Fulphila

Patients With Cancer Receiving Myelosuppressive Chemotherapy

Fulphila 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.

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

Patients With Hematopoietic Subsyndrome Of Acute Radiation Syndrome

Fulphila is indicated to increase survival in patients acutely exposed to myelosuppressive doses of radiation.

Patients With Cancer Receiving Myelosuppressive Chemotherapy

The recommended dosage of Fulphila 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 Fulphila between 14 days before and 24 hours after administration of cytotoxic chemotherapy.

Patients With Hematopoietic Subsyndrome Of Acute Radiation Syndrome

The recommended dose of Fulphila 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 Fulphila 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.

Administration

Fulphila is administered subcutaneously via a single prefilled syringe for manual use or for use with the On-body Injector for Fulphila which is co-packaged with a single prefilled syringe. Use of the On-body Injector for Fulphila is not recommended for patients with Hematopoietic Subsyndrome of Acute Radiation Syndrome. Use of the On-body Injector for Fulphila has not been studied in pediatric patients.

Prior to use‚ remove the carton from the refrigerator and allow the Fulphila prefilled syringe to reach room temperature for a minimum of 30 minutes. Discard any prefilled syringe left at room temperature for greater than 48 hours.

Visually inspect parenteral drug products (prefilled syringe) for particulate matter and discoloration prior to administration, whenever solution and container permit. Do not administer Fulphila if discoloration or particulates are observed.

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

Pediatric Patients Weighing Less Than 45 kg

The Fulphila 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 Fulphila 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 Fulphila for pediatric patients weighing less than 45 kg

Special Healthcare Provider Instructions For The On-body Injector For Fulphila

A healthcare provider must fill the On-body Injector with Fulphila using the prefilled syringe and then apply the On-body Injector for Fulphila 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 On-body Injector for Fulphila. Approximately 27 hours after the On-body Injector for Fulphila is applied to the patient's skin, Fulphila will be delivered over approximately 45 minutes. A healthcare provider may initiate administration with the On-body Injector for Fulphila on the same day as the administration of cytotoxic chemotherapy, as long as the On-body Injector for Fulphila delivers Fulphila no less than 24 hours after administration of cytotoxic chemotherapy.

The prefilled syringe co-packaged in Fulphila Onpro™ kit must only be used with the On-body Injector for Fulphila. The prefilled syringe contains additional solution to compensate for liquid loss during delivery through the On-body Injector for Fulphila. If the prefilled syringe co-packaged in Fulphila 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 On-body Injector for Fulphila, the patient may receive less than the recommended dose.

Do not use the On-body Injector for Fulphila to deliver any other drug product except the Fulphila prefilled syringe co-packaged with the On-body Injector for Fulphila.

The On-body Injector for Fulphila should be applied to intact, non-irritated skin on the arm or abdomen.

A missed dose could occur due to an On-body Injector for Fulphila failure or leakage. If the patient misses a dose, a new dose should be administered by single prefilled syringe for manual use, as soon as possible after detection.

Refer to the Healthcare Provider Instructions for Use for the On-body Injector for Fulphila for full administration information.

Advice To Give To Patients Regarding Administration Via The On-body Injector For Fulphila

Advise patients to avoid activities such as traveling, driving, or operating heavy machinery during hours 26-29 following application of the On-body Injector for Fulphila (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 Fulphila will begin and how to monitor the On-body Injector for Fulphila for completed delivery. Ensure patients understand how to identify signs of malfunction of On-body Injector for Fulphila.

Do not administer Fulphila to patients with a history of serious allergic reactions to pegfilgrastim or filgrastim.

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

Splenic Rupture

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

Acute Respiratory Distress Syndrome

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

Serious Allergic Reactions

Serious allergic reactions, including anaphylaxis, can occur in patients receiving Fulphila. 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 Fulphila in patients with serious allergic reactions. Do not administer Fulphila to patients with a history of serious allergic reactions to pegfilgrastim or filgrastim.

Allergies To Acrylics

The On-body Injector for Fulphila uses acrylic adhesive. For patients who have reactions to acrylic adhesives, use of this product may result in a significant reaction.

