Pegfilgrastim

Neulasta 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. Increase survival in patients acutely exposed to myelosuppressive doses of radiation (Hematopoietic Subsyndrome of Acute Radiation Syndrome). Limitations of Use Neulasta is not indicated for the mobilization of peripheral blood progenitor cells for hematopoietic stem cell transplantation.

1.1Patients with Cancer Receiving Myelosuppressive Chemotherapy

Neulasta is indicated in adults and pediatric patients aged newborn and older 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 . Limitations of Use Neulasta is not indicated for the mobilization of peripheral blood progenitor cells for hematopoietic stem cell transplantation.

1.2Patients with Hematopoietic Subsyndrome of Acute Radiation

Syndrome Neulasta is indicated to increase survival in adults and pediatric patients aged newborn and older acutely exposed to myelosuppressive doses of radiation .

Patients with cancer receiving myelosuppressive chemotherapy For adult patients of any weight and pediatric patients weighing 45 kg and greater, the recommended dosage is 6 mg subcutaneously once per chemotherapy cycle. For pediatric patients weighing less than 45 kg, use weight-based dosing; refer to Table 1 Do not administer between 14 days before and 24 hours after administration of chemotherapy. Patients acutely exposed to myelosuppressive doses of radiation For adults of any weight and pediatric patients weighing 45 kg and greater, the recommended dosage is two doses, 6 mg each, 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. For pediatric patients weighing less than 45 kg, use weight-based dosing; refer to Table 1.

2.1Patients with Cancer Receiving Myelosuppressive Chemotherapy

The recommended dosage of Neulasta for adults of any weight and pediatric patients weighing at least 45 kg with cancer receiving myelosuppressive chemotherapy 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 Neulasta between 14 days before and 24 hours after administration of chemotherapy.

Table 1. Dosing of Neulasta for Pediatric Patients Weighing Less Than 45 kg Body Weight Neulasta 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 Neulasta. See below See below 10 kg to 20 kg 1.5 mg 0.15 mL 21 kg to 30 kg 2.5 mg 0.25 mL 31 kg to 44 kg 4 mg 0.4 mL

2.2Patients with Hematopoietic Subsyndrome of Acute Radiation

Syndrome The recommended dosage of Neulasta for adults of any weight and pediatric patients weighing at least 45 kg with hematopoietic subsyndrome of acute radiation syndrome is two doses, 6 mg each, administered subcutaneously one week apart. For dosing in pediatric patients weighing less than 45 kg, refer to Table 1 . 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 Neulasta 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.

2.3Preparation and Administration Neulasta

is supplied in single-dose prefilled syringes for manual use or for use with the on-body injector (OBI) for Neulasta, which is co-packaged with a single-dose prefilled syringe , and in single-dose vials . Before using any of the Neulasta presentations: Remove the carton from the refrigerator and allow the Neulasta prefilled syringe or vial to reach room temperature, 68°F to 77°F (20°C to 25°C), for a minimum of 30 minutes. Do not warm in any other way. Discard any unused prefilled syringe or vial left at room temperature for greater than 48 hours.

Neulasta is a clear, colorless, preservative-free solution. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Do not administer Neulasta if discoloration or particulates are observed.

Prefilled Syringe for Manual Use For adult patients of any weight and pediatric patients weighing 45 kg and greater, the single-dose prefilled syringe for manual use is intended for subcutaneous administration of a single 6 mg/0.6 mL dose of Neulasta. The syringe does not bear graduation marks and therefore does not allow for direct administration of doses less than 6 mg/0.6 mL. The needle cap on the prefilled syringe contains dry natural rubber (derived from latex); persons with latex allergies should not administer this product. Prefilled Syringe for Use with OBI For adult patients of any weight, the single-dose prefilled syringe for use with the OBI for Neulasta, is intended for subcutaneous administration of a single 6 mg/0.6 mL dose of Neulasta.

The prefilled syringe co-packaged in the Neulasta Onpro ® kit must only be used with the OBI for Neulasta . Use of the OBI for Neulasta is not recommended for patients with hematopoietic subsyndrome of acute radiation syndrome. Use of the OBI for Neulasta has not been studied in pediatric patients. The needle cap on the prefilled syringe contains dry natural rubber (derived from latex); persons with latex allergies should not administer this product.

Vial For pediatric patients weighing less than 45 kg, the dose is prepared by withdrawing the required volume from the 4 mg/0.4 mL single-dose vial. A 0.5 mL staked tuberculin syringe with 0.01 mL graduation marks is recommended for preparation and administration for dose accuracy. Only healthcare providers should prepare and administer doses from the vials.

