Pegfilgrastim

Mechanism Of Action

Pegfilgrastim is a colony-stimulating factor that acts 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 exposure and the duration of severe neutropenia as a predictor of efficacy. Selection of the dosing regimen of Neulasta is based on reducing the duration of severe neutropenia.

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 Neulasta 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 Neulasta.

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].

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 [see Use In Specific Populations].

The pharmacokinetics and safety of pegfilgrastim were studied in 37 pediatric patients with sarcoma in Study 4 [see Clinical Studies]. The mean (± standard deviation [SD]) systemic exposure (AUC 0-inf ) of Neulasta after subcutaneous administration at 100 mcg/kg was 47.9 (± 22.5) mcg·hr/mL in the youngest age 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 the corresponding age groups were 30.1 (± 38.2) hours, 20.2 (± 11.3) hours, and 21.2 (± 16.0) hours, respectively.

The pharmacokinetics of pegfilgrastim is not available in patients acutely exposed to myelosuppressive doses of radiation. Based on limited pharmacokinetic data in irradiated non-human primates, the area under the concentration-time curve (AUC), reflecting the exposure to pegfilgrastim in non-human primates following a 300 mcg/kg dose of Neulasta, appears to be greater than in humans receiving a 6 mg dose. Results from population modeling and simulation indicate that two 6 mg doses of Neulasta administered one week apart in adults result in clinically relevant effects on duration of grade 3 and 4 neutropenia. In addition, weight based dosing in pediatric patients weighing less than 45 kg [see DOSING AND ADMINISTRATION, Table 1] provides exposures comparable to those in adults receiving two 6 mg doses one week apart.

Clinical Studies

Patients With Cancer Receiving Myelosuppressive Chemotherapy

Neulasta was evaluated in three randomized, double-blind, controlled studies. Studies 1 and 2 were active-controlled studies that employed doxorubicin 60 mg/m²and docetaxel 75 mg/m²administered every 21 days for up to 4 cycles for the treatment of metastatic breast cancer. Study 1 investigated the utility of a fixed dose of Neulasta. Study 2 employed a weight-adjusted dose. In the absence of growth factor support, similar chemotherapy regimens have been reported to result in a 100% incidence of severe neutropenia (ANC < 0.5 x 109/L) with a mean duration of 5 to 7 days and a 30% to 40% incidence of febrile neutropenia. Based on the correlation between the duration of severe neutropenia and the incidence of febrile neutropenia found in studies with filgrastim, duration of severe neutropenia was chosen as the primary endpoint in both studies, and the efficacy of Neulasta was demonstrated by establishing comparability to filgrastim-treated patients in the mean days of severe neutropenia.

In Study 1, 157 patients were randomized to receive a single subcutaneous injection of Neulasta (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 of Neulasta (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 severe neutropenia of Neulasta-treated patients did not exceed that of filgrastim-treated patients by more than 1 day in cycle 1 of chemotherapy. The mean days of cycle 1 severe neutropenia in Study 1 were 1.8 days in the Neulasta 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 Neulasta 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 similar to those for cycle 1.

Study 3 was a randomized, double-blind, placebo-controlled study that employed docetaxel 100 mg/m²administered every 21 days for up to 4 cycles for the treatment of metastatic or non-metastatic breast cancer. In this study, 928 patients were randomized to receive a single subcutaneous injection of Neulasta (6 mg) or placebo on day 2 of each chemotherapy cycle. Study 3 met the major trial outcome measure of demonstrating that the incidence of febrile neutropenia (defined as temperature ≥ 38.2°C and ANC ≤ 0.5 x109/L) was lower for Neulasta-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 the treatment of febrile neutropenia was also lower in the Neulasta-treated patients compared to the placebo-treated patients.

Study 4 was a multicenter, randomized, open-label study to evaluate the efficacy, safety, and pharmacokinetics [see CLINICAL PHARMACOLOGY] of Neulasta in pediatric and young adult patients with sarcoma. Patients with sarcoma receiving chemotherapy age 0 to 21 years were eligible. Patients were randomized to receive subcutaneous Neulasta as a single dose of 100 mcg/kg (n= 37) or subcutaneous filgrastim at a dose 5 mcg/kg/day (n=6) following myelosuppressive chemotherapy. Recovery of neutrophil counts was similar in the Neulasta and filgrastim groups. The most common adverse reaction reported was bone pain.

