NYVEPRIA- pegfilgrastim-apgf injection, solution

United States - English - NLM (National Library of Medicine)

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Active ingredient:
PEGFILGRASTIM (UNII: 3A58010674) (PEGFILGRASTIM - UNII:3A58010674)
Available from:
Pfizer Laboratories Div Pfizer Inc
Administration route:
SUBCUTANEOUS
Prescription type:
PRESCRIPTION DRUG
Therapeutic indications:
NYVEPRIA is indicated to decrease the incidence of infection, as manifested by febrile neutropenia, in patients with non-myeloid malignancies receiving myelosuppressive anti-cancer drugs associated with a clinically significant incidence of febrile neutropenia [see Clinical Studies (14)] . Limitations of Use NYVEPRIA is not indicated for the mobilization of peripheral blood progenitor cells for hematopoietic stem cell transplantation. NYVEPRIA is contraindicated in patients with a history of serious allergic reactions to pegfilgrastim products or filgrastim products. Reactions have included anaphylaxis [see Warnings and Precautions (5.3)] . Risk Summary Although available data with NYVEPRIA or pegfilgrastim product use in pregnant women are insufficient to establish whether there is a drug associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes, there are available data from published studies in pregnant women exposed to filgrastim products. These studies have not establishe
Product summary:
NYVEPRIA (pegfilgrastim-apgf) injection is a clear, colorless solution supplied in a prefilled single-dose syringe for manual use containing 6 mg pegfilgrastim-apgf, supplied with a 27-gauge 1/2-inch needle and a BD UltraSafe Plus™ Passive Needle Guard. The NYVEPRIA syringe plunger stopper and needle cover are not made with natural rubber latex. NYVEPRIA is provided in a dispensing pack containing one sterile 6 mg/0.6 mL prefilled syringe (NDC 0069-0324-01). NYVEPRIA prefilled syringe does not bear graduation marks and is intended only to deliver the entire contents of the syringe (6 mg/0.6 mL) for direct administration. Use of the prefilled syringe is not recommended for direct administration for pediatric patients weighing less than 45 kg who require doses that are less than the full contents of the syringe. Store refrigerated between 36°F to 46°F (2°C to 8°C) in the carton to protect from light. Do not shake. Discard syringes stored at room temperature for more than 15 days. Avoid freezing; if frozen, thaw in the refrigerator before administration. Discard syringe if frozen more than once.
Authorization status:
Biologic Licensing Application
Authorization number:
0069-0324-01

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NYVEPRIA- pegfilgrastim-apgf injection, solution

Pfizer Laboratories Div Pfizer Inc

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HIGHLIGHTS OF PRESCRIBING INFORMATION

These highlights do not include all the information needed to use NYVEPRIA safely and

effectively. See full prescribing information for NYVEPRIA.

NYVEPRIA™ (pegfilgrastim-apgf) injection, for subcutaneous use

Initial U.S. Approval: 2020

NYVEPRIA (pegfilgrastim-apgf) is biosimilar* to NEULASTA (pegfilgrastim)

RECENT MAJOR CHANGES

Warnings and Precautions, Thrombocytopenia (5.7)

04/2021

Warnings and Precautions, Myelodysplastic Syndrome (MDS) and Acute Myeloid

Leukemia (AML) (5.10)

04/2021

INDICATIONS AND USAGE

NYVEPRIA is a leukocyte growth factor indicated to decrease the incidence of infection, as manifested by

febrile neutropenia, in patients with non-myeloid malignancies receiving myelosuppressive anti-cancer

drugs associated with a clinically significant incidence of febrile neutropenia. (1)

Limitations of Use

NYVEPRIA is not indicated for the mobilization of peripheral blood progenitor cells for hematopoietic stem

cell transplantation. (1)

DOSAGE AND ADMINISTRATION

Patients with cancer receiving myelosuppressive chemotherapy

6 mg administered subcutaneously once per chemotherapy cycle. (2.1)

Do not administer between 14 days before and 24 hours after administration of cytotoxic

chemotherapy. (2.1)

Use weight based dosing for pediatric patients weighing less than 45 kg; refer to Table 1. (2.2)

DOSAGE FORMS AND STRENGTHS

Injection: 6 mg/0.6 mL solution in a single-dose prefilled syringe for manual use only. (3)

