NEULASTIM

Pegfilgrastim is a

PEGylated form of the recombinant human granulocyte colony-stimulating factor (G-CSF) analogue, filgrastim.

The drug is approved for use to decrease the incidence of infection, as manifested by febrile neutropenia, in susceptible patients with with non-myeloid cancer receiving myelosuppressive anti-cancer treatment.

Although the risk of developing febrile neutropenia is less than 20% in many readily used chemotherapy regimens, 7 infections pose risks of hospitalization and mortalities.

Due to the relatively short circulating half-life of filgrastim, a 20 kDa PEG moiety was covalently conjugated to the N-terminus of filgrastim (at the methionine residue) to develop longer-acting pegfilgrastim. 1, 3 Due to a longer half-life and slower elimination rate than filgrastim, pegfilgrastim requires less frequent dosing than filgrastim; however, pegfilgrastim has a comparable pharmacological activity to filgrastim and binds to the G-CSF receptor to stimulate the proliferation, differentiation, and activation of neutrophils.

First developed by

Amgen, pegfilgrastim was initially approved by the FDA in and marketed as Neulasta.

It is typically administered via a subcutaneous injection.

There are several pegfilgrastim biosimilars (Fulphila, Pelgraz or Lapelga, Pelmeg, Udenyca, Ziextenzo, Grasustek, Fylnetra, Stimufend) by Health Canada, European Union (EU), and FDA that are approved to reduce infection risk. 10, 11, 14 These biosimilars are highly similar to the reference product, Neulasta, in terms of pharmacological and pharmacokinetic profile and conditions of use.

NIOPEG (pegfilgrastim), a biosimilar of NEULASTA®, was approved by Health Canada in April for the prevention of febrile neutropenia in patients with non-myeloid malignancies receiving myelosuppressive chemotherapy 17.

Pegfilgrastim 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. 15, 16 It is also indicated to increase survival in patients acutely exposed to myelosuppressive doses of radiation (Hematopoietic Subsyndrome of Acute Radiation Syndrome).

Pegfilgrastim is a recombinant human granulocyte colony-stimulating factor (G-CSF) that promotes the production, proliferation, and maturation of neutrophils, which are white blood cells involved in both innate and adaptive immune responses. 4, 7 The safety and efficacy of pegfilgrastim in reducing the risk of febrile neutropenia and infections have been demonstrated in various tumor types and settings.

During chemotherapy-induced neutropenia, the clearance of pegfilgrastim is significantly reduced and the concentration of pegfilgrastim is sustained until the onset of neutrophil recovery.

Serum concentrations of pegfilgrastim decline as the neutrophil count increases as neutrophil and neutrophil precursors are involved in cell-mediated clearance of the drug.

Due the addition of polyethylene glycol group to its structure, Pegfilgrastim is a long-acting form of filgrastim with an extended serum half-life and reduced renal clearance.

Although it is more slowly absorbed than filgrastim, self-regulation of pegfilgrastim is more efficient and the drug effects are maintained during one chemotherapy cycle (2-3 weeks).

Pegfilgrastim has a lower absolute bioavailability than filgrastim following subcutaneous administration.

The absorption of pegfilgrastim is largely dependent on the lymphatic system due to the attached PEG group contributing to the large size of the drug.

It is slowly absorbed following subcutaneous administration with a time to peak concentration (T max ) of about one to two days.

Pegfilgrastim appears to have a volume of distribution of approximately 170 L.

It is not know whether pegfilgrastim is metabolized into major metabolites.

Once it binds to the therapeutic target, pegfilgrastim is internalized by the neutrophil and undergoes nonspecific degradation.

The polyethylene glycol moiety limits the renal clearance by glomerular filtration of pegfilgrastim, making neutrophil-mediated clearance as the predominant route of elimination.

This elimination pathway is initiated by the binding of pegfilgrastim to the G-CSF receptor on the neutrophil cell surface, leading to the internalization of the pegfilgrastim-receptor complex via endocytosis and subsequent degradation inside the cell.

While hepatic clearance has not been well characterized for pegfilgrastim, its non-PEGylated precursor filgrastim is known to be unaffected by changes in hepatic clearance.

The serum half-life of

Pegfilgrastim is highly variable depending on the absolute neutrophil count, with the range of 15-80 hours following subcutaneous administration.

The median serum half-life of 42 hours. 3, 8.

Pegfilgrastim has a self-regulating clearance that involves neutrophil-induced clearance. 1, 4 The clearance is dependent on the number of neutrophils and body weight of the patient: the clearance increases with increasing number of granulocytes and lower body weights.

Pegfilgrastim is not eliminated from the circulation until neutrophils start to recover following chemotherapy-induced neutropenia and its clearance is increased as neutrophil counts also increase.

