Kepivance

Cytoprotectant Agents

Hazardous Drugs Classification
NIOSH 2016 List: Group 2
NIOSH (Draft) 2020 List: Table 2
Observe and exercise appropriate precautions for handling, preparation, administration, and disposal of hazardous drugs.
Use double chemotherapy gloves and a protective gown. Prepare in a biological safety cabinet or compounding aseptic containment isolator with a closed system drug transfer device. Eye/face and respiratory protection may be needed during preparation and administration.

Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.

For intravenous use only.
Preparation of Injection:
The lyophilized powder should ONLY be reconstituted with Sterile Water for Injection, USP.
Use aseptic technique and slowly inject 1.2 ml of Sterile Water for Injection, USP to yield a final concentration of 5 mg/ml.
Swirl contents gently. Do not shake or vigorously agitate the vial. Generally, dissolution takes < 3 minutes.
Do not filter the injection during preparation.
Protect from light.
The reconstituted solution contains no preservatives and is for single use only. Following reconstitution, it is recommended that the product be used immediately. If not used immediately, the reconstituted solution may be stored refrigerated in its carton at 2—8 degrees C (36—46 degrees F) for up to 24 hours. Do NOT freeze. NOTE: Prior to injection, palifermin may be allowed to reach room temperature for a maximum of 1 hour but should be protected from light. Discard any injection left at room temperature for > 1 hour.
IV bolus administration of the Injection:
The reconstituted solution should be clear and colorless.
Do not filter the injection during administration.
Administer by IV bolus injection.
NOTE: If heparin is used to maintain an IV line, saline should be used to rinse the line prior to and after palifermin administration to avoid increased palifermin exposure resulting from a drug interaction.

hyperamylasemia / Delayed / 38.0-38.0
rash / Early / 3.0-3.0

erythema / Early / 32.0-32.0
edema / Delayed / 28.0-28.0
hypertension / Early / 7.0-7.0
antibody formation / Delayed / 2.0-2.0
hyperesthesia / Delayed / Incidence not known
palmar-plantar erythrodysesthesia (hand and foot syndrome) / Delayed / Incidence not known
cataracts / Delayed / Incidence not known

fever / Early / 39.0-39.0
pruritus / Rapid / 35.0-35.0
tongue discoloration / Delayed / 17.0-17.0
dysgeusia / Early / 16.0-16.0
dysesthesia / Delayed / 12.0-12.0
arthralgia / Delayed / 10.0-10.0
hypoesthesia / Delayed / Incidence not known
paresthesias / Delayed / Incidence not known
infection / Delayed / Incidence not known

Kepivance

Rx

Recombinant human keratinocyte growth factor (KGF)
Indicated as supportive care in patients with hematologic malignancies who are receiving a myelotoxic preparative regimen followed by an autologous hematopoietic stem cell transplantation that is predicted to result in a high incidence of WHO Grade 3 or higher mucositis
Not recommended for use in patients with nonhematologic malignancies, in patients receiving an allogeneic stem cell transplantation, or in combination with melphalan 200 mg/m2 as a conditioning regimen

60 mcg/kg IV bolus injection given once daily for 3 consecutive days before and once daily for 3 consecutive days after myelotoxic therapy for a total of 6 doses. Administer the first 3 doses prior to myelotoxic therapy, with the third dose given 24 to 48 hours before myelotoxic therapy is started. Administer the last 3 doses after myelotoxic therapy is complete; administer the first of these doses on the same day of hematopoietic stem cell infusion but after the infusion is complete and at least 7 days after the most recent administration of palifermin. Do not administer within 24 hours before, during, or within 24 hours after myelotoxic chemotherapy; concomitant use of palifermin and chemotherapy led to increased severity and duration of oral mucositis in a clinical trial. The incidence of World Health Organization (WHO) grade 3 or 4 mucositis was significantly less with palifermin therapy compared with placebo (63% vs. 98%; p < 0.001) in patients with hematologic cancers who received myelosuppressive conditioning therapy prior to an autologous hematopoietic stem-cell transplantation (HSCT) in a randomized, double-blind, phase III trial (n = 212). The median duration of WHO grade 3 or 4 mucositis was 6 days (range, 1 to 22 days) in the palifermin arm and 9 days (range, 1 to 27 days) in the placebo arm (p < 0.001). Additionally, patients who received palifermin required significantly less parenteral or transdermal opioid analgesics for mucositis (morphine equivalents, 212 mg vs. 535 mg; p < 0.001) for a significantly shorter amount of time (7 days vs. 11 days (range, 0 to 32 days); p < 0.001) compared with patients who received placebo in this study. Conditioning chemotherapy was administered starting 1 day after total-body irradiation and consisted of etoposide 60 mg/kg IV given 4 days prior to HSCT and cyclophosphamide 100 mg/kg IV given 2 days prior to HSCT.

