PegaGen®


(Pegylated Filgrastim)

Bone Pain Flies Away ...


INDICATIONS AND USAGE

PegaGen 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.

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

DOSAGE AND ADMINISTRATION

The recommended dosage of PegaGen is a single subcutaneous injection of 6 mg administered once per chemotherapy cycle in adults. Do not administer PegaGen between 14 days before and 24 hours after administration of cytotoxic chemotherapy.

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

NOTE: The needle cover on the single-use prefilled syringe contains dry natural rubber (latex); persons with latex allergies should not administer this product.

DOSAGE FORMS AND STRENGTHS

6 mg per 0.6 mL in single use prefilled syringe.

CONTRAINDICATIONS

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

WARNINGS AND PRECAUTIONS

Splenic Rupture

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

Acute Respiratory Distress Syndrome

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

Serious Allergic Reactions

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

Use in Patients With Sickle Cell Disorders

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

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.

ADVERSE REACTIONS

>10%:

Cardiovascular: Peripheral edema (12%)
Central nervous system: Headache (16%)
Gastrointestinal: Vomiting (13%)
Neuromuscular & skeletal: Bone pain (31% to 57%), myalgia (21%), arthralgia (16%), weakness (13%) 

1% to 10%:

Gastrointestinal: Constipation (10%)
Miscellaneous: Antibody formation (1% to 6%)

<1% (Limited to important or life-threatening):

Acute respiratory distress syndrome (ARDS), allergic reaction, anaphylaxis, cutaneous vasculitis, erythema, fever, flushing, hyperleukocytosis, hypoxia, injection site reactions (erythema, induration, pain), leukocytosis, rash, sickle cell crisis, splenic rupture, Sweet's syndrome (acute febrile dermatosis), urticaria. Cytopenias resulting from an antibody response to exogenous growth factors have been reported on rare occasions in patients treated with other recombinant growth factors.

DRUG INTERACTIONS

No formal drug interaction studies between PegaGen and other drugs have been performed. Increased hematopoietic activity of the bone marrow in response to growth factor therapy may result in transiently positive bone-imaging changes. Consider these findings when interpreting bone-imaging results.

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. PegaGen 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 ecommended human dose (based on body surface area) [see Nonclinical Toxicology (Reproductive and Developmental Toxicology)].

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

Safety and effectiveness of PegaGen in pediatric patients have not been established. The adverse reaction profile and pharmacokinetics of pegfilgrastim were studied in 37 pediatric patients with sarcoma. The mean (± standard deviation [SD]) systemic exposure (AUC0-inf) of pegfilgrastim after subcutaneous administration at 100 mcg/kg was 22.0 (± 13.1) mcg·hr/mL in the 6 to 11 years age group (n = 10), 29.3 (± 23.2) mcg·hr/mL in the 12 to 21 years age group (n = 13), and 47.9 (± 22.5) mcg·hr/mL in the youngest age group (0 to 5 years, n = 11). The terminal elimination half-lives of the corresponding age groups were 20.2 (± 11.3) hours, 21.2 (± 16.0) hours, and 30.1 (± 38.2) hours, respectively. The most common adverse reaction was bone pain.

Geriatric Use

Of the 932 patients with cancer who received PegaGen in clinical studies, 139 (15%) were age 65 and over, and 18 (2%) were age 75 and over. No overall differences in safety or effectiveness were observed between patients age 65 and older and younger patients.

Renal Impairment

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. Therefore, pegfilgrastim dose adjustment in patients with renal dysfunction is not necessary [Clinical Pharmacology (Pharmacokinetics)].

OVERDOSAGE

The maximum amount of PegaGen 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 PegaGen-induced leukocytosis has not been studied.

DESCRIPTION

PegaGen (pegfilgrastim) is a covalent conjugate of recombinant methionyl human G-CSF (filgrastim) and monomethoxypolyethylene glycol. Filgrastim is a water-soluble 175 amino acid protein with a molecular weight of approximately 19 kilodaltons (kD). Filgrastim is obtained from the bacterial fermentation of a strain of E coli transformed with a genetically engineered plasmid containing the human G-CSF gene. To produce pegfilgrastim, a 20 kD monomethoxypolyethylene glycol molecule is covalently bound to the N-terminal methionyl residue of filgrastim. The average molecular weight of pegfilgrastim is approximately 39 kD.

PegaGen is supplied in 0.6 mL prefilled syringes for subcutaneous injection. Each syringe contains 6 mg pegfilgrastim (based on protein weight) in a sterile, clear, colorless, preservative-free solution (pH 4.0) containing acetate, polysorbate 20, sodium, and sorbitol in water  for  Injection, USP.

CLINICAL PHARMACOLOGY

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.

Pharmacokinetics

The pharmacokinetics of pegfilgrastim were studied in 379 patients with cancer. The pharmacokinetics of pegfilgrastim were 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 PegaGen ranged from 15 to 80 hours after subcutaneous injection.

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 (Geriatric Use)]. The pharmacokinetics of pegfilgrastim were studied in pediatric patients with sarcoma [see Use in Specific Populations (Pediatric Use)].

Renal dysfunction had no effect on the pharmacokinetics of pegfilgrastim. [see Use in Specific Populations (Renal Impairment)]. The pharmacokinetic profile in patients with hepatic insufficiency has not been assessed.

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).

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