Ziextenzo

Patients With Cancer Receiving Myelosuppressive Chemotherapy

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

Limitations Of Use

ZIEXTENZO is not indicated for the mobilization of peripheral blood progenitor cells for hematopoietic stem cell transplantation.

Patients With Cancer Receiving Myelosuppressive Chemotherapy

The recommended dosage of ZIEXTENZO is a single subcutaneous injection of 6 mg administered once perchemotherapy cycle. For dosing in pediatric patients weighing less than 45 kg, refer to Table 1. Do notadminister ZIEXTENZO between 14 days before and 24 hours after administration of cytotoxic chemotherapy.

Administration

ZIEXTENZO is administered subcutaneously via a single-dose prefilled syringe for manual use.

Prior to use‚ remove the carton from the refrigerator and allow the ZIEXTENZO prefilled syringe to reach roomtemperature for a minimum of 15-30 minutes. Discard any prefilled syringe left at room temperature for greaterthan 72 hours.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. ZIEXTENZO is supplied as a clear and colorless toslightly yellowish solution. Do not administer ZIEXTENZO if discoloration or particulates are observed.

The needle cap on the prefilled syringes contains dry natural rubber (derived from latex) which may cause allergic reactions; persons with latex allergies should not administer these products.

Pediatric Patients Weighing Less Than 45 kg

The ZIEXTENZO 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 necessary to accurately measure doses ofZIEXTENZO less than 0.6 mL (6 mg) for direct administration to patients. Thus, the direct administration topatients 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 ZIEXTENZO for pediatric patients weighing less than 45 kg

ZIEXTENZO is contraindicated in patients with a history of serious allergic reactions to pegfilgrastim productsor filgrastim products. Reactions have included anaphylaxis .

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

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 ZIEXTENZO.

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 ZIEXTENZO, for ARDS. Discontinue ZIEXTENZO in patients with ARDS.

Serious Allergic Reactions

Serious allergic reactions, including anaphylaxis, can occur in patients receiving pegfilgrastim products. Themajority of reported events occurred upon initial exposure. Allergic reactions, including anaphylaxis, can recurwithin days after the discontinuation of initial anti-allergic treatment. Permanently discontinue ZIEXTENZO in patients with serious allergic reactions. Do not administer ZIEXTENZO to patients with a history of seriousallergic reactions to pegfilgrastim products or filgrastim products.

Use In Patients With Sickle Cell Disorders

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

Glomerulonephritis

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

Leukocytosis

White blood cell (WBC) counts of 100 x 10⁹/L or greater have been observed in patients receivingpegfilgrastim. Monitoring of complete blood count (CBC) during ZIEXTENZO therapy is recommended.

Capillary Leak Syndrome

Capillary leak syndrome has been reported after G-CSF administration, including pegfilgrastim, and ischaracterized 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.

Potential For Tumor Growth Stimulatory Effects On Malignant Cells

The granulocyte colony-stimulating factor (G-CSF) receptor through which pegfilgrastim products andfilgrastim 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 whichpegfilgrastim products are not approved, cannot be excluded.

Aortitis

Aortitis has been reported in patients receiving pegfilgrastim. It may occur as early as the first week after startof 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). Consideraortitis in patients who develop these signs and symptoms without known etiology. Discontinue ZIEXTENZOif aortitis is suspected.

Nuclear Imaging

Increased hematopoietic activity of the bone marrow in response to growth factor therapy has been associatedwith transient positive bone imaging changes. This should be considered when interpreting bone imagingresults.

Patient Counseling Information

Advise the patient to read the FDA-approved patient labeling (PATIENT INFORMATION and Instructions for Use).

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

• Splenic rupture and splenomegaly
• Acute Respiratory Distress Syndrome
• Serious allergic reactions
• Sickle cell crisis
• Glomerulonephritis
• Capillary Leak Syndrome
• Aortitis

Instruct patients who self-administer ZIEXTENZO using the single-dose prefilled syringe of the:

• Importance of following the Instructions for Use.
• Dangers of reusing syringes.
• Importance of following local requirements for proper disposal of used syringes.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment Of Fertility

No carcinogenicity or mutagenesis studies have been performed with pegfilgrastim products.

Pegfilgrastim did not affect reproductive performance or fertility in male or female rats at cumulative weeklydoses approximately 6 to 9 times higher than the recommended human dose (based on body surface area).

Use In Specific Populations

Pregnancy

Risk Summary

Although available data with ZIEXTENZO 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 fetaloutcomes, 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 birthdefects, miscarriage, or adverse maternal or fetal outcomes.

In animal studies, no evidence of reproductive/developmental toxicity occurred in the offspring of pregnant ratsthat 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 .

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. generalpopulation, the estimated background risks of major birth defects and miscarriage in clinically recognizedpregnancies is 2-4% and 15-20%, respectively.