Patients With Hematopoietic Subsyndrome Of Acute Radiation Syndrome

Efficacy studies of Neulasta could not be conducted in humans with acute radiation syndrome for ethical and feasibility reasons. Approval of this indication was based on efficacy studies conducted in animals and data supporting Neulasta's effect on severe neutropenia in patients with cancer receiving myelosuppressive chemotherapy [see DOSAGE AND ADMINISTRATION].

The recommended dose of Neulasta is two doses, 6 mg each, administered one week apart for humans exposed to myelosuppressive doses of radiation. For pediatric patients weighing less than 45 kg, dosing of Neulasta is weight based and is provided in Table 1 [see DOSAGE AND ADMINISTRATION]. This dosing regimen is based on population modeling and simulation analyses. The exposure associated with this dosing regimen is expected to provide sufficient pharmacodynamic activity to treat humans exposed to myelosuppressive doses of radiation [see CLINICAL PHARMACOLOGY]. The safety of Neulasta at a dose of 6 mg has been assessed on the basis of clinical experience in patients with cancer receiving myelosuppressive chemotherapy.

The efficacy of Neulasta for the acute radiation syndrome setting was studied in a randomized, placebo-controlled non-human primate model of radiation injury. Rhesus macaques were randomized to either a control (n=23) or treated (n=23) cohort. On study day 0, animals (n = 6 to 8 per irradiation day) were exposed to total body irradiation (TBI) of 7.50 ± 0.15 Gy delivered at 0.8 ± 0.03 Gy/min, representing a dose that would be lethal in 50% of animals by 60 days of follow-up (LD50/60). Animals were administered subcutaneous injections of a blinded treatment (control article [5% dextrose in water] or pegfilgrastim [300-319 mcg/kg/day]) on study day 1 and on study day 8. The primary endpoint was survival. Animals received medical management consisting of intravenous fluids, antibiotics, blood transfusions, and other support as required.

Pegfilgrastim significantly (at 0.0014 level of significance) increased 60-day survival in irradiated non-human primates: 91% survival (21/23) in the pegfilgrastim group compared to 48% survival (11/23) in the control group.

Do not take pegfilgrastim if you have had a serious allergic reaction to pegfilgrastim or filgrastim.

Occasionally pain and redness may occur at the injection site. If there is a lump, swelling, or bruising at the injection site that does not go away, talk to the doctor.

Pegfilgrastim should only be injected on the day the doctor has determined and should not be injected until approximately 24 hours after receiving chemotherapy.

The needle cover on the single-use prefilled syringe contains dry natural rubber (latex), which should not be handled by persons sensitive to this substance.

Pegfilgrastim may cause serious side effects including:

• Spleen rupture: Your spleen may become enlarged and can rupture while taking pegfilgrastim. A ruptured spleen can cause death. The spleen is located in the upper left section of your stomach area. Call your doctor right away if you have pain in the left upper stomach area or left shoulder tip area. This pain could mean your spleen is enlarged or ruptured.

• A serious lung problem called Acute Respiratory Distress Syndrome (ARDS). Call your doctor or seek emergency care right away if you have shortness of breath, trouble breathing, or a fast rate of breathing.

• Serious Allergic Reactions. Pegfilgrastim can cause serious allergic reactions. These reactions can cause shortness of breath, wheezing, dizziness, swelling around the mouth or eyes, fast pulse, sweating, and hives. If you start to have any of these symptoms, call your doctor or seek emergency care right away. If you have an allergic reaction during the injection of pegfilgrastim, stop the injection. Call your doctor right away.

• Sickle Cell Crises. You may have a serious sickle cell crisis if you have a sickle cell disorder and take pegfilgrastim. Serious and sometimes fatal sickle cell crises can occur in patients with sickle cell disorders receiving filgrastim, a medicine similar to pegfilgrastim. Call your doctor right away if you have symptoms of sickle cell crisis such as pain or difficulty breathing.

