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| Safety & Tolerability |
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Safety data are based upon 409 patients with hematologic malignancies (NHL, Hodgkin's disease, AML, ALL, CML, CLL,
or multiple myeloma) who received Kepivance® and 241 patients who received placebo in 3 randomized,
placebo-controlled clinical studies and a pharmacokinetic study. Patients received Kepivance® either before,
or before and after regimens of myelotoxic CT, with or without TBI, followed by PBPC support.
The patients
were predominantly between the ages of 41 and 60 years
(median 48 yrs), male (62%), white (83%).
NHL was the most common
malignancy, followed by Hodgkin's disease, multiple myeloma, and leukemia.1
The most common serious adverse reaction attributed to Kepivance® was skin rash, which was reported
in less than 1% (3/409) of patients treated with Kepivance®. Grade 3 skin rashes occurred in 14 patients,
9 of 409 (3%) receiving Kepivance® and 5 of 241 (2%) receiving placebo. In seven patients (5 Kepivance®,
2 placebo), study drug was discontinued due to skin rash. Other serious adverse reactions occurred at a
similar rate in patients who received Kepivance® (20%) or placebo (21%). The most frequently reported
serious adverse events in Kepivance® and placebo-treated patients were fever, gastrointestinal events,
and respiratory events.1
The most common adverse reactions attributed to Kepivance® 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 Kepivance®, with a median duration of 5 days.1
In patients receiving Kepivance®, dysesthesia (including hyperesthesia, hypoesthesia, and paresthesia)
was usually localized to the perioral region, whereas in patients receiving placebo dysesthesias were more
likely to occur in extremities. Adverse events occurring more frequently in Kepivance®-treated patients as
compared to placebo-treated patients (a higher incidence of ≥ 5%) are listed in Table 1.1
Table 1. Adverse
Event Occurring With ≥ 5% Higher Incidence in Kepivance® vs. Placebo1
| Rash |
50% |
62% |
| Fever |
34% |
39% |
| Pruritus |
24% |
35% |
| Erythema |
22% |
32% |
| Edema |
21% |
28% |
| Pain |
11% |
16% |
Mouth/tongue thickness
or discoloration |
8% |
17% |
| Taste altered |
8% |
16% |
Dysesthesia (hyperesthesia/
hypoesthesia/paresthesia) |
7% |
12% |
| Arthralgia |
5% |
10% |
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Adopted from Kepivance® prescribing information.
Based on the overall clinical study program consisting of 650 patients with hematologic malignancies enrolled in 3
randomized, placebo-controlled studies and a pharmacokinetic study.1
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Hypertension. In a phase 1 placebo-controlled study in patients undergoing hematopoietic transplantation and receiving
Kepivance® (3 doses pre-myelotoxic therapy and 3 doses post-transplant), the proportion of Kepivance®-treated patients reporting
an adverse event of hypertension in the 60- and 80-mcg/kg/day Kepivance® cohorts was greater than in the placebo group
(2/15 patients [13%], 2/14 [14%], and 2/23 [9%], respectively). These events were transient and did not require treatment
discontinuation in any patient. In an integrated analysis of adverse events across Kepivance® studies in the hematology
transplant setting, hypertensive events were reported in 30/409 Kepivance® (7%) patients and 13/241 placebo (5%) patients.1
Proteinuria. In a placebo-controlled study conducted in 145 patients with metastatic colorectal cancer receiving
multi-cycle chemotherapy (5-FU/ lecovorin), serial urine specimens were collected for 27 placebo-treated and 54 Kepivance®-treated
patients. Among the 54 Kepivance®-treated patients, 9 patients with a baseline urinalysis negative for protein subsequently developed
2+ or greater proteinuria after treatment with Kepivance®.1 Among the 27 placebo-treated patients evaluated, none developed 2+ or
greater proteinuria. Because of the study design, the number of cycles with urine analysis data collected was higher in the
Kepivance®- treated patients. In addition, for the 9 patients with proteinuria, underlying medical conditions known to be
associated with proteinuria were present at baseline. A causal relationship between Kepivance® and proteinuria
has not been established.1
Laboratory values. Reversible elevations in serum lipase and amylase, which did not require treatment
intervention, are shown in Table 2 of the Kepivance® prescribing information. In general,
peak increases were observed during the period of cytotoxic therapy and returned to baseline by the day of
PBPC infusion. Fractionation of amylase revealed it to be predominantly salivary in origin.1
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As with all therapeutic proteins, there is a potential for immunogenicity. The clinical significance of
antibodies to Kepivance® is unknown but may include lessened activity and/or cross reactivity
with other members of the FGF family of growth factors.1
A sensitive electrochemiluminescence-based binding assay was performed on post-treatment sera from 645
patients treated with Kepivance® in clinical studies. Twelve (2%) of these 645 patients tested positive for
antibodies to Kepivance® following treatment. None of the samples had evidence of neutralizing activity in a cell-based assay.1
The incidence of antibody positivity is highly dependent on the specific assay and its sensitivity. Additionally,
the observed incidence of antibody positivity in an assay may be influenced by several factors including sample handling,
timing of sample collection, concomitant medications and underlying disease. For these reasons, comparison of the
incidence of antibodies to Kepivance® with the incidence of antibodies to other products may be misleading.1
The safety and efficacy of Kepivance® have not been established in patients with nonhematologic
malignancies. The effects of Kepivance® on stimulation of KGF receptorexpressing,
non-hematopoietic tumors in patients are not known. Kepivance® 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.1
Patients should be informed of the possible adverse effects of Kepivance®, including muco-cutaneous adverse effects. These include rash, erythema, edema, pruritus, oral/perioral dysesthesia, tongue discoloration, tongue thickening, and alteration of taste. Patients should be instructed to report these adverse effects, or any other adverse reactions, to the prescribing physician.