The apparent serum clearance is 14 mL/h/kg.

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The maximum safe dose of pegfilgrastim has not been established; however, the highest dose used in clinical trials was 300 mcg/kg.

Overdosage of pegfilgrastim may result in leukocytosis and bone pain.

Events of edema, dyspnea, and pleural effusion have been reported in a single patient who self-administered pegfilgrastim on 8 consecutive days in error.

In the event of overdose, the patient should be monitored for signs and symptoms of toxicity and responded with appropriate general supportive care. 8, 7.

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

Reactions have included anaphylaxis.

Patients with a history of serious allergic reaction to human granulocyte colony-stimulating factors such as pegfilgrastim products or filgrastim products.

Patients with cancer receiving myelosuppressive chemotherapy 6 mg administered subcutaneously once per chemotherapy cycle.

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

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

Patients acutely exposed to myelosuppressive doses of radiation Two doses, 6 mg each, administered subcutaneously one week apart.

Administer the first dose as soon as possible after suspected or confirmed exposure to myelosuppressive doses of radiation, and a second dose one week after.

Use weight based dosing for pediatric patients weighing less than 45 kg; refer to Table 1. 2.1 Patients with Cancer Receiving Myelosuppressive Chemotherapy The recommended dosage of UDENYCA 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

UDENYCA between 14 days before and 24 hours after administration of cytotoxic chemotherapy. 2.2 Patients with Hematopoietic Subsyndrome of Acute Radiation Syndrome The recommended dose of UDENYCA is two doses, 6 mg each, administered subcutaneously one week apart.

Administer the first dose as soon as possible after suspected or confirmed exposure to radiation levels greater than 2 gray (Gy).

Administer the second dose one week after the first dose.

Obtain a baseline complete blood count (CBC).

Do not delay administration of UDENYCA if a CBC is not readily available.

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. 2.3 Administration UDENYCA is administered subcutaneously via a single-dose prefilled autoinjector, a single-dose prefilled syringe for manual use or for use with the on-body injector (OBI) for UDENYCA, which is co-packaged with a single dose prefilled syringe for OBI.

Use of the OBI for UDENYCA is not recommended for patients with Hematopoietic Subsyndrome of Acute Radiation Syndrome.

Use of the

OBI has not been studied in pediatric patients.

Prior to use‚ remove the carton from the refrigerator and allow UDENYCA to reach room temperature for a minimum of 30 minutes.

Discard any

UDENYCA left at room temperature for greater than 48 hours.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

UDENYCA if discoloration or particulates are observed.

The needle cap on the prefilled syringe and prefilled autoinjector is not made with natural rubber latex.

Less than 45 kg The UDENYCA 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 of UDENYCA 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.

Dosing of

UDENYCA for pediatric patients weighing less than 45 kg Body Weight UDENYCA Dose Volume to Administer Less than 10 kg For pediatric patients weighing less than 10 kg, administer 0.1 mg/kg (0.01 mL/kg) of UDENYCA 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 The UDENYCA prefilled autoinjector is not suitable for use in pediatric patients weighing less than 45 kg. The UDENYCA prefilled autoinjector delivers the entire contents (6 mg in 0.6 mL) in a single injection and is not adjustable. 2.4 Advice to Give to Patients or Caregivers Regarding Administration via the Prefilled Autoinjector Only adults can self-administer UDENYCA with the prefilled autoinjector.

If subcutaneous injections can be given at home, refer the patient or caregiver to the dose delivery information provided in the Instructions for Use.

Provide training to patients or caregivers to ensure they understand how to administer UDENYCA via the prefilled autoinjector.

Ensure patients or caregivers understand how to identify that a full dose has been administered by listening for the second 'click' and checking that the 'Orange Indicator' completely blocks the viewing window.

Instruct patients or caregivers using the prefilled autoinjector to notify their healthcare provider immediately in order to determine the need for a replacement dose of UDENYCA if they suspect that the full dose may not have been administered. 2.5 Special Healthcare Provider Instructions for the On-body Injector for UDENYCA A healthcare provider must fill the on-body injector (OBI) with UDENYCA using the prefilled syringe and then apply the OBI for UDENYCA to the patient's skin (abdomen or back of arm).

The back of the arm may only be used if there is a caregiver available to monitor the status of the OBI for UDENYCA.

Approximately 27 hours after the OBI for UDENYCA is applied to the patient's skin, UDENYCA will be delivered over approximately 5 minutes.

A healthcare provider may initiate administration with the OBI for UDENYCA on the same day as the administration of cytotoxic chemotherapy, as long as the OBI for UDENYCA delivers UDENYCA no less than 24 hours after administration of cytotoxic chemotherapy.