No dosage adjustments are recommended; however, the drug has not been specifically assessed in patients with hepatic impairment.

No dosage adjustments are recommended; however, the drug has not been specifically assessed in patients with renal impairment.

Dalteparin: (Moderate) The co-administration of palifermin and unfractionated heparin may result in a 4 to 5-fold increase in palifermin exposure; however, this interaction does not appear to affect the pharmacodynamics of either drug. If heparin is used to maintain an IV line, rinse the line with saline prior to and after palifermin administration. The palifermin AUC value was increased by 5-fold and the mean clearance was decreased by 80% after a single 60 mcg/kg dose of palifermin was administered with therapeutic levels of unfractionated heparin compared with no heparin in 27 healthy subjects. The activated partial thromboplastin time (aPTT) was not affected by this interaction. The palifermin AUC value was increased by 425% and the palifermin clearance, volume of distribution, and half-life was decreased by 76.5%, 73.1%, and 38.8%, respectively, following the administration of palifermin 40 mcg/kg/day for 3 days in combination with therapeutic levels of unfractionated heparin compared with no heparin in 31 healthy subjects. Palifermin administration results in a dose-dependent epithelial cell proliferation that may be assessed by Ki67 immunohistochemical staining. In this study, the pharmacokinetics of palifermin did not affect Ki67 expression in buccal biopsies. The co-administration of palifermin and low-molecular weight heparins (LMWHs), such as enoxaparin and dalteparin, is expected to have a similar interaction.
Enoxaparin: (Moderate) The co-administration of palifermin and unfractionated heparin may result in a 4 to 5-fold increase in palifermin exposure; however, this interaction does not appear to affect the pharmacodynamics of either drug. If heparin is used to maintain an IV line, rinse the line with saline prior to and after palifermin administration. The palifermin AUC value was increased by 5-fold and the mean clearance was decreased by 80% after a single 60 mcg/kg dose of palifermin was administered with therapeutic levels of unfractionated heparin compared with no heparin in 27 healthy subjects. The activated partial thromboplastin time (aPTT) was not affected by this interaction. The palifermin AUC value was increased by 425% and the palifermin clearance, volume of distribution, and half-life was decreased by 76.5%, 73.1%, and 38.8%, respectively, following the administration of palifermin 40 mcg/kg/day for 3 days in combination with therapeutic levels of unfractionated heparin compared with no heparin in 31 healthy subjects. Palifermin administration results in a dose-dependent epithelial cell proliferation that may be assessed by Ki67 immunohistochemical staining. In this study, the pharmacokinetics of palifermin did not affect Ki67 expression in buccal biopsies. The co-administration of palifermin and low-molecular weight heparins (LMWHs), such as enoxaparin and dalteparin, is expected to have a similar interaction.
Heparin: (Moderate) The co-administration of palifermin and unfractionated heparin may result in a 4 to 5-fold increase in palifermin exposure; however, this interaction does not appear to affect the pharmacodynamics of either drug. If heparin is used to maintain an IV line, rinse the line with saline prior to and after palifermin administration. The palifermin AUC value was increased by 5-fold and the mean clearance was decreased by 80% after a single 60 mcg/kg dose of palifermin was administered with therapeutic levels of unfractionated heparin compared with no heparin in 27 healthy subjects. The activated partial thromboplastin time (aPTT) was not affected by this interaction. The palifermin AUC value was increased by 425% and the palifermin clearance, volume of distribution, and half-life was decreased by 76.5%, 73.1%, and 38.8%, respectively, following the administration of palifermin 40 mcg/kg/day for 3 days in combination with therapeutic levels of unfractionated heparin compared with no heparin in 31 healthy subjects. Palifermin administration results in a dose-dependent epithelial cell proliferation that may be assessed by Ki67 immunohistochemical staining. In this study, the pharmacokinetics of palifermin did not affect Ki67 expression in buccal biopsies. The co-administration of palifermin and low-molecular weight heparins (LMWHs), such as enoxaparin and dalteparin, is expected to have a similar interaction.
Low Molecular Weight Heparins: (Moderate) The co-administration of palifermin and unfractionated heparin may result in a 4 to 5-fold increase in palifermin exposure; however, this interaction does not appear to affect the pharmacodynamics of either drug. If heparin is used to maintain an IV line, rinse the line with saline prior to and after palifermin administration. The palifermin AUC value was increased by 5-fold and the mean clearance was decreased by 80% after a single 60 mcg/kg dose of palifermin was administered with therapeutic levels of unfractionated heparin compared with no heparin in 27 healthy subjects. The activated partial thromboplastin time (aPTT) was not affected by this interaction. The palifermin AUC value was increased by 425% and the palifermin clearance, volume of distribution, and half-life was decreased by 76.5%, 73.1%, and 38.8%, respectively, following the administration of palifermin 40 mcg/kg/day for 3 days in combination with therapeutic levels of unfractionated heparin compared with no heparin in 31 healthy subjects. Palifermin administration results in a dose-dependent epithelial cell proliferation that may be assessed by Ki67 immunohistochemical staining. In this study, the pharmacokinetics of palifermin did not affect Ki67 expression in buccal biopsies. The co-administration of palifermin and low-molecular weight heparins (LMWHs), such as enoxaparin and dalteparin, is expected to have a similar interaction.