CONTRAINDICATIONS

Patients with a history of serious allergic reactions to human granulocyte colony-stimulating factors such

as pegfilgrastim products or filgrastim products. (4)

WARNINGS AND PRECAUTIONS

Fatal splenic rupture: Evaluate patients who report left upper abdominal or shoulder pain for an

enlarged spleen or splenic rupture. (5.1)

Acute respiratory distress syndrome (ARDS): Evaluate patients who develop fever, lung infiltrates, or

respiratory distress. Discontinue NYVEPRIA in patients with ARDS. (5.2)

Serious allergic reactions, including anaphylaxis: Permanently discontinue NYVEPRIA in patients with

serious allergic reactions. (5.3)

Fatal sickle cell crises: Discontinue NYVEPRIA if sickle cell crisis occurs. (5.4)

Glomerulonephritis: Evaluate and consider dose-reduction or interruption of NYVEPRIA if causality is

likely. (5.5)

Thrombocytopenia: Monitor platelet counts. (5.7)

Myelodysplastic Syndrome (MDS) and Acute Myeloid Leukemia (AML): Monitor patients with breast and

lung cancer using NYVEPRIA in conjunction with chemotherapy and/or radiotherapy for signs and

symptoms of MDS/AML. (5.10)

ADVERSE REACTIONS

Most common adverse reactions (≥5% difference in incidence compared to placebo) are bone pain and

pain in extremity. (6.1)

To report SUSPECTED ADVERSE REACTIONS, contact Pfizer Inc. at 1-800-438-1985 or FDA at

To report SUSPECTED ADVERSE REACTIONS, contact Pfizer Inc. at 1-800-438-1985 or FDA at

1-800-FDA-1088 or www.fda.gov/medwatch.

*Biosimilar means that the biological product is approved based on data demonstrating that it is highly

similar to an FDA-approved biological product, known as a reference product, and that there are no

clinically meaningful differences between the biosimilar product and the reference product.

Biosimilarity of NYVEPRIA has been demonstrated for the condition(s) of use (e.g., indication(s), dosing

regimen(s)), strength(s), dosage form(s), and route(s) of administration described in its Full Prescribing

Information.

See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling.

Revised: 4/2021

FULL PRESCRIBING INFORMATION: CONTENTS*

1 INDICATIONS AND USAGE

2 DOSAGE AND ADMINISTRATION

2.1 Patients with Cancer Receiving Myelosuppressive Chemotherapy

2.2 Administration

3 DOSAGE FORMS AND STRENGTHS

4 CONTRAINDICATIONS

5 WARNINGS AND PRECAUTIONS

5.1 Splenic Rupture

5.2 Acute Respiratory Distress Syndrome

5.3 Serious Allergic Reactions

5.4 Use in Patients with Sickle Cell Disorders

5.5 Glomerulonephritis

5.6 Leukocytosis

5.7 Thrombocytopenia

5.8 Capillary Leak Syndrome

5.9 Potential for Tumor Growth Stimulatory Effects on Malignant Cells

5.10 Myelodysplastic Syndrome (MDS) and Acute Myeloid Leukemia (AML) in Patients

with Breast and Lung Cancer

5.11 Aortitis

5.12 Nuclear Imaging

6 ADVERSE REACTIONS

6.1 Clinical Trials Experience

6.2 Immunogenicity

6.3 Postmarketing Experience

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

8.2 Lactation

8.4 Pediatric Use

8.5 Geriatric Use

10 OVERDOSAGE

11 DESCRIPTION

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

12.2 Pharmacodynamics

12.3 Pharmacokinetics

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

14 CLINICAL STUDIES

16 HOW SUPPLIED/STORAGE AND HANDLING

17 PATIENT COUNSELING INFORMATION

FULL PRESCRIBING INFORMATION

1 INDICATIONS AND USAGE

NYVEPRIA is indicated to decrease the incidence of infection, as manifested by febrile

neutropenia, in patients with non-myeloid malignancies receiving myelosuppressive anti-

cancer drugs associated with a clinically significant incidence of febrile neutropenia [see

Clinical Studies (14)].

Limitations of Use

NYVEPRIA is not indicated for the mobilization of peripheral blood progenitor cells for

hematopoietic stem cell transplantation.