The prefilled syringe co-packaged in UDENYCA

ONBODY must only be used with the OBI for UDENYCA.

The prefilled syringe contains additional solution to compensate for liquid loss during filling of the OBI and delivery through the OBI for UDENYCA.

If the prefilled syringe co-packaged in UDENYCA ONBODY is used for manual subcutaneous injection, the patient will receive an overdose.

If the single-dose prefilled syringe for manual use is used with the OBI for UDENYCA, the patient may receive less than the recommended dose.

Do not use the OBI for

UDENYCA to deliver any other drug product except the UDENYCA prefilled syringe co-packaged with the OBI for UDENYCA.

The OBI for

UDENYCA should be applied to intact, non-irritated skin on the arm or abdomen.

A missed dose could occur due to an OBI for UDENYCA failure or leakage.

If the patient misses a dose, a new dose should be administered by single-dose prefilled syringe for manual use, as soon as possible after detection.

Refer to the Healthcare Provider Instructions for Use for the OBI for UDENYCA for full administration information. 2.6 Advice to give to Patients Regarding Administration via the On-body Injector for UDENYCA Advise patients to avoid activities such as traveling, driving, or operating heavy machinery during hours 26-29 following application of the on-body injector (OBI) for UDENYCA (this includes the 5-minute delivery period plus an hour post-delivery).

Patients should have a caregiver nearby for the first use.

Refer the patient to the dose delivery information written on the Patient Instructions for Use.

Provide training to patients to ensure they understand when the dose delivery of UDENYCA will begin and how to monitor the OBI for UDENYCA for completed delivery.

Ensure patients understand how to identify signs of malfunction of OBI for UDENYCA.

Instruct patients using the

OBI to notify their healthcare professional immediately in order to determine the need for a replacement dose of UDENYCA if they suspect that the device may not have performed as intended.

single-dose prefilled syringe for manual use UDENYCA (pegfilgrastim-cbqv) injection is a clear, colorless, preservative-free solution supplied in a prefilled single-dose syringe containing 6 mg pegfilgrastim-cbqv, supplied with a 29-gauge, 1⁄2-inch needle with an UltraSafe Passive ™ Needle Guard.

The needle cap of the prefilled syringe is not made with natural rubber latex.

UDENYCA is provided in a dispensing pack containing one sterile 6 mg/0.6 mL prefilled syringe (NDC 69448-025-63).

UDENYCA 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 2° to 8°C (36° to 46°F) in the carton to protect from light.

Do not shake.

UDENYCA stored at room temperature for more than 48 hours.

Avoid freezing; if frozen, thaw in the refrigerator before administration.

UDENYCA if frozen more than once.

UDENYCA single-dose prefilled autoinjector

UDENYCA (pegfilgrastim-cbqv) injection is a clear, colorless, preservative-free solution supplied in a prefilled single-dose autoinjector containing 6 mg pegfilgrastim-cbqv.

The needle cap of the prefilled autoinjector is not made with natural rubber latex.

UDENYCA is provided in a dispensing pack containing one 6 mg/0.6 mL prefilled autoinjector (NDC 69448-026-63).

UDENYCA prefilled autoinjector is not suitable for use in pediatric patients weighing less than 45 kg. The UDENYCA prefilled autoinjector delivers the entire contents (6 mg in 0.6 mL) in a single injection and is not adjustable.

ONBODY is provided in a carton containing one sterile prefilled syringe and one sterile on-body injector (OBI) for UDENYCA (NDC 69448-027-63).

UDENYCA injection single-dose prefilled syringe contains 0.67 mL of a clear, colorless solution that delivers 6 mg/0.6 mL of pegfilgrastim-cbqv when used with the OBI for UDENYCA.

The prefilled syringe is supplied with a 29-gauge, 1/2-inch needle.

The syringe does not bear graduation marks and is only to be used with the OBI for UDENYCA.

ONBODY in the refrigerator at 2°C to 8°C (36°F to 46°F) until 30 minutes prior to use.

Because the OBI for

UDENYCA is at room temperature during the period of use, UDENYCA ONBODY should not be held at room temperature longer than 12 hours prior to use.

ONBODY if stored at room temperature for more than 12 hours.

Do not use the OBI for

UDENYCA if its packaging has been previously opened.

Risk Summary Although available data with

UDENYCA 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 embryo lethality 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. general population, the estimated background risks of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

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 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).

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

Of the 932 patients with cancer who received pegfilgrastim in clinical studies, 139 (15%) were age and over, and 18 (2%) were age and over.

No overall differences in safety or effectiveness were observed between patients age and older and younger patients.