"The U.S. Food and Drug Administration today approved Dotarem (gadoterate meglumine) for use in magnetic resonance imaging (MRI) of the brain, spine and associated tissues of patients ages 2 years and older.
Dotarem is a gadolinium-based"...
Mechanism of Action
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, 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, mammar gland, skin (hair follicles and sebaceous gland), and the lens of the eye. The KGF receptor has been reported to not be present on cells of the hematopoietic lineage. Endogenous KGF is produced by mesenchymal cells and is upregulated in response to epithelial tissue injury.
In mice and rats, Kepi vance enhanced proliferation of epithelial cells (as measured by Ki67 immunohistochemical staining and BrDU uptake) and demonstrated an increase in tissue thickness of the tongue, buccal mucosa, and gastrointestinal tract. Kepivance has been studied in murine models of chemotherapy and radiation- induced gastrointestinal injury. In such models, administration of Kepivance prior to and/or after the cytotoxic insult improved survival and reduced weight loss compared to control animals.
Kepivance has been shown to enhance the growth of human epithelial tumor cell lines in vitro at concentrations ≥ 10 mcg/mL (> l5-fold higher than average therapeutic concentrations in humans). In nude mouse xenograft models; three consecutive daily treatments of Kepi vance at doses of 1,500 and 4,000 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 of7 KGF receptor-expressing human tumor cell lines.
Epithelial cell proliferation was assessed by Ki67 immunohistochemical staining in healthy subjects. A 3-fold or greater increase in Ki67 staining was observed in buccal biopsies from 3 of 6 healthy subjects given Kepivance at 40 mcg/g/day intravenously for 3 days, when measured 24 hours after the third dose. Dose-dependent epithelial cell proliferation was observed in healthy subjects given single intravenous doses of 120 to 250 mcg/g 48 hours post-dosing.
The pharmacokinetics of Kepivance Were studied in healthy subjects and patients with hematologic malignancies. After single intravenous doses of20 to 250 mcg/kg in healthy subjects and 60 mcglg in cancer patients, Kepivance concentrations declined over 95% in the first 30 minutes post-dose. A slight increase or plateau in concentration occuned at approximately 1 to 4 hours, followed by a terminal decline phase. Kepivance exhibited linear pharmacokinetics with extravascular distribution. In cancer patients compared with healthy subjects, after a 60 mcg/kg single dose of Kepivance the average total body clearance (CL) was 2- to 4-fold higher, and volume of distribution at steady state (Vss) was 2-fold higher. The elimination half-life was similar between healthy subjects and cancer patients (average 4.5 hours with a range of3.3 to 5.7 hours). No accumulation of Kepivance occurred after 3 consecutive daily doses of 20 and 40 mcg/kg in healthy subjects or 60 mcg/kg in cancer patients.
The potential pharmacokinetic interaction between palifermin and heparin was evaluated in a single-dose study in 27 healthy subjects receiving palifermin (60 mcg/kg) co-administered with and without therapeutic levels of unfractionated heparin. This co-administration resulted in a 5-fold increase in palifermin AUC and 80% decrease in the mean CL. There was no significant effect ofpalifermin on heparin activity with respect to activated parial thromboplastin time (aPTT). The clinical relevance of this observed increase in palifermin systemic exposure is unclear [see DRUG INTERACTIONS].
Results from a pharmacokinetics study in 24 subjects with varing degrees of renal impairment demonstrated that renal impairment has little or no influence on Kepivance phanacokinetics [see Use in Spectfc Populations].
In a single-dose study, subjects received a l80-mcg/kg or 90-mcg/g dose of palifermin administered by intravenous bolus injection. Subjects over the age of 65 (n=8) had an approximately 30% lower rate ofCL on average than those 65 and younger (n=19). No dosè adjustment is recommended for the geriatric population [see Use in Spectfc Populations].
Reproductive and Developmental Toxicology
In animal reproductive toxicity studies, paliferminis embryotoxic at doses that are 2.5 times (rabbits) and 5 to > 8 times (rats) the MRHD, based on body weight (mcg/kg). Pregnant rabbits received intravenous palifermin during organogenesis at doses equivalent to 1.0 and 2.5 times the MRHD, based on body weight (mcg/kg). Increased post-implantation loss and decreased fetal body weights occuned along with maternal toxicity (clinical signs and reductions in body weight gain/food consumption) at doses 2.5 times the MRHD.
In pregnant rats, animals received intravenous palifermin during organogenesis at doses of 5 to > 8 times the MRHD based on body weight (mcg/kg). Increased post-implantation loss, decreased fetal body weight, and/or increased skeletal variations occurred in the presence of maternal toxicity at doses > 8 times the MRHD.
Autologous transplantation preparative regimens that include total body irradiation
The safety and effcacy of Kepivance in decreasing the incidence and duration of severe oral mucositis in patients with hematologic malignancies (NHL, Hodgkin's disease, acute myeloid leukemia, acute lymphoblastic leukemia, chronic myeloid leukemia, chronic lymphocytic leukemia, or multiple myeloma) receiving myelotoxic therapy requiring hematopoietic stem cell support were established in a randomized placebo-controlled clinical trial of212 patients (Study 1) and a randomized, schedule-ranging, placebo-controlled clinical trial of 169 patients (Study 2).