2 DOSAGE AND ADMINISTRATION

2.1 Patients with Cancer Receiving Myelosuppressive Chemotherapy

The recommended dosage of NYVEPRIA is a single subcutaneous injection of 6 mg

administered once per chemotherapy cycle. For dosing in pediatric patients weighing

less than 45 kg, refer to Table 1. Do not administer NYVEPRIA between 14 days before

and 24 hours after administration of cytotoxic chemotherapy.

2.2 Administration

NYVEPRIA is administered subcutaneously via a single-dose prefilled syringe for manual

use.

Prior to use‚ remove the carton from the refrigerator and allow the NYVEPRIA prefilled

syringe to reach room temperature for a minimum of 30 minutes. Discard any prefilled

syringe left at room temperature for greater than 15 days.

Parenteral drug products should be inspected visually for particulate matter and

discoloration prior to administration, whenever solution and container permit. NYVEPRIA

is supplied as a clear and colorless solution. Do not administer NYVEPRIA if discoloration

or particulates are observed.

The NYVEPRIA syringe plunger stopper and needle cover are not made with natural

rubber latex.

Pediatric Patients Weighing Less than 45 kg

The NYVEPRIA prefilled syringe is not designed to allow for direct administration of doses

less than 0.6 mL (6 mg). The syringe does not bear graduation marks, which are

Sections or subsections omitted from the full prescribing information are not listed.

necessary to accurately measure doses of NYVEPRIA less than 0.6 mL (6 mg) for direct

administration to patients. Thus, the direct administration to patients requiring dosing of

less than 0.6 mL (6 mg) is not recommended due to the potential for dosing errors.

Refer to Table 1.

Table 1. Dosing of NYVEPRIA for Pediatric Patients Weighing Less than 45 kg

Body Weight

NYVEPRIA Dose

Volume to Administer

Less than 10 kg

See below

See below

10 – 20 kg

1.5 mg

0.15 mL

21 – 30 kg

2.5 mg

0.25 mL

31 – 44 kg

4 mg

0.4 mL

3 DOSAGE FORMS AND STRENGTHS

NYVEPRIA is a clear, colorless, preservative-free solution available as:

Injection: 6 mg/0.6 mL in a single-dose prefilled syringe for manual use only.

4 CONTRAINDICATIONS

NYVEPRIA is contraindicated in patients with a history of serious allergic reactions to

pegfilgrastim products or filgrastim products. Reactions have included anaphylaxis [see

Warnings and Precautions (5.3)].

5 WARNINGS AND PRECAUTIONS

5.1 Splenic Rupture

Splenic rupture, including fatal cases, can occur following the administration of

pegfilgrastim products. Evaluate for an enlarged spleen or splenic rupture in patients

who report left upper abdominal or shoulder pain after receiving NYVEPRIA.

5.2 Acute Respiratory Distress Syndrome

Acute respiratory distress syndrome (ARDS) can occur in patients receiving

pegfilgrastim products. Evaluate patients who develop fever and lung infiltrates or

respiratory distress after receiving NYVEPRIA, for ARDS. Discontinue NYVEPRIA in

patients with ARDS.

5.3 Serious Allergic Reactions

Serious allergic reactions, including anaphylaxis, can occur in patients receiving

pegfilgrastim products. The majority of reported events occurred upon initial exposure.

Allergic reactions, including anaphylaxis, can recur within days after the discontinuation

of initial anti-allergic treatment. Permanently discontinue NYVEPRIA in patients with

serious allergic reactions. Do not administer NYVEPRIA to patients with a history of

serious allergic reactions to pegfilgrastim products or filgrastim products.

For pediatric patients weighing less than 10 kg, administer 0.1 mg/kg (0.01 mL/kg) of NYVEPRIA.

5.4 Use in Patients with Sickle Cell Disorders

Severe and sometimes fatal sickle cell crises can occur in patients with sickle cell

disorders receiving pegfilgrastim products. Discontinue NYVEPRIA if sickle cell crisis

occurs.

5.5 Glomerulonephritis

Glomerulonephritis has occurred in patients receiving pegfilgrastim 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 pegfilgrastim products. If glomerulonephritis is

suspected, evaluate for cause. If causality is likely, consider dose-reduction or

interruption of NYVEPRIA.

5.6 Leukocytosis

White blood cell (WBC) counts of 100 × 10 /L or greater have been observed in patients

receiving pegfilgrastim products. Monitoring of complete blood count (CBC) during

NYVEPRIA therapy is recommended.

