non-human primates at 10 mcg/kg dose of filgrastim, appears to be similar to that in humans at 5 mcg/kg. Simulations conducted using the population pharmacokinetic model indicates that the exposures to filgrastim at a filgrastim dose of 10 mcg/kg in patients acutely exposed to myelosuppressive doses of radiation are expected to exceed the exposures at a dose of 10 mcg/kg in irradiated non-human primates.

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, NYPOZI dose adjustment in patients with hepatic impairment is not necessary.

NYPOZI™ (filgrastim-txid)

NYPOZI is a trademark of Tanvex BioPharma USA, Inc.
Manufactured by:
Tanvex BioPharma USA, Inc,
10394 Pacific Center Court
San Diego, CA 92121
US License No. 2259

The recommended dose of NYPOZI is 10 mcg/kg as a single daily subcutaneous injection for patients exposed to myelosuppressive doses of radiation. Administer NYPOZI as soon as possible after suspected or confirmed exposure to radiation doses greater than 2 gray (Gy).

Estimate a patient's absorbed radiation dose (i.e., level of radiation exposure) based on information from public health authorities, biodosimetry if available, or clinical findings such as time to onset of vomiting or lymphocyte depletion kinetics.

Obtain a baseline CBC and then serial CBCs approximately every third day until the ANC remains greater than 1,000/mm³ for 3 consecutive CBCs. Do not delay administration of NYPOZI if a CBC is not readily available.

Continue administration of NYPOZI until the ANC remains greater than 1,000/mm³ for 3 consecutive CBCs or exceeds 10,000/mm³ after a radiation-induced nadir.

NYPOZI is supplied in single-dose prefilled syringes (for subcutaneous or intravenous use) [see Dosage Forms and Strengths (3)]. Prior to use‚ remove the prefilled syringe from the refrigerator and allow NYPOZI to reach room temperature for a minimum of 30 minutes and a maximum of 24 hours. Discard any 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. Do not administer NYPOZI if particulates or discoloration are observed.

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

NYPOZI is a clear, colorless to slightly yellowish, preservative-free solution available as:

Prefilled syringe:

• Injection: 300 mcg/0.5 mL in a single-dose prefilled syringe with BD UltraSafe Passive™ Needle Guard
• Injection: 480 mcg/0.8 mL in a single-dose prefilled syringe with BD UltraSafe Passive™ Needle Guard

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

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) has been reported in patients receiving filgrastim products. Evaluate patients who develop fever and lung infiltrates or respiratory distress for ARDS. Discontinue NYPOZI 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 NYPOZI in patients with serious allergic reactions. NYPOZI is contraindicated in patients with a history of serious allergic reactions to human granulocyte colony-stimulating factors such as filgrastim products or pegfilgrastim products.

Severe and sometimes fatal sickle cell crises can occur, in patients with sickle cell disorders receiving filgrastim products. Discontinue NYPOZI 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 NYPOZI.

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 NYPOZI 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 standard symptomatic treatment, which may include a need for intensive care.

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

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 NYPOZI therapy in patients with cutaneous vasculitis. NYPOZI may be started at a reduced dose when the symptoms resolve and the ANC has decreased.

NYPOZI is a growth factor that primarily stimulates neutrophils. The granulocyte-colony stimulating factor (G-CSF) receptor through which NYPOZI acts has also been found on tumor cell lines. The possibility that NYPOZI 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 NYPOZI 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.

The safety and efficacy of NYPOZI 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 NYPOZI 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 NYPOZI have not been evaluated in patients receiving concurrent radiation therapy. Avoid the simultaneous use of NYPOZI 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. This should be considered when interpreting bone-imaging results.

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 NYPOZI if aortitis is suspected.

The following serious adverse reactions are discussed in greater detail in other sections of the labeling:

• Splenic Rupture [see Warnings and Precautions (5.1)]
• Acute Respiratory Distress Syndrome [see Warnings and Precautions (5.2)]
• Serious Allergic Reactions [see Warnings and Precautions (5.3)]
• Sickle Cell Disorders [see Warnings and Precautions (5.4)]
• Glomerulonephritis [see Warnings and Precautions (5.5)]
• Alveolar Hemorrhage and Hemoptysis [see Warnings and Precautions (5.6)]
• Capillary Leak Syndrome [see Warnings and Precautions (5.7)]
• Myelodysplastic Syndrome [see Warnings and Precautions (5.8)]
• Acute Myeloid Leukemia [see Warnings and Precautions (5.8)]
• Thrombocytopenia [see Warnings and Precautions (5.9)]
• Leukocytosis [see Warnings and Precautions (5.10)]
• Cutaneous Vasculitis [see Warnings and Precautions (5.11)]
• Aortitis [see Warnings and Precautions (5.15)]

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.