Data

Animal Data

Pregnant rabbits were dosed with pegfilgrastim subcutaneously every other day during the period oforganogenesis. At cumulative doses ranging from the approximate human dose to approximately 4 times therecommended 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 incidencesof post-implantation losses and spontaneous abortions (more than half the pregnancies) were observed atcumulative doses approximately 4 times the recommended human dose, which were not seen when pregnantrabbits 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 oforganogenesis, from mating through the first half of pregnancy, and from the first trimester through deliveryand lactation. No evidence of fetal loss or structural malformations was observed in any study. Cumulativedoses 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 pupsevaluated at the end of lactation).

Lactation

Risk Summary

There are no data on the presence of pegfilgrastim products in human milk, the effects on the breastfed child, orthe 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 beconsidered along with the mother’s clinical need for ZIEXTENZO and any potential adverse effects on the breastfed child from ZIEXTENZO or from the underlying maternal condition.

Pediatric Use

The safety and effectiveness of pegfilgrastim have been established in pediatric patients. No overall differencesin safety were identified between adult and pediatric patients based on postmarketing surveillance and review ofthe 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 .

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.

No Information provided

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

• Splenic Rupture
• Acute Respiratory Distress Syndrome
• Serious Allergic Reactions
• Use in Patients with Sickle Cell Disorders
• Glomerulonephritis
• Leukocytosis
• Capillary Leak Syndrome
• Potential for Tumor Growth Stimulatory Effects on Malignant Cells
• Aortitis

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 with rates in the clinical trials of another drug and may notreflect the rates observed in clinical practice.

Pegfilgrastim clinical trials safety data are based upon 932 patients receiving pegfilgrastim in seven randomizedclinical 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 patientsreceived 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 studyin patients with metastatic or non-metastatic breast cancer receiving docetaxel 100 mg/m² every 21 days (Study3). 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

Leukocytosis

In clinical studies, leukocytosis (WBC counts > 100 x 10⁹/L) was observed in less than 1% of 932 patients with non-myeloid malignancies receiving pegfilgrastim. No complications attributable to leukocytosis were reportedin clinical studies.

Immunogenicity

As with all therapeutic proteins, there is a potential for immunogenicity. The detection of antibody formation ishighly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence ofantibody (including neutralizing antibody) positivity in an assay may be influenced by several factors, includingassay methodology, sample handling, timing of sample collection, concomitant medications, and underlyingdisease. For these reasons, comparison of the incidence of antibodies in the studies described below with theincidence 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 detectionfor this assay is 500 ng/mL. Pre-existing binding antibodies were detected in approximately 6% (51/849) ofpatients 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 ofneutralizing antibodies detected using a cell-based bioassay.

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)
• Acute respiratory distress syndrome (ARDS)
• Allergic reactions/hypersensitivity, including anaphylaxis, skin rash, urticaria, generalized erythema,and flushing
• Sickle cell crisis
• Glomerulonephritis
• Leukocytosis
• Capillary Leak Syndrome
• Injection site reactions
• Sweet"s syndrome (acute febrile neutrophilic dermatosis), cutaneous vasculitis
• Aortitis
• Alveolar hemorrhage

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 .

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.

Pharmacodynamics

Animal data and clinical data in humans suggest a correlation between pegfilgrastim products’ exposure and theduration of severe neutropenia as a predictor of efficacy. Selection of the dosing regimen of ZIEXTENZO is based on reducing the duration of severe neutropenia.

Pharmacokinetics

The pharmacokinetics of pegfilgrastim was studied in 379 patients with cancer. The pharmacokinetics ofpegfilgrastim 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 ofneutrophils. In addition to numbers of neutrophils, body weight appeared to be a factor. Patients with higherbody weights experienced higher systemic exposure to pegfilgrastim after receiving a dose normalized for bodyweight. 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) .

Renal Impairment

In a study of 30 subjects with varying degrees of renal dysfunction, including end stage renal disease, renaldysfunction 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 with sarcoma in Study 4 . The mean (± standard deviation (SD)) systemic exposure (AUC0-inf) of pegfilgrastim after subcutaneous administration at 100 mcg/kg was 47.9 (± 22.5) mcg•hr/mL in the youngestage group (0 to 5 years, n = 11), 22.0 (± 13.1) mcg•hr/mL in the 6 to 11 years age group (n = 10), and 29.3 (±23.2) mcg•hr/mL in the 12 to 21 years age group (n = 13). The terminal elimination half-lives of thecorresponding age groups were 30.1 (± 38.2) hours, 20.2 (± 11.3) hours, and 21.2 (± 16.0) hours, respectively.