5.7 Thrombocytopenia

Thrombocytopenia has been reported in patients receiving pegfilgrastim products.

Monitor platelet counts.

5.8 Capillary Leak Syndrome

Capillary leak syndrome has been reported after G-CSF administration, including

pegfilgrastim products, and is characterized by hypotension, hypoalbuminemia, edema

and hemoconcentration. Episodes vary in frequency, severity and may be life-

threatening if treatment is delayed. Patients who develop symptoms of capillary leak

syndrome should be closely monitored and receive standard symptomatic treatment,

which may include a need for intensive care.

5.9 Potential for Tumor Growth Stimulatory Effects on Malignant Cells

The granulocyte-colony stimulating factor (G-CSF) receptor through which pegfilgrastim

products and filgrastim products act has been found on tumor cell lines. The possibility

that pegfilgrastim products act as a growth factor for any tumor type, including myeloid

malignancies and myelodysplasia, diseases for which pegfilgrastim products are not

approved, cannot be excluded.

5.10 Myelodysplastic Syndrome (MDS) and Acute Myeloid Leukemia (AML) in

Patients with Breast and Lung Cancer

MDS and AML have been associated with the use of pegfilgrastim products in

conjunction with chemotherapy and/or radiotherapy in patients with breast and lung

cancer. Monitor patients for signs and symptoms of MDS/AML in these settings.

5.11 Aortitis

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

5.12 Nuclear Imaging

Increased hematopoietic activity of the bone marrow in response to growth factor

therapy has been associated with transient positive bone imaging changes. This should

be considered when interpreting bone imaging results.

6 ADVERSE REACTIONS

The following clinically significant 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)]

Use in Patients with Sickle Cell Disorders [see Warnings and Precautions (5.4)]

Glomerulonephritis [see Warnings and Precautions (5.5)]

Leukocytosis [see Warnings and Precautions (5.6)]

Thrombocytopenia [see Warnings and Precautions (5.7)]

Capillary Leak Syndrome [see Warnings and Precautions (5.8)]

Potential for Tumor Growth Stimulatory Effects on Malignant Cells [see Warnings and

Precautions (5.9)]

Myelodysplastic Syndrome [see Warnings and Precautions (5.10)]

Acute Myeloid Leukemia [see Warnings and Precautions (5.10)]

Aortitis [see Warnings and Precautions (5.11)]

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction

rates observed in the clinical trials of a drug cannot be directly compared to rates in the

clinical trials of another drug and may not reflect the rates observed in practice.

Pegfilgrastim clinical trials safety data are based upon 932 patients receiving

pegfilgrastim in seven randomized clinical trials. The population was 21 to 88 years of

age and 92% female. The ethnicity was 75% Caucasian, 18% Hispanic, 5% Black, and 1%

Asian. Patients with breast (n = 823), lung and thoracic tumors (n = 53) and lymphoma

(n = 56) received pegfilgrastim after nonmyeloablative cytotoxic chemotherapy. Most

patients received a single 100 mcg/kg (n = 259) or a single 6 mg (n = 546) dose per

chemotherapy cycle over 4 cycles.

The following adverse reaction data in Table 2 are from a randomized, double-blind,

placebo-controlled study in patients with metastatic or non-metastatic breast cancer

receiving docetaxel 100 mg/m every 21 days (Study 3). A total of 928 patients were

randomized to receive either 6 mg pegfilgrastim (n = 467) or placebo (n = 461). The

patients were 21 to 88 years of age and 99% female. The ethnicity was 66% Caucasian,

31% Hispanic, 2% Black, and <1% Asian, Native American, or other.

The most common adverse reactions occurring in ≥5% of patients and with a between-

group difference of ≥5% higher in the pegfilgrastim arm in placebo-controlled clinical

trials are bone pain and pain in extremity.

Table 2. Adverse Reactions with ≥5% Higher Incidence in Pegfilgrastim

Patients Compared to Placebo in Study 3

Body System

Adverse Reaction

Placebo

(N = 461)

Pegfilgrastim 6 mg SC on

Day 2

(N = 467)

Musculoskeletal and connective tissue disorders

Bone pain

Pain in extremity

Leukocytosis

In clinical studies, leukocytosis (WBC counts >100 × 10 /L) was observed in less than

1% of 932 patients with non-myeloid malignancies receiving pegfilgrastim. No

complications attributable to leukocytosis were reported in clinical studies.