Administer Neulasta subcutaneously. Discard unused portion of Neulasta in single-dose vials. Do not save unused drug for later administration.

2.4Special Healthcare Provider Instructions for the On-body

Injector for Neulasta A healthcare provider must fill the on-body injector (OBI) with Neulasta using the prefilled syringe and then apply the OBI for Neulasta 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 Neulasta. Approximately 27 hours after the OBI for Neulasta is applied to the patient's skin, Neulasta will be delivered over approximately 45 minutes.

A healthcare provider may initiate administration with the OBI for Neulasta on the same day as the administration of chemotherapy, as long as the OBI for Neulasta delivers Neulasta no less than 24 hours after administration of chemotherapy. The prefilled syringe co-packaged in Neulasta Onpro ® kit must only be used with the OBI for Neulasta. The prefilled syringe contains additional solution to compensate for liquid loss during delivery through the OBI for Neulasta.

If the prefilled syringe co-packaged in Neulasta Onpro kit 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 Neulasta, the patient may receive less than the recommended dose. Do not use the OBI for Neulasta to deliver any other drug product except the Neulasta prefilled syringe co-packaged with the OBI for Neulasta.

The OBI for Neulasta should be applied to intact, non-irritated skin on the arm or abdomen. A missed dose could occur due to an OBI for Neulasta 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 Neulasta for full administration information.

2.5Advice to Give to Patients Regarding Administration

via the On-body Injector for Neulasta 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 Neulasta (this includes the 45-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 Neulasta will begin and how to monitor the OBI for Neulasta for completed delivery. Ensure patients understand how to identify signs of malfunction of OBI for Neulasta . Instruct patients using the OBI to notify their healthcare professional immediately in order to determine the need for a replacement dose of Neulasta if they suspect that the device may not have performed as intended .

Fatal splenic rupture: Evaluate patients who report left upper abdominal or shoulder pain for an enlarged spleen or splenic rupture. Acute respiratory distress syndrome (ARDS): Evaluate patients who develop fever, lung infiltrates, or respiratory distress. Discontinue Neulasta in patients with ARDS. Serious hypersensitivity reactions, including anaphylaxis: Permanently discontinue Neulasta in patients with serious hypersensitivity reactions. The on-body injector for Neulasta uses acrylic adhesive. For patients who have reactions to acrylic adhesives, use of this product may result in a significant reaction. Fatal sickle cell crises: Discontinue Neulasta if sickle cell crisis occurs. Glomerulonephritis: Evaluate and consider dose-reduction or interruption of Neulasta if causality is likely. Thrombocytopenia: Monitor platelet counts. Myelodysplastic Syndrome (MDS) and Acute Myeloid Leukemia (AML): Monitor patients with breast and lung cancer using Neulasta in conjunction with chemotherapy and/or radiotherapy for signs and symptoms of MDS/AML. Potential device failures: Instruct patients to notify their healthcare provider if they suspect the on-body injector may not have performed as intended. Aortitis: Discontinue Neulasta if aortitis is suspected.

5.1Splenic Rupture Splenic

rupture, including fatal cases, can occur following the administration of Neulasta. Evaluate for an enlarged spleen or splenic rupture in patients who report left upper abdominal or shoulder pain after receiving Neulasta.

5.2Acute Respiratory Distress Syndrome Acute

respiratory distress syndrome (ARDS) can occur in patients receiving Neulasta. Evaluate patients who develop fever and lung infiltrates or respiratory distress after receiving Neulasta, for ARDS. Discontinue Neulasta in patients with ARDS.

5.3Serious Hypersensitivity Reactions Serious

hypersensitivity reactions, including anaphylaxis, can occur in patients receiving Neulasta. The majority of reported events occurred upon initial exposure. Hypersensitivity reactions, including anaphylaxis, can recur within days after the discontinuation of initial therapies to manage the reaction.

Permanently discontinue Neulasta in patients with serious hypersensitivity reactions. Neulasta is contraindicated in patients with a history of a serious hypersensitivity reaction to pegfilgrastim or filgrastim.

5.4Allergies to Acrylics The

on-body injector (OBI) for Neulasta uses acrylic adhesive. For patients who have reactions to acrylic adhesives, use of this product may result in a significant reaction.

5.5Use in Patients with Sickle Cell Disorders

Severe and sometimes fatal sickle cell crises can occur in patients with sickle cell disorders receiving Neulasta. Discontinue Neulasta if sickle cell crisis occurs.