Kepivance Intravenous Inj Pwd F/Sol: 6.25mg

60 mcg/kg/day IV for 6 days.

60 mcg/kg/day IV for 6 days.

Safety and efficacy have not been established.

Safety and efficacy have not been established.

Mechanism of Action: Palifermin is a recombinant human keratinocyte growth factor (rHuKGF). Keratinocyte growth factor (KGF) is a 28-kDa member of the fibroblast growth factor (FGF) family, and specifically binds to a KGF receptor, which is expressed only in epithelial cells. Like the endogenous keratinocyte growth factor, palifermin targets epithelial cells to encourage epithelial cell proliferation, differentiation, migration, and upregulation. The actions are cytoprotective to these cells, aiding host defenses. The KGF receptor, one of four 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, and the lens of the eye. The KGF receptor has been reported to not be present on cells of the hematopoietic cell line. Endogenous KGF is produced by mesenchymal cells and is upregulated in response to epithelial tissue injury. Palifermin has been studied in murine models of chemotherapy and radiation-induced gastrointestinal injury. In such models, administration of palifermin prior to and/or after the cytotoxic insult improved survival and reduced weight loss compared to control animals. Epithelial cell proliferation in healthy subjects has been studied at doses of 40—250 mcg/kg. A 3-fold or greater increase in Ki67 immunohistochemical staining was observed in buccal biopsies from 3 of 6 healthy subjects given palifermin 40 mcg/kg IV for 3 days while a dose-dependent epithelial cell proliferation was observed 48 hours post-dose in healthy subjects given a 120—250 mcg/kg single IV dose.Palifermin has been shown to enhance the growth of human epithelial tumor cell lines in vitro at concentrations >= 10 mcg/ml (> 15-fold higher than average therapeutic concentrations in humans) and to increase the rate of tumor cell line growth in a human carcinoma xenograft model. In nude mouse xenograft models, three consecutive daily doses of palifermin 1500 and 4000 mcg/kg (25- and 67-fold higher than the recommended human dose, respectively) repeated weekly for 4 to 6 weeks were associated with a dose-dependent increase in the growth rate of 1 of 7 KGF receptor-expressing human tumor cell lines (see Contraindications).

Palifermin is administered intravenously (IV). Palifermin exhibits linear pharmacokinetics with extravascular distribution. After a single dose of 60 mcg/kg/day, the mean AUC was 38.2 ng*hr/mL and mean clearance 1730 mL/hr/kg. At this dose, the total body clearance is 2- to 4-fold higher, and volume of distribution at steady state is 2-fold higher in cancer patients compared with healthy subjects. The elimination half-life is similar between healthy subjects and cancer patients (mean 4.5 hours, range 3.3—5.7 hours).

Following a single intravenous injection of 20—250 mcg/kg IV (healthy subjects) and 60 mcg/kg IV (cancer patients), palifermin concentrations decline greater than 95% in the first 30 minutes post-dose. A slight increase or plateau in concentration occurs at approximately 1—4 hours, followed by a terminal elimination phase.

Palifermin may cause fetal harm if used during pregnancy, based on data from animal studies. Increased post-implantation loss and decreased fetal body weights occurred in the off-spring of female rabbits following palifermin doses that resulted about 5 times the exposure (AUC) observed in humans at the recommended dose. Additionally, increased skeletal variations were reported in the off-spring of female rats who received palifermin doses that resulted about 35 times the exposure observed in humans at the recommended dose.

It is not known if palifermin is secreted in human milk or if it has effects on the breast-fed infant or on milk production. Due to the risk of serious adverse reactions in a nursing child, women should discontinue breast-feeding during palifermin therapy and for at least 2 weeks after the last dose.