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)]
• extramedullary hematopoiesis

NYPOZI 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 – 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 are 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 - 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 products administration is unknown [see Warnings and Precautions (5.7), Adverse Reactions (6)].

The use of filgrastim to increase survival in pediatric patients acutely exposed to myelosuppressive doses of radiation is based on studies of filgrastim conducted in animals and clinical data supporting the use of filgrastim in other approved indications [see Dosage and Administration (2.1 to 2.4) and Clinical Studies (14.6)].

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.

The maximum tolerated dose of filgrastim products has not been determined. In filgrastim clinical trials of patients with cancer receiving myelosuppressive chemotherapy‚ WBC counts > 100‚000/mm³ have been reported in less than 5% of patients‚ but were not associated with any reported adverse clinical effects.

Patients in the BMT studies received up to 138 mcg/kg/day without toxic effects, although there was a flattening of the dose response curve above daily doses of greater than 10 mcg/kg/day.

Filgrastim-txid, a leukocyte growth factor, is a 175 amino acid human granulocyte colony-stimulating factor (G-CSF) manufactured by recombinant DNA technology. Filgrastim-txid is produced by Escherichia coli (E. coli) bacteria into which has been inserted the human granulocyte colony-stimulating factor gene. Filgrastim-txid has a molecular weight of 18‚800 daltons. The protein has an amino acid sequence that is identical to the natural sequence predicted from human DNA sequence analysis‚ except for the addition of an N-terminal methionine necessary for expression in E. coli. Because filgrastim-txid is produced in E. coli‚ the product is non-glycosylated and thus differs from G-CSF isolated from a human cell.

NYPOZI (filgrastim-txid) injection is a sterile‚ clear‚ colorless to slightly yellowish‚ preservative-free liquid containing filgrastim-txid at a specific activity of 1.3 ± 0.3 × 10⁸ IU/mg (as measured by a cell mitogenesis assay). The product is available in single-dose prefilled syringes for subcutaneous or intravenous use. The single-dose prefilled syringes contain either 300 mcg/0.5 mL or 480 mcg/0.8 mL of filgrastim-txid. The pH is 4.0. See table below for product composition of each single-dose prefilled syringe.

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.

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 chemoluminescence) 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.

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 rate of filgrastim was 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%.

The observed incidence of anti-drug antibodies is highly dependent on the sensitivity and specificity of the assay. Differences in assay methods preclude meaningful comparisons of the incidence of anti-drug antibodies in the studies described below with the incidence of anti-drug antibodies in other studies, including those of filgrastim or of other filgrastim products.

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. Because of the low occurrence of anti-drug antibodies, the effect of these antibodies on the pharmacokinetics, pharmacodynamics, safety, and/or effectiveness of filgrastim products is unknown.

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

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.

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.

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 < 1000/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.

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 ≥1000/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).

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 (Study10).

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 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 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).

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).

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 > 1500/mm³
• Partial response: median ANC ≥ 500/mm³ and ≤ 1500/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:

• 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.

Efficacy studies of filgrastim products could not be conducted in humans with acute radiation syndrome for ethical and feasibility reasons. Approval of this indication was based on efficacy studies conducted in animals and data supporting the use of filgrastim for other approved indications [see Dosage and Administration (2.1 to 2.4)].

Because of the uncertainty associated with extrapolating animal efficacy data to humans, the selection of human dose for NYPOZI is aimed at providing exposures to filgrastim that exceed those observed in animal efficacy studies. The 10 mcg/kg daily dose is selected for humans exposed to myelosuppressive doses of radiation because the exposure associated with such a dose is expected to exceed the exposure associated with a 10 mcg/kg dose in non-human primates [see Clinical Pharmacology (12.3)]. The safety of filgrastim at a daily dose of 10 mcg/kg has been assessed on the basis of clinical experience in approved indications.