In Study 1, patients received high-dose cytotoxic therapy consisting of fractionated total-body inadiation (TBI) (12 Gy total dose), high-dose etoposide (60 mg/g), and high-dose cyclophosphamide (100 mg/g) followed by hematopoietic stem cell support. Patients were randomized to receive either Kepivance (n = 106) or placebo (n = 106). Kepivance 60 mcg/g was administered as a daily intravenous injection for 3 consecutive days prior to initiation of cytotoxic therapy and for 3 consecutive days following infusion of hematopoietic stem cells. The major effcacy outcome was the number of days during which patients experienced severe oral mucositis (Grade 3/4 on the WHO (World Health Organization) scale)1. Other analyses included the incidence, duration, and severity of oral mucositis and the use of opioid analgesia. There was no evidence of a delay in time to hematopoietic recovery in patients who received Kepivance as compared to patients who received placebo. The results of Study 1 are presented in Table 2 and Figure 1.
Table 2: Study 1 Effcacy Outcomes
(n = 106)
(n = 106)
|Median (25th, 75th percentile) Days of WHO Grade 3/4 Oral Mucositis*||3 (0,6)||9 (6, 13)|
|Incidence of WHO Grade 3/4 Oral Mucositis||63% (67/06)||98% (104/106)|
|Median (25th, 75th percentile) Days of WHO Grade 3/4 Oral Mucositis in Affected Patients||6 (3, 8)
(n = 67)
|9 (6, 13)
(n = 104)
|Incidence of WHO Grade 4 Oral Mucositis||20%||62%|
|Median (25th, 75th percentile) Cumulative Opiod Dose (morphine mg equivalents)||212 (3, 558)||535 (269, 1429)|
|* P < 0.001 compared to placebo, using Generalized Cochran-Mantel-Haenszel (CMH) test stratified for study center.|
Figure 1: Study 1 - Incidence of Oral Mucositis by Maximum
Grade WHO Oral Mucositis Scale
Study 2 was a randomized, multi-center, placebo-controlled trial comparing varying schedules of Kepivance. All patients received high-dose cytotoxic therapy consisting of fractionated TBI (I2cGy total dose), high-dose etoposide (60 mglkg), and high-dose cyclophosphaiide (75-100 mg/g) followed by hematopoietic stem cell support. The results for Study i were supported by results observed in the subset of patients in Study 2 who received the same dose and schedule of Kepi vance administered in Study 1. One ann of Study 2 that included patients who received Kepivance for 3 consecutive days prior to initiation of cytotoxic therapy, a dose given on the last day ofTBI prior to etoposide, and for 3 consecutive days following infusion of hematopoietic stem cells was prematurely closed by the Safety Committee for lack of effcacy and a trend towards increased severity and duration of oral mucositis as compared to placebo-treated patients, The Safety Committee attributed the safety finding to Kepivance having been administered within 24 hours of chemotherapy, which resulted in an increased sensitivity of the rapidly dividing epithelial cells in the immediate post-chemotherapy period [see DOSAGE AND ADMINISTRATION and DRUG INTERACTIONS]
Lack of Effcacy: Autologous transplantation preparative regimen using high dose melphalan
In a post approval study, Study 3, designed to determine the effcacy of Kepivance with a high dose melphalan preparative regimen, patients with multiple myeloma were evaluated in a multicenter, randomized, double-blind, placebo-controlled triaL. The conditioning regimen was melphalan (200 mg/m2) on day -2 followed by autologous hematopoietic stem cell support. A total of281 patients were randomized to 3 ans: Kepivance before melphalan on days -6, -5, -4 and afer melphalan on days 0, I, and 2 (pre-post) (n=115); Kepivance before melphalan on days -6, -5, -4 (pre) (n=109); or placebo (n=57).
The main outcome of the study was maximum severity of WHO oral mucositis. The median age of enrolled patients was 57 years (range 32-69), and 55% were male. The results are presented in Figure 2. The prespecified primary analysis was a comparison between the Kepivance pre-post and pre arms to placebo. The incidence of WHO Grade 3 and 4 in the Kepivance pre-post arm was 38%, compared to 37% in the placebo arm. There were no significant differences between either of the Kepivance regimens and the placebo arm in the incidence of severe oral mucositis.
Figure 2: Incidence of Oral Mucositis by Maximum Grade WHO
Oral Mucositis Scale in High Dose Melphalan Study
A subset of subjects enrolled in the multiple myeloma study were included in an evaluation for the risk of cataract development in patients receiving Kepivance treatment. Ophthalmologic examinations were performed on 101 patients enrolled in a double-blind, randomized, placebo-controlled study of two different schedules of Kepivance (pre and post chemotherapy and pre chemotherapy only) for reduction in severity of oral mucositis in subjects with multple myeloma receiving high dose melphalan followed by autologous peripheral blood stem cell transplantation. For the primary cataract endpoint of incidence of cataact development or cataract progression at Month 12, there was a greater proportion of subjects that experienced cataract development in the Kepivance group: 48% (25/52) compared with the placebo group; 29% (4/14) (diffèrence of 17 (95% CI: -11, 46)) [see ADVERSE REACTIONS - Clinical Trial Experience]
1. WHO Oral Mucositis Scale: Grade 1 = soreness/eryhema; Grade 2 = eryhema, ulcers, can eat solids; Grade 3 = ulcers, requires liquid diet only; Grade 4 = alimentation not possible
Last reviewed on RxList: 12/7/2011
This monograph has been modified to include the generic and brand name in many instances.
Additional Kepivance Information
Report Problems to the Food and Drug Administration
You are encouraged to report negative side effects of prescription drugs to the FDA. Visit the FDA MedWatch website or call 1-800-FDA-1088.
Find out what women really need.