Jane S. Ricciuti, RPh, MS


January 20, 2005

In This Article

Chemoprotectant Agents

(palifermin) Injection

Manufacturer: Amgen, Inc.

Drug Approval Classification: Original New Drug Application (Approval Date: 12/15/04)

Indication: Kepivance (palifermin) injection is indicated to decrease the incidence and duration of severe oral mucositis in patients with hematologic malignancies receiving myelotoxic therapy requiring hematopoietic stem cell support. The safety and efficacy of palifermin have not been established in patients with nonhematologic malignancies.

Dosing: The recommended dosage of palifermin is 60 mcg/kg/day, administered as an intravenous (IV) bolus injection for 3 consecutive days before and 3 consecutive days after myelotoxic therapy for a total of 6 doses. For pre-myelotoxic therapy, the first 3 doses should be administered prior to myelotoxic therapy, with the third dose 24 to 48 hours before myelotoxic therapy. For post-myelotoxic therapy, the last 3 doses should be administered post-myelotoxic therapy; the first of these doses should be administered after, but on the same day of hematopoietic stem cell infusion and at least 4 days after the most recent administration of palifermin.

Clinical Summary: Palifermin is a modified version of a naturally occurring human protein called keratinocyte growth factor (KGF). KGF is an endogenous protein in the fibroblast growth factor (FGF) family that binds to the KGF receptor. Binding of KGF to its receptor has been reported to result in proliferation, differentiation, and migration of epithelial cells. The KGF receptor, 1 of 4 receptors in the FGF family, has been reported to be present on epithelial cells in many tissues examined including the tongue, buccal mucosa, esophagus, stomach, intestine, salivary gland, lung, liver, pancreas, kidney, bladder, mammary gland, skin (hair follicles and sebaceous gland), and the lens of the eye.

Palifermin was studied in 2 clinical trials. Study 1 was a randomized, placebo-controlled, clinical study of 212 patients, and Study 2 was a randomized, schedule-ranging, placebo-controlled, clinical study of 169 patients.

In Study 1, patients received high-dose cytotoxic therapy consisting of fractionated total-body irradiation (TBI) (12 Gy total dose), high-dose etoposide (60 mg/kg), and high-dose cyclophosphamide (100 mg/kg) followed by peripheral blood progenitor cell (PBPC) support for the treatment of hematologic malignancies. Patients were randomized to receive either palifermin (n = 106) or placebo (n = 106). Palifermin was administered as a daily IV injection of 60 mcg/kg for 3 consecutive days prior to initiation of cytotoxic therapy and for 3 consecutive days following infusion of PBPC. The main efficacy endpoint of Study 1 was the number of days during which patients experienced severe oral mucositis (grade 3/4 on the WHO [World Health Organization] scale). Compared with placebo-treated patients, palifermin -treated patients reported less mouth and throat soreness.

In Study 2, patients received high-dose cytotoxic therapy consisting of fractionated TBI (12cGy total dose), high-dose etoposide (60 mg/kg), and high-dose cyclophosphamide (75-100 mg/kg) followed by PBPC support for the treatment of hematologic malignancies. Compared with placebo, there was a reduction in median days of WHO grade 3/4 oral mucositis (4 vs 6 days), lower incidence of WHO grade 3/4 oral mucositis (67% vs 80%), and lower incidence of WHO grade 4 oral mucositis (26% vs 50%) for palifermin.

Adverse Effects: The labeling notes that the effects of palifermin on stimulation of KGF receptor-expressing, non-hematopoietic tumors in patients are not known. Palifermin has been shown to enhance the growth of human epithelial tumor cell lines in vitro and to increase the rate of tumor cell line growth in a human carcinoma xenograft model.

The most common serious adverse reaction attributed to palifermin was skin rash, which was reported in less than 1% (3/409) of patients treated with palifermin. Grade 3 skin rashes occurred in 14 patients, 9 of 409 (3%) receiving palifermin and 5 of 241 (2%) receiving placebo. The most common adverse reactions attributed to palifermin were skin toxicities (rash, erythema, edema, pruritus), oral toxicities (dysesthesia, tongue discoloration, tongue thickening, alteration of taste), pain arthralgias, and dysesthesia. The median time to onset of cutaneous toxicity was 6 days following the first of 3 consecutive daily doses of palifermin, with a median duration of 5 days.

Pharmacokinetics: Palifermin exhibited linear pharmacokinetics. Total body clearance appeared to be 2- to 4-fold higher, and volume of distribution at steady state appeared to be 2-fold higher in cancer patients compared with healthy subjects after a 60 mcg/kg single dose of palifermin. The elimination half-life was similar between healthy subjects and cancer patients (average 4.5 hours with a range of 3.3 to 5.7 hours).

No formal drug-drug interaction studies have been conducted.

Kepivance (palifermin) Injection Labeling


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