The efficacy of filgrastim was studied in a randomized, blinded, placebo-controlled study in a non-human primate model of radiation injury. The planned sample size was 62 animals, but the study was stopped at the interim analysis with 46 animals because efficacy was established. Rhesus macaques were randomized to a control (n = 22) or treated (n = 24) group. Animals were exposed to total body irradiation of 7.4 ± 0.15 Gy delivered at 0.8 ± 0.03 Gy/min, representing a dose that would be lethal in 50% of animals by 60 days of follow-up (LD50/60). Starting on day 1 after irradiation, animals received daily subcutaneous injections of placebo (5% dextrose in water) or filgrastim (10 mcg/kg/day). Blinded treatment was stopped when one of the following criteria was met: ANC ≥ 1,000/mm³ for 3 consecutive days, or ANC ≥ 10,000/mm³ for more than 2 consecutive days within study day 1 to 5, or ANC ≥ 10,000/mm³ any time after study day 5. Animals received medical management consisting of intravenous fluids, antibiotics, blood transfusions, and other support as required.

Filgrastim significantly (at 0.023 level of significance) reduced 60-day mortality in the irradiated non-human primates: 21% mortality (5/24) in the filgrastim group compared to 59% mortality (13/22) in the control group.

NYPOZI (filgrastim-txid) injection is a clear, colorless to slightly yellowish, preservative-free solution supplied as prefilled syringes:

Single-dose‚ preservative-free, prefilled syringes with 29 gauge, half inch needle with a BD UltraSafe Passive™ Needle Guard, containing 300 mcg/0.5 mL of filgrastim-txid.

• Carton of 1 prefilled syringe (NDC 72374-101-01)
• Carton of 10 prefilled syringes (NDC 72374-101-10)

Single-dose‚ preservative-free, prefilled syringes with 29 gauge, half inch needle with a BD UltraSafe Passive™ Needle Guard, containing 480 mcg/0.8 mL of filgrastim-txid.

• Carton of 1 prefilled syringe (NDC 72374-102-01)
• Carton of 10 prefilled syringes (NDC 72374-102-10)

Storage:

Store NYPOZI in the refrigerator at 2°C to 8°C (36°F to 46°F) in the original carton to protect from light. Do not leave NYPOZI in direct sunlight. Avoid shaking. Do not freeze. Transport via pneumatic tube has not been studied. Prior to injection‚ NYPOZI may be allowed to reach room temperature for a maximum of 24 hours.

Advise the patient to read the FDA-approved patient labeling (Patient Information and Instructions for Use). Review the steps for direct patient administration with patients and caregivers. Training by the healthcare provider should aim to ensure that patients and caregivers can successfully perform all of the steps in the Instructions for Use of NYPOZI prefilled syringe with BD UltraSafe Passive™ Needle Guard, including showing the patient or caregiver how to measure the required dose, particularly if a patient is on a dose other than the entire 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 NYPOZI.

Advise patients of the following risks and potential risks with NYPOZI:

• Rupture or enlargement of the spleen may occur. Symptoms include left upper quadrant abdominal pain or left shoulder pain. Advise patients to report pain in these areas to their physician immediately [see Warnings and Precautions (5.1)].
• Dyspnea, with or without fever, progressing to Acute Respiratory Distress Syndrome, may occur. Advise patients to report dyspnea to their physician immediately [see Warnings and Precautions (5.2)].
• Serious allergic reactions may occur, which may be signaled by rash‚ facial edema‚ wheezing‚ dyspnea‚ hypotension‚ or tachycardia. Advise patient to seek immediate medical attention if signs or symptoms of hypersensitivity reaction occur [see Warnings and Precautions (5.3)].
• In patients with sickle cell disease, sickle cell crisis and death have occurred. Discuss potential risks and benefits for patients with sickle cell disease prior to the administration of human granulocyte colony-stimulating factors [see Warnings and Precautions (5.4)].
• Glomerulonephritis may occur. Symptoms include swelling of the face or ankles, dark colored urine or blood in the urine, or a decrease in urine production. Advise patients to report signs or symptoms of glomerulonephritis to their physician immediately [see Warnings and Precautions (5.5)].
• There may be an increased risk of Myelodysplastic Syndrome and/or Acute Myeloid Leukemia in patients with congenital neutropenia who receive filgrastim products and in patients with breast and lung cancer who receive filgrastim products in conjunction with chemotherapy and/or radiation therapy. Symptoms of MDS and AML may include tiredness, fever, and easy bruising or bleeding. Advise patients to report to their physician signs and symptoms of MDS/AML [see Warnings and Precautions (5.8)].
• Cutaneous vasculitis may occur, which may be signaled by purpura or erythema. Advise patients to report signs or symptoms of vasculitis to their physician immediately [see Warnings and Precautions (5.11)].
• Aortitis may occur. Symptoms may include fever, abdominal pain, malaise, back pain, and increased inflammatory markers. Advise patients to report signs and symptoms of aortitis to their physician immediately [see Warnings and Precautions (5.15)].