Clinical Studies

Patients With Cancer Receiving Myelosuppressive Chemotherapy

Pegfilgrastim was evaluated in three randomized, double-blind, controlled studies. Studies 1 and 2 were active-controlled studies that employed doxorubicin 60 mg/m² and docetaxel 75 mg/m² administered every 21 days forup to 4 cycles for the treatment of metastatic breast cancer. Study 1 investigated the utility of a fixed dose ofpegfilgrastim. Study 2 employed a weight-adjusted dose. In the absence of growth factor support, similarchemotherapy regimens have been reported to result in a 100% incidence of severe neutropenia (ANC < 0.5 x10⁹/L) with a mean duration of 5 to 7 days and a 30% to 40% incidence of febrile neutropenia. Based on thecorrelation between the duration of severe neutropenia and the incidence of febrile neutropenia found in studieswith filgrastim, duration of severe neutropenia was chosen as the primary endpoint in both studies, and theefficacy of pegfilgrastim was demonstrated by establishing comparability to filgrastim-treated patients in themean days of severe neutropenia.

In Study 1, 157 patients were randomized to receive a single subcutaneous injection of pegfilgrastim (6 mg) on day 2 of each chemotherapy cycle or daily subcutaneous filgrastim (5 mcg/kg/day) beginning on day 2 of each chemotherapy cycle. In Study 2, 310 patients were randomized to receive a single subcutaneous injection ofpegfilgrastim (100 mcg/kg) on day 2 or daily subcutaneous filgrastim (5 mcg/kg/day) beginning on day 2 of each chemotherapy cycle.

Both studies met the major efficacy outcome measure of demonstrating that the mean days of severeneutropenia of pegfilgrastim-treated patients did not exceed that of filgrastim-treated patients by more than 1day in cycle 1 of chemotherapy. The mean days of cycle 1 severe neutropenia in Study 1 were 1.8 days in thepegfilgrastim arm compared to 1.6 days in the filgrastim arm (difference in means 0.2 (95% CI -0.2, 0.6)) and in Study 2 were 1.7 days in the pegfilgrastim arm compared to 1.6 days in the filgrastim arm (difference in means 0.1 (95% CI -0.2, 0.4)).

A secondary endpoint in both studies was days of severe neutropenia in cycles 2 through 4 with results similarto those for cycle 1.

Study 3 was a randomized, double-blind, placebo-controlled study that employed docetaxel 100 mg/m² administered every 21 days for up to 4 cycles for the treatment of metastatic or non-metastatic breast cancer. Inthis study, 928 patients were randomized to receive a single subcutaneous injection of pegfilgrastim (6 mg) or placebo on day 2 of each chemotherapy cycle. Study 3 met the major trial outcome measure of demonstratingthat the incidence of febrile neutropenia (defined as temperature ≥ 38.2°C and ANC ≤ 0.5 x 10⁹/L) was lowerfor pegfilgrastim-treated patients as compared to placebo-treated patients (1% versus 17%, respectively, p <0.001). The incidence of hospitalizations (1% versus 14%) and IV anti-infective use (2% versus 10%) for thetreatment of febrile neutropenia was also lower in the pegfilgrastim-treated patients compared to the placebo-treated patients.

Study 4 was a multicenter, randomized, open-label study to evaluate the efficacy, safety, and pharmacokinetics of pegfilgrastim in pediatric and young adult patients with sarcoma. Patients with sarcoma receiving chemotherapy age 0 to 21 years were eligible. Patients were randomized toreceive subcutaneous pegfilgrastim as a single-dose of 100 mcg/kg (n = 37) or subcutaneous filgrastim at a dose5 mcg/kg/day (n = 6) following myelosuppressive chemotherapy. Recovery of neutrophil counts was similar in the pegfilgrastim and filgrastim groups. The most common adverse reaction reported was bone pain.

Dosage Forms And Strengths

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

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

Storage And Handling

ZIEXTENZO single-dose prefilled syringe for manual use

ZIEXTENZO injection is a clear, colorless to slightly yellowish solution supplied in a prefilled single-dosesyringe for manual use containing 6 mg pegfilgrastim-bmez, supplied with a 27-gauge, ½-inch needle with anUltraSafe Passive™ Needle Guard.

The needle cap of the prefilled syringe contains dry natural rubber (a derivative of latex) which may cause allergic reactions.

ZIEXTENZO is provided in a dispensing pack containing one sterile 6 mg/0.6 mL prefilled syringe (NDC61314-866-01).

ZIEXTENZO prefilled syringe does not bear graduation marks and is intended only to deliver the entirecontents 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 72 hours. Avoid freezing; if frozen, thaw in the refrigeratorbefore administration. Discard syringe if frozen more than once.

Manufactured by:Sandoz Inc. Princeton, NJ 08540US License No. 2003 Product of Slovenia. Revised: Nov 2019