Use In Patients With Sickle Cell Disorders

Severe sickle cell crises can occur in patients with sickle cell disorders receiving Fulphila. Severe and sometimes fatal sickle cell crises can occur in patients with sickle cell disorders receiving filgrastim, the parent compound of pegfilgrastim.

Glomerulonephritis

Glomerulonephritis has occurred in patients receiving Fulphila. 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 Fulphila. If glomerulonephritis is suspected, evaluate for cause. If causality is likely, consider dose-reduction or interruption of Fulphila.

Leukocytosis

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

Capillary Leak Syndrome

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

Potential 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 pegfilgrastim acts as a growth factor for any tumor type, including myeloid malignancies and myelodysplasia, diseases for which pegfilgrastim is not approved, cannot be excluded.

Patient Counseling Information

Advise the patient to read the FDA-approved patient labeling (PATIENT INFORMATION).

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

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

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

Instruct patients who self-administer Fulphila 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.

Advise patients on the use of the On-body Injector for Fulphila:

• Review the Patient Information and Patient Instructions for Use with the patient and provide the instructions to the patient.
• Refer the patient to the dose delivery information written on the Patient Instructions for Use.
• Tell the patient when their dose delivery of Fulphila will begin and when their dose delivery should be completed.
• Advise the patient that serious allergic reactions can happen with Fulphila. Patients should have a caregiver nearby for the first use. Patients should plan to be in a place where they can appropriately monitor the On-body Injector for Fulphila during the approximately 45 minute Fulphila delivery and for an hour after the delivery. Advise the patient to avoid traveling, driving, or operating heavy machinery during hours 26-29 following application of the On-body Injector for Fulphila.
• If the On-body Injector for Fulphila is placed on the back of the arm, remind the patient that a caregiver must be available to monitor the On-body Injector for Fulphila.
• If a patient calls the healthcare provider regarding any On-body Injector for Fulphila problems, the healthcare provider is advised to call Amgen at 1-800-772-6436.
• Advise the patient:
  • to call their healthcare provider immediately if the status light on the On-body Injector for Fulphila is flashing red (see the Patient Instructions for Use).
  • to inform their healthcare provider if the adhesive on the On-body Injector for Fulphila becomes saturated with fluid, or there is dripping, as this may be evidence of significant product leakage, resulting in inadequate or missed dose (see the Patient Instructions for Use).
  • to keep the On-body Injector for Fulphila dry for approximately the last 3 hours prior to the dose delivery start to better enable potential leak detection.
  • that the On-body Injector for Fulphila should only be exposed to temperatures between 41°F and 104°F (5°C-40°C)
  • to keep the On-body Injector for Fulphila at least 4 inches away from electrical equipment such as cell phones, cordless telephones, microwaves and other common appliances. Failure to keep the On-body Injector for Fulphila at least this recommended distance may interfere with operation and can lead to a missed or incomplete dose of Fulphila.
  • that if the needle is exposed after On-body Injector for Fulphila removal, place the used On-body Injector for Fulphila in a sharps disposal container to avoid accidental needle stick and call their healthcare provider immediately.
  • to remove the On-body Injector for Fulphila after the green light shines continuously and to place the used On-body Injector for Fulphila in a sharps disposal container (see the Patient Instructions for Use).
• Advise the patient:
  • do not reapply the On-body Injector for Fulphila if the On-body Injector for Fulphila comes off before full dose is delivered and instead call their healthcare provider immediately.
  • avoid bumping the On-body Injector for Fulphila or knocking the On-body Injector for Fulphila off the body.
  • do not expose the On-body Injector for Fulphila to medical imaging studies, e.g. X-ray scan, MRI, CT scan, ultrasound and oxygen rich environments such as hyperbaric chambers to avoid On-body Injector for Fulphila damage and patient injury.
• Advise the patient to avoid:
  • airport X-ray scans and request a manual pat down instead; remind patients who elect to request a manual pat down to exercise care to avoid having the On-body Injector for Fulphila dislodged during the pat down process.
  • sleeping on the On-body Injector for Fulphila or applying pressure on the On-body Injector for Fulphila as this may affect On-body Injector for Fulphila performance.
  • getting body lotions, creams, oils and cleaning agents near the On-body Injector for Fulphila as these products may loosen the adhesive.
  • using hot tubs, whirlpools, or saunas and avoid exposing the On-body Injector for Fulphila to direct sunlight as these may affect the drug.
  • peeling off or disturbing the On-body Injector for Fulphila adhesive before delivery of full dose is complete.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment Of Fertility

No carcinogenicity or mutagenesis studies have been performed with pegfilgrastim.