Advise patients acutely exposed to myelosuppressive doses of radiation (Hematopoietic Syndrome of Acute Radiation Syndrome) that efficacy studies of filgrastim products for this indication could not be conducted in humans for ethical and feasibility reasons and that, therefore, approval of this use was based on efficacy studies conducted in animals [see Clinical Studies (14.6)].

Instruct patients who self-administer NYPOZI using the prefilled syringes of the:

• Importance of following the applicable Instructions for Use.
• Dangers of reusing needles or syringes.
• Importance of following local requirements for proper disposal of used syringes and needles.
• Importance of informing the healthcare provider if difficulty occurs when measuring or administering partial contents of the NYPOZI prefilled syringe.

Guide to Parts

Image (Nypozi 01)

Important: The needle is covered by the gray needle cap before use.

Important

Read the Patient Information for important information you need to know about NYPOZI before using these Instructions for Use.

Before you use a NYPOZI prefilled syringe, read this important information.

Storing your NYPOZI prefilled syringe

• Store the NYPOZI prefilled syringe in the refrigerator between 36°F to 46°F (2°C to 8°C).
• Do not freeze NYPOZI prefilled syringes.
• Keep the prefilled syringe in the original carton to protect it from light or physical damage.
• Take the prefilled syringe out of the refrigerator 30 minutes before use and allow it to reach room temperature before preparing an injection.
• Throw away (dispose of) any prefilled syringe that has been left at room temperature for longer than 24 hours.
• After you inject your dose, throw away (dispose of) any unused NYPOZI left in the prefilled syringe. Do not save unused NYPOZI in the prefilled syringe for later use.
• Keep the NYPOZI prefilled syringe out of the reach of children.

Using your prefilled syringe

• It is important that you do not try to give the injection unless you or your caregiver has received training from your healthcare provider.
• Make sure the name NYPOZI appears on the carton and prefilled syringe label.
• Do not inject a dose of NYPOZI less than 0.3 mL (180 mcg) from a NYPOZI prefilled syringe. A dose less than 0.3 mL cannot be accurately measured using the NYPOZI prefilled syringe.
• Do not use a prefilled syringe after the expiration date on the label.
• Do not shake the prefilled syringe.
• Do not remove the gray needle cap from the prefilled syringe until you are ready to inject.
• Do not use the prefilled syringe if the carton is open or damaged.
• Do not use a prefilled syringe if it has been dropped on a hard surface. The prefilled syringe may be broken even if you cannot see the break. Use a new prefilled syringe.
• The prefilled syringe has a needle guard that will be activated to cover the needle after the injection is given. The needle guard will help prevent needle stick injuries to anyone who handles the prefilled syringe.
• Avoid touching the syringe needle guard wings before use. Touching them may cause the syringe needle guard to be activated too early. Use another prefilled syringe that has not been activated and is ready to use.

Call your healthcare provider if you have any questions.

Step 1: Prepare

A Remove the prefilled syringe carton from the refrigerator.

Put the original carton with any unused prefilled syringes back in the refrigerator.

Remove the syringe blister pack from the carton. On a clean, well-lit, flat surface, place the syringe blister pack at room temperature for 30 minutes before you give an injection.

• Do not use the prefilled syringe if the carton is damaged.
• Do not try to warm the prefilled syringe by using a heat source such as hot water or microwave.
• Keep the prefilled syringe in the blister pack until you are ready to use it.
• Do not leave the prefilled syringe in direct sunlight.
• Do not shake the prefilled syringe.

Open the blister pack by peeling away the cover. Grab the transparent needle guard to remove the prefilled syringe from the blister pack.



Image (Nypozi 02)

For safety reasons:

• Do not grab the plunger rod.
• Do not grab the gray needle cap.

B Inspect the medicine and prefilled syringe.



Image (Nypozi 03)

Turn the prefilled syringe so you can see through the viewing window and dose markings. Make sure the medicine in the prefilled syringe is clear and colorless to slightly yellowish.

Check to make sure that the plastic transparent needle guard is covering the barrel of the glass syringe. If the transparent needle guard is covering the gray needle cap (shown below), the needle guard has already been activated. Do not use the prefilled syringe if the needle guard has been activated.



Image (Nypozi 04)

Syringe with Activated Needle Guard
• Do not use the prefilled syringe if:
  • The medicine is cloudy or discolored or contains flakes or particles.
  • Any part appears cracked or broken.
  • The prefilled syringe has been dropped.
  • The gray needle cap is missing or not securely attached.
  • The expiration date printed on the label has passed.
  • In all cases, use a new prefilled syringe and call your healthcare provider.