The safety and efficacy of Kepivance® have not been established in patients with nonhematologic malignancies. Patients should be informed of the evidence of tumor growth and stimulation in cell culture and in animal models of non-hematopoietic human tumors.1
No formal drug-drug interaction studies have been conducted for Kepivance® with drugs
that may be used in the intended patient population. Kepivance® has been shown to bind
to heparin in vitro. Therefore, if heparin is used to maintain an IV line, saline should be
used to rinse the line prior to and after Kepivance® administration.
Kepivance® should not be administered within 24 hours before, during infusion of, or
within 24 hours after administration of myelotoxic chemotherapy.
In a clinical trial,
administration of Kepivance® within 24 hours of chemotherapy resulted in increased
severity and duration of oral mucositis.1
Carcinogenicity: The carcinogenic potential of Kepivance® has not been evaluated in
long-term animal studies.
Mutagenicity: No clastogenic or mutagenic effects of Kepivance® were observed in the
Ames or mammalian chromosomal aberration assays; however, such studies are generally
not informative for biological products.
Impairment of Fertility: When Kepivance® was administered intravenously daily to
male and female rats prior to and during mating, reproductive performance, fertility, and
sperm assessment parameters were not affected at doses up to 100 mcg/kg/day. Systemic
toxicity (clinical signs of toxicity and/or body weight effects), decreased epididymal
sperm counts, and increased post-implantation loss were observed at doses
≥ 300 mcg/kg/day (5-fold higher than the recommended human dose). Increased preimplantation
loss and a decreased fertility index were observed at a Kepivance® dose of
1,000 mcg/kg/day.1
Kepivance® has been shown to be embryotoxic in rabbits and rats when given in doses
that are 2.5 and 8 times the human dose, respectively.
Increased post-implantation loss and decreased fetal body weights were observed when
Kepivance® was administered to pregnant rabbits from days 6 to 18 of gestation at IV
doses ≥ 150 mcg/kg/day (2.5-fold higher than the recommended human dose). However,
treatment with these doses was also associated with maternal toxicity (clinical signs and
reductions in body weight gain/food consumption). No evidence of developmental
toxicity was observed in rabbits at doses up to 60 mcg/kg/day.
Increased post-implantation loss, decreased fetal body weight and/or increased skeletal
variations were observed when Kepivance® was administered to pregnant rats from days
6 to 17 or 19 of gestation at IV doses 500 mcg/kg/day (> 8-fold higher than the
recommended human dose). Treatment with these doses was also frequently associated
with maternal toxicity (clinical signs and body weight effects). No evidence of
developmental toxicity was observed in rats at doses up to 300 mcg/kg/day.
There are no adequate and well-controlled studies in pregnant women. Kepivance®
should be used during pregnancy only if the potential benefit to the mother justifies the
potential risk to the fetus.1
It is not known whether Kepivance® is excreted in human milk. Because many drugs are
excreted in human milk, caution should be exercised when Kepivance® is administered to a nursing woman.1
The safety and effectiveness of Kepivance® in pediatric patients have not been established.1
Clinical studies of Kepivance® did not include sufficient numbers of subjects
age 65 years and over to determine whether they respond differently from younger subjects.
Among 409 patients with hematologic malignancies who received Kepivance® in clinical studies, 9 (2%) were ≥ age 65.1
| 1 |
Kepivance® (palifermin) prescribing information. |
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ABOUT ORAL MUCOSITIS
ABOUT KEPIVANCE®
TOOLS AND RESOURCES
FOR NURSES
FOR PHARMACISTS
IMPORTANT PRODUCT SAFETY INFORMATION
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