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Potential For Stimulation Of Tumor Growth
The safety and efficacy o f Kepivance have not been established in patients with non-hematologic malignancies. The effects o f Kepivance on stimulation of KGF receptor-expressing, non-hematopoietic tumors in patients are not known. Kepivance has been shown to enhance the growth o f human epithelial tumor cell lines in vitro and to increase the rate o f tumor cell line growth in a human carcinoma xenograft model [ see CLINICAL PHARMACOLOGY].
Carcinogenesis, Mutagenesis, Impairment Of Fertility
No treatment-related increase in the incidence of neoplastic lesions occurred in transgenic rasH2 mice treated with 9 weekly intravenous doses of palifermin, at 167-fold higher than the recommended human dose (on a mcg/kg basis).
No clastogenic or mutagenic effects o f palifermin were observed in mammalian chromosomal aberration or Ames genotoxicity assays.
Impairment Of Fertility
Reproductive performance, fertility, and sperm assessment parameters were not affected when palifermin was administered intravenously to male and female rats prior to and during mating at doses up to 100 mcg/kg/day. Decreased epididymal sperm counts, and increased post-implantation losses were observed at doses ≥ 300 mcg/kg/day (5-fold higher than the recommended human dose, on a mcg/kg basis). Increased pre-implantation loss and a decreased fertility index were observed at a palifermin dose o f 1000 mcg/kg/day.
Use In Specific Populations
No gender-related differences were observed in the pharmacokinetics of Kepivance at doses ≤ 60 mcg/kg.
Pregnancy Category C
There are no adequate and well-controlled studies o f Kepivance in pregnant woman. Palifermin is embryotoxic in rabbits and rats. In reproductive toxicology studies, increased post-implantation loss and decrease in fetal body weight were observed in both rabbit (2.5 times the maximum recommended human dose [MRHD], adjusted for body weight) and rat (8 times the MRHD, on a mcg/kg basis) [see Nonclinical Toxicology]. Kepivance should be used during pregnancy only if the potential benefit to the mother justifies the potential risk to the fetus.
It is not known whether Kepivance is secreted in human milk. Because many drugs are excreted in human milk, and because o f the potential for serious adverse reactions in nursing infants from Kepivance, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.
Information on the dosing and safety o f Kepivance in the pediatric population is limited. However, use o f Kepivance in pediatric patients ages 1 to 16 years is supported by evidence from adequate and well-controlled studies of Kepivance in adults and a phase 1 study that included 27 pediatric patients with acute leukemia undergoing hematopoietic stem cell transplant. Three age groups were studied: ages 1 to 2 (n=9), ages 3 to 11 (n=9), and ages 12 to 16 (n=9); 56% were male, 26% were Caucasian, 63% Hispanic; 81% ALL, 19% AML. The patients received high-dose cytotoxic therapy consisting o f fractionated total body irradiation (TBI) (12 Gy total dose), high dose etoposide (1500 mg/m²), and high dose cyclophosphamide (120 mg/kg) followed by allogeneic hematopoietic stem cell support. The dose intensity o f this preparative regimen is comparable to the dose intensity o f the Study 1 preparative regimen. See Clinical Studies . Kepivance was administered as a daily intravenous injection for 3 consecutive days prior to initiation o f cytotoxic therapy and for 3 consecutive days following infusion of hematopoietic stem cells. Three dose levels, 40, 60, and 80 mcg/kg/dose, were evaluated. There was no dose limiting toxicity identified at any dose level. Adverse events were similar to those reported in adult studies. The incidence of palifermin related adverse events was highest in the 80 ^g/kg cohort. The overall incidence of WHO grade 3 and 4 oral mucositis was 10/27 (37%).
The pharmacokinetics o f Kepivance was evaluated in the phase 1 study. Age (1 to 16 years) did not affect the pharmacokinetics of palifermin over the dose range (40 to 80 mcg/kg). Palifermin concentrations declined in the first 30 minutes after dosing. An increase in palifermin concentrations occurred at around 2 to 4 hours post-dose for some subjects, which was followed by a second, slow decline phase. A similar trend has been observed in adult patients. The mean half-life range was 2.6 to 5.6 hours in pediatric patients following the first 60 mcg/kg dose o f Kepivance. No accumulation was observed following 3 consecutive doses o f Kepivance. Palifermin exposure did not increase linearly with increasing doses. The first dose AUC0-inf (mean) o f Kepivance 60 mcg/kg/day in adult patients (18 to 63 years) was 38.2 ng*hr/mL compared to 46.1 ng*hr/mL (range of means: 22.8 to 81.6) for pediatric patients (1 to 16 years). The mean clearance was 1730 mL/hr/kg for adults and 2481 mL/hr/kg (range of means: 1700 to 3460) in pediatric patients.
Clinical studies o f Kepivance did not include sufficient numbers o f subjects aged 65 years and older to determine whether they responded differently from younger subjects. [see CLINICAL PHARMACOLOGY].
Patients With Renal Impairment
No dose adjustment is recommended for patients with renal impairment [see CLINICAL PHARMACOLOGY].
Patients With Hepatic Impairment
The pharmacokinetic profile in patients with hepatic insufficiency has not been assessed.This monograph has been modified to include the generic and brand name in many instances.
Last reviewed on RxList: 4/19/2016
Additional Kepivance Information
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