5.6Glomerulonephritis Glomerulonephritis

has occurred in patients receiving Neulasta. 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 Neulasta. If glomerulonephritis is suspected, evaluate for cause.

If causality is likely, consider dose-reduction or interruption of Neulasta.

5.7Leukocytosis White

blood cell (WBC) counts of 100 × 10 9 /L or greater have been observed in patients receiving Neulasta. Monitoring of complete blood count (CBC) during Neulasta therapy is recommended.

5.8Thrombocytopenia Neulasta

can cause thrombocytopenia. Monitor platelet counts during Neulasta therapy.

5.9Capillary Leak Syndrome Capillary

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

5.10Potential for Tumor Growth Stimulatory Effects

on Malignant Cells The granulocyte colony-stimulating factor (G-CSF) receptor through which pegfilgrastim and filgrastim act has been found on tumor cell lines. The possibility that Neulasta acts as a growth factor for any tumor type, including myeloid malignancies and myelodysplasia, diseases for which pegfilgrastim is not approved, cannot be excluded.

5.11Myelodysplastic Syndrome

(MDS) and Acute Myeloid Leukemia (AML) in Patients with Breast and Lung Cancer MDS and AML have been associated with the use of Neulasta 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.

5.12Potential Device Failures Missed or

partial doses have been reported in patients receiving Neulasta via the on-body injector (OBI) due to the device not performing as intended. In the event of a missed or partial dose, patients may be at increased risk of events such as neutropenia, febrile neutropenia and/or infection than if the dose had been correctly delivered. Instruct patients using the OBI to notify their healthcare professional immediately in order to determine the need for a replacement dose of Neulasta if they suspect that the device may not have performed as intended.

5.13Aortitis Aortitis

has been reported in patients receiving Neulasta. 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 Neulasta if aortitis is suspected.

5.14Nuclear Imaging Increased

hematopoietic activity of the bone marrow in response to growth factor therapy, including Neulasta, has been associated with transient positive bone imaging changes. This should be considered when interpreting bone imaging results.

Neulasta is contraindicated in patients with a history of a serious hypersensitivity reaction to pegfilgrastim or filgrastim. Reactions have included anaphylaxis . In patients with a history of serious hypersensitivity reaction to pegfilgrastim or filgrastim.

8.1Pregnancy Risk Summary Although

available data with Neulasta 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 . 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 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).

The following clinically significant adverse reactions are discussed in greater detail in other sections of the labeling: Splenic Rupture Acute Respiratory Distress Syndrome Serious Hypersensitivity Reactions Allergies to Acrylics Use in Patients with Sickle Cell Disorders Glomerulonephritis Leukocytosis Thrombocytopenia Capillary Leak Syndrome Potential for Tumor Growth Stimulatory Effects on Malignant Cells Myelodysplastic syndrome Acute myeloid leukemia Aortitis Most common adverse reactions (≥ 5% difference in incidence compared to placebo) are bone pain and pain in extremity. To report SUSPECTED ADVERSE REACTIONS, contact Amgen Inc. at 1-800-77-AMGEN (1-800-772-6436) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

6.1Clinical 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 not reflect the rates observed in clinical practice. Neulasta clinical trials safety data are based upon 932 patients receiving Neulasta 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 Neulasta 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 2 every 21 days (Study 3). A total of 928 patients were randomized to receive either 6 mg Neulasta (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 Neulasta Patients Compared to Placebo in Study 3 Body System Adverse Reaction Placebo (N = 461) Neulasta 6 mg SC on Day 2 (N = 467) Musculoskeletal and connective tissue disorders Bone pain 26% 31% Pain in extremity 4% 9% Leukocytosis In clinical studies, leukocytosis (WBC counts > 100 × 10 9 /L) was observed in less than 1% of 932 patients with non-myeloid malignancies receiving Neulasta. No complications attributable to leukocytosis were reported in clinical studies.

6.3Postmarketing Experience The

following adverse reactions have been identified during post approval use of Neulasta. 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 Thrombocytopenia Capillary Leak Syndrome Injection site reactions Sweet's syndrome (acute febrile neutrophilic dermatosis), cutaneous vasculitis Application site reactions (including events such as application site hemorrhage, application site pain, application site discomfort, application site bruise, and application site erythema) have been reported with the use of the on-body injector for Neulasta.

Contact dermatitis and local skin reactions such as rash, pruritus, and urticaria have been reported with the use of the on-body injector for Neulasta, possibly indicating a hypersensitivity reaction to the adhesive. Myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) in patients with breast and lung cancer receiving chemotherapy and/or radiotherapy Aortitis Alveolar hemorrhage