6.2 Immunogenicity

As with all therapeutic proteins, there is potential for immunogenicity. The detection of

antibody formation is highly dependent on the sensitivity and specificity of the assay.

Additionally, the observed incidence of antibody (including neutralizing antibody)

positivity in an assay may be influenced by several factors, including assay methodology,

sample handling, timing of sample collection, concomitant medications, and underlying

disease. For these reasons, comparison of the incidence of antibodies in the studies

described below with the incidence of antibodies in other studies or to other

pegfilgrastim products may be misleading.

Binding antibodies to pegfilgrastim were detected using a BIAcore assay. The

approximate limit of detection for this assay is 500 ng/mL. Pre-existing binding

antibodies were detected in approximately 6% (51/849) of patients with metastatic

breast cancer. Four of 521 pegfilgrastim-treated subjects who were negative at baseline

developed binding antibodies to pegfilgrastim following treatment. None of these 4

patients had evidence of neutralizing antibodies detected using a cell-based bioassay.

6.3 Postmarketing Experience

The following adverse reactions have been identified during post-approval use of

pegfilgrastim 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 (ARDS) [see Warnings and Precautions (5.2)]

Allergic reactions/hypersensitivity, including anaphylaxis, skin rash, urticaria,

generalized erythema, and flushing [see Warnings and Precautions (5.3)]

Sickle cell crisis [see Warnings and Precautions (5.4)]

Glomerulonephritis [see Warnings and Precautions (5.5)]

Leukocytosis [see Warnings and Precautions (5.6)]

Thrombocytopenia [see Warnings and Precautions (5.7)]

Capillary Leak Syndrome [see Warnings and Precautions (5.8)]

Injection site reactions

Sweet's syndrome (acute febrile neutrophilic dermatosis), cutaneous vasculitis

Myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) in patients with

breast and lung cancer receiving chemotherapy and/or radiotherapy [see Warnings

and Precautions (5.10)]

Aortitis [see Warnings and Precautions (5.11)]

Alveolar hemorrhage

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary

Although available data with NYVEPRIA or pegfilgrastim product use in pregnant women

are insufficient to establish whether there is a drug associated risk of major birth

defects, miscarriage, or adverse maternal or fetal outcomes, there are available data

from published studies in pregnant women exposed to filgrastim products. These

studies have not established an association of filgrastim product use during pregnancy

with major birth defects, miscarriage, or adverse maternal or fetal outcomes.

In animal studies, no evidence of reproductive/developmental toxicity occurred in the

offspring of pregnant rats that received cumulative doses of pegfilgrastim approximately

10 times the recommended human dose (based on body surface area). In pregnant

rabbits, increased embryolethality and spontaneous abortions occurred at 4 times the

maximum recommended human dose simultaneously with signs of maternal toxicity

(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 risk

of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and

15 to 20%, respectively.

Data

Animal Data

Pregnant rabbits were dosed with pegfilgrastim subcutaneously every other day during

the period of organogenesis. At cumulative doses ranging from the approximate human

dose to approximately 4 times the recommended human dose (based on body surface

area), the treated rabbits exhibited decreased maternal food consumption, maternal

weight loss, as well as reduced fetal body weights and delayed ossification of the fetal

skull; however, no structural anomalies were observed in the offspring from either

study. Increased incidences of post-implantation losses and spontaneous abortions

(more than half the pregnancies) were observed at cumulative doses approximately 4

times the recommended human dose, which were not seen when pregnant rabbits were

exposed to the recommended human dose.

Three studies were conducted in pregnant rats dosed with pegfilgrastim at cumulative

doses up to approximately 10 times the recommended human dose at the following

stages of gestation: during the period of organogenesis, from mating through the first

half of pregnancy, and from the first trimester through delivery and lactation. No

evidence of fetal loss or structural malformations was observed in any study.

Cumulative doses equivalent to approximately 3 and 10 times the recommended human

dose resulted in transient evidence of wavy ribs in fetuses of treated mothers (detected

at the end of gestation but no longer present in pups evaluated at the end of lactation).

8.2 Lactation

Risk Summary

There are no data on the presence of pegfilgrastim products in human milk, the effects

on the breastfed child, or the effects 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 NYVEPRIA and any potential adverse effects on

the breastfed child from NYVEPRIA or from the underlying maternal condition.