  C Gather all materials needed for injection.

  Wash your hands thoroughly with soap and water.

  On a clean, well-lit work surface, place the:

  • Prefilled syringe, and the following items, that are not included in the NYPOZI carton
  • Alcohol wipe
  • Cotton ball or gauze pad
  • Adhesive bandage
  • Sharps disposal container or other appropriate disposal container
  

  Image (Nypozi 05)

  Step 2: Get ready

  D Prepare and clean your injection site

  

  Image (Nypozi 06)

  You can use:

  • Thigh
  • Stomach area (abdomen), except for a 2-inch area right around your navel (belly button)
  • Upper outer area of your buttocks (only if someone else is giving you the injection)
  • Outer area of upper arm (only if someone else is giving you the injection)

  Clean your injection site with an alcohol wipe.

  • Let your skin dry.
  • Do not touch this cleansed area again before injecting.

  If you want to use the same injection site, make sure it is not the same spot on the injection site area you used for a previous injection.

  • Do not inject into areas where the skin is tender, bruised, red, scaly or hard. Avoid injecting into areas with scars or stretch marks.

  E Hold the prefilled syringe by the syringe barrel (the clear plastic needle guard) with the needle pointing up. Carefully pull the gray needle cap straight off and away from your body.

  

  Image (Nypozi 07)

  • Do not remove the gray needle cap from the prefilled syringe until you are ready to inject.
  • Do not twist or bend the gray needle cap.
  • Do not hold the prefilled syringe by the plunger rod.
  • Do not put the gray needle cap back onto the prefilled syringe.

  Important: Throw away the gray needle cap into the sharps or other appropriate disposal container.

  F  

  

  Image (Nypozi 08)

    Check your prescription before you inject your dose

  Your healthcare provider has prescribed either a "full" syringe dose or a "partial" syringe dose of NYPOZI.

  • If you are prescribed a full dose, you will inject all of the medicine from your prefilled syringe. For a full dose, go directly to Step 3: Subcutaneous (under the skin) injection.
  • If you are prescribed a partial dose of NYPOZI, start with Step G below.

  G Check the syringe for an air bubble. Point the needle up and gently tap the syringe with your fingers until the air bubble rises to the top of the syringe.

  

  Image (Nypozi 09)

  H Hold the syringe as shown below and press slowly on the plunger to push out the excess medicine until the top edge of the conical base of the plunger stopper lines up with the syringe marking for your prescribed dose. As you push the plunger rod up, air and extra medication is removed. Check to make sure the plunger lines up with the syringe markings for your prescribed dose. If you remove too much medicine, get a new prefilled syringe and start again at Step 1.

  • See the figure below (Step 2) for an example of a dose of 0.4 mL. Your dose may be different than the example shown.
  • Call your healthcare provider if you have problems measuring your prescribed dose.
  

  Image (Nypozi 10)

  Step 3: Subcutaneous (under the skin) injection

  I With one hand gently pinch the skin at the injection site to create a firm surface.

  

  Image (Nypozi 11)

  Important: Keep the skin pinched while injecting.

  J Hold the pinch. With your other hand insert the needle into the skin at a 45 to 90 degree angle as shown.

  

  Image (Nypozi 12)

  K Using slow and constant pressure, slowly press down on the plunger rod as far as it will go so that the plunger head is completely between the needle guard wings.

  

  Image (Nypozi 13)

  • Do not pull back the plunger rod while the needle is inserted.

  When done, keep the plunger fully pressed down while you carefully pull the needle straight out from the injection site.

  

  Image (Nypozi 14)

  Important: When you remove the syringe, if it looks like the medicine is still in the syringe barrel, this means you have not received a full dose. Call your healthcare provider right away.

  Step 4: Finish

  L  

  

  Image (Nypozi 15)

    Before you finish!

  Slowly release the plunger and allow the needle guard to automatically cover the exposed needle.

  Keep your hands away from the needle at all times.

  

  Image (Nypozi 16)

  M Discard (throw away) your used prefilled syringe.