Before receiving pegfilgrastim, tell your healthcare provider if you:

• are allergic to pegfilgrastim, filgrastim, or any other medications
• are being treated with radiation therapy
• have or have ever had cancer of the blood or bone marrow or sickle cell disease. Call your healthcare provider right away if you have a sickle cell crisis during your treatment.
• are pregnant
• are breastfeeding

Tell your healthcare provider about all the medicines you take including prescription and non-prescription medicines, vitamins, and herbal supplements.

If you receive too much pegfilgrastim, call your local Poison Control Center or seek emergency medical attention right away.

You should not use this medicine if you are allergic to pegfilgrastim or filgrastim (Neupogen).

To make sure you can safely use pegfilgrastim, tell your doctor if you have any of these other conditions:

• sickle cell disorder;

• kidney disease;

• chronic myeloid leukemia;

• myelodysplasia (also called "preleukemia"); or

• a latex allergy.

It is not known whether this medicine will harm an unborn baby. Tell your doctor if you are pregnant or plan to become pregnant.

If you are pregnant, your name may be listed on a pregnancy registry. This is to track the outcome of the pregnancy and to evaluate any effects of pegfilgrastim on the baby.

It is not known whether pegfilgrastim passes into breast milk or if it could harm a nursing baby. Tell your doctor if you are breast-feeding a baby.

Call your doctor for instructions if you miss a dose of pegfilgrastim, or if you have a problem with the On-body Injector device.

Absorption

Special Populations

When dose is normalized based on body weight, systemic exposure to the drug is increased in patients with higher body weights.1

Elimination

Elimination Route

Conjugation of filgrastim with PEG results in delayed renal clearance (compared with filgrastim).1 10 11

Neutrophil receptor binding is an important factor in pegfilgrastim clearance.1 Serum clearance is related to the number of circulating neutrophils; serum concentrations of the drug decline rapidly with resolution of neutropenia.1

Half-life

Conjugation with PEG results in increased plasma half-life (15–80 hours) compared with filgrastim (about 3.5 hours).1 10

Special Populations

Nonlinear pharmacokinetics in patients with cancer; clearance decreases with increasing dosages.1

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Hypersensitivity (serious allergic reaction) to pegfilgrastim, filgrastim, or any component of the formulation

Canadian labeling: Additional contraindications (not in US labeling): Hypersensitivity to E. coli-derived proteins.

May interfere with bone imaging studies; increased hematopoietic activity of the bone marrow may appear as transient positive bone imaging changes

6 mg subcutaneously once per chemotherapy cycle, beginning at least 24 hours after completion of chemotherapy; do not administer between 14 days before and 24 hours after administration of cytotoxic chemotherapy

Use: To decrease the incidence of infection, as manifested by febrile neutropenia, in patients with non-myeloid malignancies receiving myelosuppressive anticancer drugs associated with a clinically significant incidence of febrile neutropenia

6 mg subcutaneously once per chemotherapy cycle, beginning at least 24 hours after completion of chemotherapy; do not administer between 14 days before and 24 hours after administration of cytotoxic chemotherapy

Use: To decrease the incidence of infection, as manifested by febrile neutropenia, in patients with non-myeloid malignancies receiving myelosuppressive anticancer drugs associated with a clinically significant incidence of febrile neutropenia

Doses are to be given subcutaneously once per chemotherapy cycle, beginning at least 24 hours after completion of chemotherapy; do not administer between 14 days before and 24 hours after administration of cytotoxic chemotherapy:
Less than 10 kg: 0.1 mg/kg
10 to 20 kg: 1.5 mg
21 to 30 kg: 2.5 mg
31 to 44 kg: 4 mg
45 kg or greater: 6 mg

Comments:
-The prefilled syringe is not designed to allow administration of doses less than 0.6 mL (6 mg) because it does not have graduation marks, which are necessary to accurately measure doses less than 0.6 mL; therefore, administration to patients requiring less than 0.6 mL is not recommended.

Use: To decrease the incidence of infection, as manifested by febrile neutropenia, in patients with non-myeloid malignancies receiving myelosuppressive anticancer drugs associated with a clinically significant incidence of febrile neutropenia

Data not available

Data not available