8.4 Pediatric Use

The safety and effectiveness of pegfilgrastim have been established in pediatric patients.

No overall differences in safety were identified between adult and pediatric patients

based on postmarketing surveillance and review of the scientific literature.

Use of pegfilgrastim in pediatric patients for chemotherapy-induced neutropenia is

based on adequate and well-controlled studies in adults with additional pharmacokinetic

and safety data in pediatric patients with sarcoma [see Clinical Pharmacology (12.3) and

Clinical Studies (14)].

8.5 Geriatric Use

Of the 932 patients with cancer who received pegfilgrastim in clinical studies, 139 (15%)

were aged 65 and over, and 18 (2%) were aged 75 and over. No overall differences in

safety or effectiveness were observed between patients aged 65 and older and younger

patients.

10 OVERDOSAGE

Overdosage of pegfilgrastim products may result in leukocytosis and bone pain. Events

of edema, dyspnea, and pleural effusion have been reported in a single patient who

administered pegfilgrastim on 8 consecutive days in error. In the event of overdose, the

patient should be monitored for adverse reactions [see Adverse Reactions (6)].

11 DESCRIPTION

Pegfilgrastim-apgf is a covalent conjugate of recombinant methionyl human G-CSF and

monomethoxypolyethylene glycol. Recombinant methionyl human G-CSF is a water-

soluble 175 amino acid protein with a molecular weight of approximately 19 kilodaltons

(kD). Recombinant methionyl human G-CSF is obtained from the bacterial fermentation

of a strain of E. coli transformed with a genetically engineered plasmid containing the

human G-CSF gene. To produce pegfilgrastim-apgf, a 20 kD monomethoxypolyethylene

glycol molecule is covalently bound to the N-terminal methionyl residue of recombinant

methionyl human G-CSF. The average molecular weight of pegfilgrastim-apgf is

approximately 39 kD.

NYVEPRIA for manual subcutaneous injection is supplied in 0.6 mL prefilled syringes. The

prefilled syringe does not bear graduation marks and is designed to deliver the entire

contents of the syringe (6 mg/0.6 mL).

The delivered 0.6 mL dose from the prefilled syringe for manual subcutaneous injection

contains 6 mg pegfilgrastim-apgf (based on protein weight) in a sterile, clear, colorless,

preservative-free solution (pH 4.0) containing acetate (0.35 mg), polysorbate 20 (0.02

mg), sodium (0.01 mg), and sorbitol (30 mg) in Water for Injection, USP.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Pegfilgrastim products are colony-stimulating factors that act on hematopoietic cells by

binding to specific cell surface receptors, thereby stimulating proliferation,

differentiation, commitment, and end cell functional activation.

12.2 Pharmacodynamics

Animal data and clinical data in humans suggest a correlation between pegfilgrastim

products' exposure and the duration of severe neutropenia as a predictor of efficacy.

Selection of the dosing regimen of NYVEPRIA is based on reducing the duration of

severe neutropenia.

12.3 Pharmacokinetics

The pharmacokinetics of pegfilgrastim was studied in 379 patients with cancer. The

pharmacokinetics of pegfilgrastim was nonlinear, and clearance decreased with

increases in dose. Neutrophil receptor binding is an important component of the

clearance of pegfilgrastim, and serum clearance is directly related to the number of

neutrophils. In addition to numbers of neutrophils, body weight appeared to be a factor.

Patients with higher body weights experienced higher systemic exposure to

pegfilgrastim after receiving a dose normalized for body weight. A large variability in the

pharmacokinetics of pegfilgrastim was observed. The half-life of pegfilgrastim ranged

from 15 to 80 hours after subcutaneous injection.

Specific Populations

No gender-related differences were observed in the pharmacokinetics of pegfilgrastim,

and no differences were observed in the pharmacokinetics of geriatric patients (≥65

years of age) compared with younger patients (<65 years of age) [see Use in Specific

Populations (8.5)].

Renal Impairment

In a study of 30 subjects with varying degrees of renal dysfunction, including end stage

renal disease, renal dysfunction had no effect on the pharmacokinetics of pegfilgrastim.

Pediatric Patients with Cancer Receiving Myelosuppressive Chemotherapy

The pharmacokinetics and safety of pegfilgrastim were studied in 37 pediatric patients

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