  

  Image (Nypozi 17)

  • Put the used prefilled syringe in a FDA-cleared sharps or other appropriate disposal container right away after use. Do not throw away (dispose of) your NYPOZI prefilled syringe in your household trash.
  • If you do not have a FDA-cleared sharps disposal container, you may use a household container that is:
    • made of a heavy-duty plastic,
    • can be closed with a tight-fitting, puncture-resistant lid, without sharps being able to come out,
    • upright and stable during use,
    • leak-resistant, and
    • properly labeled to warn of hazardous waste inside the container.
    • When your sharps disposal container is almost full, you will need to follow your community guidelines for the right way to dispose of your sharps disposal container. There may be state or local laws about how you should throw away used needles, syringes, and prefilled syringes. For more information about safe sharps disposal, and for specific information about sharps disposal in the state that you live in, go to the FDA's website at: http://www.fda.gov/safesharpsdisposal.
    • Do not reuse the prefilled syringe.
    • Do not recycle the prefilled syringe or sharps disposal container or throw them into household trash.

    Important: Always keep the sharps disposal container out of the reach of children.

    N Examine the injection site.

    If there is blood, press a cotton ball or gauze pad on your injection site. Do not rub the injection site. Apply an adhesive bandage if needed.

    tanvex
    NYPOZI™
    (filgrastim-txid) Injection

    Manufactured by:
    Tanvex BioPharma USA, Inc., San Diego, CA 92121
    Product of USA
    US License No. 2259

    This Instructions for Use has been approved by the U.S. Food and Drug Administration.
    Issued: June 2024

1 x 300 mcg/0.5 mL Single-Dose Prefilled Syringe with a Needle Guard

NDC 72374-101-01

Rx Only

NYPOZI™
(filgrastim-txid) injection

300 mcg/0.5 mL

A Recombinant Granulocyte Colony Stimulating Factor (rG-CSF) derived from E. Coli
For Subcutaneous Use or Intravenous Use Only

If required for intravenous administration, dilute in 5% Dextrose Injection
to a concentration of 15 mcg/mL. To protect from adsorption to plastic
materials, add Albumin (Human) to a final concentration of 2 mg/mL.

Single-Dose Prefilled Syringe. Discard Unused Portion.

tanvex

Principal Display Panel ((1) 0.5 mL Syringe Carton)

10 x 300 mcg/0.5 mL Single-Dose Prefilled Syringes with a Needle Guard

NDC 72374-101-10

Rx Only

NYPOZI™
(filgrastim-txid) injection

300 mcg/0.5 mL

A Recombinant Granulocyte Colony Stimulating Factor (rG-CSF) derived from E. Coli
For Subcutaneous Use or Intravenous Use Only

If required for intravenous administration, dilute in 5% Dextrose Injection to a
concentration of 15 mcg/mL. To protect from adsorption to plastic materials,
add Albumin (Human) to a final concentration of 2 mg/mL.

Single-Dose Prefilled Syringe. Discard Unused Portion.

Manufactured by:
Tanvex BioPharma USA, Inc., San Diego, CA 92121 USA
U.S. License No. 2259

tanvex

Principal Display Panel ((10) 0.5 mL Syringe Carton)

1 x 480 mcg/0.8 mL Single-Dose Prefilled Syringe with a Needle Guard

NDC 72374-102-01

Rx Only

NYPOZI™
(filgrastim-txid) injection

480 mcg/0.8 mL

A Recombinant Granulocyte Colony Stimulating Factor (rG-CSF) derived from E. Coli
For Subcutaneous Use or Intravenous Use Only

If required for intravenous administration, dilute in 5% Dextrose Injection
to a concentration of 15 mcg/mL. To protect from adsorption to plastic
materials, add Albumin (Human) to a final concentration of 2 mg/mL.

Single-Dose Prefilled Syringe. Discard Unused Portion.

tanvex

Principal Display Panel ((1) 0.5 mL Syringe Carton)

10 x 480 mcg/0.8 mL Single-Dose Prefilled Syringes with a Needle Guard

NDC 72374-102-10

Rx Only

NYPOZI™
(filgrastim-txid) injection

480 mcg/0.8 mL

A Recombinant Granulocyte Colony Stimulating Factor (rG-CSF) derived from E. Coli
For Subcutaneous Use or Intravenous Use Only

If required for intravenous administration, dilute in 5% Dextrose Injection to a
concentration of 15 mcg/mL. To protect from adsorption to plastic materials,
add Albumin (Human) to a final concentration of 2 mg/mL.

Single-Dose Prefilled Syringe. Discard Unused Portion.

Manufactured by:
Tanvex BioPharma USA, Inc., San Diego, CA 92121 USA
U.S. License No. 2259

tanvex

Principal Display Panel ((10) 0.5 mL Syringe Carton)