Leukine (Page 5 of 9)

8.5 Geriatric Use

Clinical studies of LEUKINE did not include a sufficient numbers of subject aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients.

10 OVERDOSAGE

Doses up to 100 mcg/kg/day (4,000 mcg/m2 /day or 16 times the recommended dose) were administered to four patients in a Phase 1 uncontrolled clinical study by continuous IV infusion for 7 to 18 days. Increases in WBC up to 200,000 cells/mm3 were observed. Adverse events reported were dyspnea, malaise, nausea, fever, rash, sinus tachycardia, headache, and chills. All these events were reversible after discontinuation of LEUKINE.

In case of overdosage, discontinue LEUKINE therapy and monitor the patient for WBC increase and respiratory symptoms.

11 DESCRIPTION

Sargramostim is a glycosylated recombinant human granulocyte-macrophage colony-stimulating factor (rhu GM-CSF) produced by recombinant DNA technology in a yeast (S. cerevisiae) expression system. Sargramostim is a glycoprotein of 127 amino acids characterized by three primary molecular species having molecular masses of 19,500, 16,800 and 15,500 Daltons.

The amino acid sequence of sargramostim differs from the natural human GM-CSF by a substitution of leucine at position 23, and the carbohydrate moiety may be different from the native protein. Sargramostim differs from human GM-CSF by one amino acid at position 23, where leucine is substituted for arginine.

LEUKINE (sargramostim) for injection is supplied as a sterile, preservative-free, white lyophilized powder in a single-dose vial for subcutaneous or intravenous use. Each single-dose vial delivers 250 mcg sargramostim. Inactive ingredients are mannitol (40 mg), sucrose (10 mg), and tromethamine (1.2 mg). Reconstitution with 1 mL of the appropriate diluent (sterile water for injection or bacteriostatic water for injection) yields a solution containing 250 mcg/mL sargramostim at a pH range of 7.1 — 7.7 with a deliverable volume of 1 mL (250 mcg).

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Sargramostim (GM-CSF) belongs to a group of growth factors termed colony-stimulating factors which support survival, clonal expansion, and differentiation of hematopoietic progenitor cells. GM-CSF induces partially committed progenitor cells to divide and differentiate in the granulocyte-macrophage pathways which include neutrophils, monocytes/macrophages and myeloid-derived dendritic cells.

GM-CSF is also capable of activating mature granulocytes and macrophages. GM-CSF is a multilineage factor and, in addition to dose-dependent effects on the myelomonocytic lineage, can promote the proliferation of megakaryocytic and erythroid progenitors. However, other factors are required to induce complete maturation in these two lineages. The various cellular responses (i.e., division, maturation, activation) are induced through GM-CSF binding to specific receptors expressed on the cell surface of target cells.

The biological activity of GM-CSF is species-specific. Consequently, in vitro studies have been performed on human cells to characterize the pharmacological activity of GM-CSF. In vitro exposure of human bone marrow cells to GM-CSF at concentrations ranging from 1-100 ng/mL results in the proliferation of hematopoietic progenitors and in the formation of pure granulocyte, pure macrophage, and mixed granulocyte macrophage colonies. Chemotactic, anti-fungal, and anti-parasitic activities of granulocytes and monocytes are increased by exposure to GM-CSF in vitro. GM-CSF increases the cytotoxicity of monocytes toward certain neoplastic cell lines and activates polymorphonuclear neutrophils to inhibit the growth of tumor cells.

12.2 Pharmacodynamics

LEUKINE stimulates hematopoietic precursor cells and increases neutrophil, eosinophil, megakaryocyte, macrophage, and dendritic cell production. In AML adult patients undergoing induction chemotherapy [see Clinical Studies (14.1)], LEUKINE at daily doses of 250 mcg/m2 significantly shortened the median duration of ANC <500/mm3 by 4 days and <1000/mm3 by 7 days following induction; 75% of patients receiving sargramostim achieved ANC greater than 500/mm3 by day 16 compared to day 25 for patients receiving placebo. Animal data and clinical data in humans suggest a correlation between sargramostim exposure and the duration of severe neutropenia as a predictor of efficacy. At doses of 250 mcg/m2 (approximately 7 mcg/kg in a 70 kg human with a body surface area of 1.96), daily LEUKINE treatment reduced the duration of severe neutropenia.

12.3 Pharmacokinetics

Intravenous Administration (IV)

Peak concentrations of sargramostim were observed in blood samples obtained during or immediately after completion of LEUKINE infusion.

Subcutaneous Administration (SC)

Based on a population pharmacokinetics analysis of lyophilized LEUKINE data, the mean Cmax after a 7 mcg/kg SC dose (equivalent to a 250 mcg/m2 dose in a 70 kg human with a body surface area of 1.96) was 3.03 ng/mL and mean AUC0-24 was 21.3 ng•h/mL (Table 4). There is no accumulation of GM-CSF after repeat SC dosing and steady state conditions are met after a single SC dose.

Table 4: Sargramostim serum Cmax and AUC Exposure (CV%) in Humans after Subcutaneous Administration
Data type Sargramostim dose Formulation Number of healthy subjects AUC (CV%) (ng·h/mL ) Cmax (CV%) (ng/mL)
Observed 6.5 mcg/kg Lyophilized LEUKINE 39 20.4 (28.7%) 3.15 (35.2%)
Population PK model simulation 7 mcg/kg Lyophilized LEUKINE 500 21.3 (32.6) 3.03 (31.0)

Absorption

After SC administration GM-CSF was detected in the serum early (15 min) and reached maximum serum concentrations between 2.5 and 4 h. The absolute bioavailability with the SC route, when compared to the IV route, was 75%.

Distribution

The observed volume of distribution after IV (Vz) administration was 96.8.

Elimination

LEUKINE administered SC to healthy adult volunteers, GM-CSF had a terminal elimination half-life of 1.4 h. The observed total body clearance/subcutaneous bioavailability (CL/F) was 23 L/h. Specific metabolism studies were not conducted, because LEUKINE is a protein and is expected to degrade to small peptides and individual amino acids.

Special Populations

Adult patients acutely exposed to myelosuppressive doses of radiation (H-ARS)

The pharmacokinetics of sargramostim are not available in adult patients acutely exposed to myelosuppressive doses of radiation. Pharmacokinetic data in irradiated and non-irradiated non-human primates and in healthy human adults were used to derive human doses for patients acutely exposed to myelosuppressive doses of radiation. Modeling and simulation of the healthy human adult pharmacokinetic data indicate that sargramostim Cmax and AUC exposures at a LEUKINE dose of 7 mcg/kg in patients acutely exposed to myelosuppressive doses of radiation are expected to exceed sargramostim Cmax (97.6% of patients) and AUC (100% of patients) exposures at a LEUKINE dose of 7 mcg/kg in non-human primates.

Pediatric patients acutely exposed to myelosuppressive doses of radiation (H-ARS)

The pharmacokinetics of sargramostim was not available in pediatric patients acutely exposed to myelosuppressive doses of radiation. The pharmacokinetics of sargramostim in pediatric patients after being exposed to myelosuppressive doses of radiation were estimated by scaling the adult population pharmacokinetic model to the pediatric population. The model-predicted mean AUC0-24 values at 7, 10, and 12 mcg/kg doses of LEUKINE in pediatric patients weighing greater than 40 kg (~adolescents), 15 to 40 kg (~young children), and 0 to less than 15 kg (~newborns to toddlers), respectively, were similar to AUC values in adults after a 7 mcg/kg dose.

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