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

Reproductive And Developmental Toxicology

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), 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).

Use In Specific Populations

Pregnancy

Pregnancy Category C

There are no adequate and well-controlled studies in pregnant women. Pegfilgrastim was embryotoxic and increased pregnancy loss in pregnant rabbits that received cumulative doses approximately 4 times the recommended human dose (based on body surface area). Signs of maternal toxicity occurred at these doses. Fulphila should be used during pregnancy only if the potential benefit to the mother justifies the potential risk to the fetus.

In animal reproduction studies, when pregnant rabbits received pegfilgrastim at cumulative doses approximately 4 times the recommended human dose (based on body surface area), increased embryolethality and spontaneous abortions occurred. Signs of maternal toxicity (reductions in body weight gain/food consumption) and decreased fetal weights occurred at maternal doses approximately equivalent to the recommended human dose (based on body surface area). There were no structural anomalies observed in rabbit offspring at any dose tested. 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).

Nursing Mothers

It is not known whether pegfilgrastim is secreted in human milk. Other recombinant G-CSF products are poorly secreted in breast milk and G-CSF is not orally absorbed by neonates. Caution should be exercised when administered to a nursing woman.

Pediatric Use

The safety and effectiveness of Fulphila 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 Fulphila 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.

The use of Fulphila to increase survival in pediatric patients acutely exposed to myelosuppressive doses of radiation is based on efficacy studies conducted in animals and clinical data supporting the use of Fulphila in patients with cancer receiving myelosuppressive chemotherapy. Efficacy studies of Fulphila could not be conducted in humans with acute radiation syndrome for ethical and feasibility reasons. Results from population modeling and simulation indicate that two doses of Fulphila (Table 1), administered one week apart provide pediatric patients with exposures comparable to that in adults receiving two 6 mg doses one week apart.

Geriatric Use

Of the 932 patients with cancer who received Fulphila 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.

Renal Impairment

Renal dysfunction had no effect on the pharmacokinetics of pegfilgrastim. Therefore, pegfilgrastim dose adjustment in patients with renal dysfunction is not necessary.

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
• Allergies to Acrylics
• Use in Patients with Sickle Cell Disorders
• Glomerulonephritis
• Leukocytosis
• Capillary Leak Syndrome
• Potential for Tumor Growth Stimulatory Effects on Malignant Cells

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 not reflect the rates observed in clinical practice.

Fulphila clinical trials safety data are based upon 932 patients receiving Fulphila 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 Fulphila 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/m²every 21 days (Study 3). A total of 928 patients were randomized to receive either 6 mg Fulphila (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 Fulphila 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 Fulphila. No complications attributable to leukocytosis were reported in clinical studies.

Immunogenicity

As with all therapeutic proteins, there is a potential for immunogenicity. 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.

The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay, and the observed incidence of 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 to Fulphila with the incidence of antibodies to other products may be misleading.

Postmarketing Experience

The following adverse reactions have been identified during post approval use of Fulphila. 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, and 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

The maximum amount of Fulphila that can be safely administered in single or multiple doses has not been determined. Single subcutaneous doses of 300 mcg/kg have been administered to 8 healthy volunteers and 3 patients with non-small cell lung cancer without serious adverse effects. These patients experienced a mean maximum absolute neutrophil count (ANC) of 55 x 10⁹/L, with a corresponding mean maximum WBC of 67 x 10⁹/L. The absolute maximum ANC observed was 96 x 10⁹/L with a corresponding absolute maximum WBC observed of 120 x 10⁹/L. The duration of leukocytosis ranged from 6 to 13 days. The effectiveness of leukapheresis in the management of symptomatic individuals with Fulphila-induced leukocytosis has not been studied.

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

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 Fulphila ranged from 15 to 80 hours after subcutaneous injection. In healthy volunteers, the pharmacokinetics of pegfilgrastim were comparable when delivered subcutaneously via a manual prefilled syringe versus via the On-body Injector for Fulphila.