Palifermin

Kepivance is a mucocutaneous epithelial human growth factor indicated to decrease the incidence and duration of severe oral mucositis in patients with hematologic malignancies receiving myelotoxic therapy in the setting of autologous hematopoietic stem cell support. Kepivance is indicated as supportive care for preparative regimens predicted to result in ≥ WHO Grade 3 mucositis in the majority of patients. ( 1.1 ) Limitations of Use The safety and efficacy of Kepivance have not been established in patients with non-hematologic malignancies ( 1.2 , 5.1 ) Kepivance was not effective in decreasing the incidence of severe mucositis in patients with hematologic malignancies receiving myelotoxic therapy in the setting of allogeneic hematopoietic stem cell support. ( 1.2 , 14.3 ) Kepivance is not recommended for use with melphalan 200 mg/m 2 as a conditioning regimen ( 14.2 ).

1.1 Indications Kepivance is indicated to decrease the incidence and duration of severe oral mucositis in patients with hematologic malignancies receiving myelotoxic therapy in the setting of autologous hematopoietic stem cell support. Kepivance is indicated as supportive care for preparative regimens predicted to result in ≥ WHO Grade 3 mucositis in the majority of patients. Kepivance is a mucocutaneous epithelial human growth factor indicated to decrease the incidence and duration of severe oral mucositis in patients with hematologic malignancies receiving myelotoxic therapy in the setting of autologous hematopoietic stem cell support. Kepivance is indicated as supportive care for preparative regimens predicted to result in ≥ WHO Grade 3 mucositis in the majority of patients.

1.2 Limitations of Use The safety and efficacy of Kepivance have not been established in patients with non-hematologic malignancies )]. The safety and efficacy of Kepivance have not been established in patients with non-hematologic malignancies [see Warnings and Precautions ( 5.1 )]. Kepivance was not effective in decreasing the incidence of severe mucositis in patients with hematologic malignancies receiving myelotoxic therapy in the setting of allogeneic hematopoietic stem cell support. Kepivance was not effective in decreasing the incidence of severe mucositis in patients with hematologic malignancies receiving myelotoxic therapy in the setting of allogeneic hematopoietic stem cell support [See Clinical Studies ( 14.3 )] . Kepivance is not recommended for use with melphalan 200 mg/m as a conditioning regimen. Kepivance is not recommended for use with melphalan 200 mg/m 2 as a conditioning regimen [See Clinical Studies ( 14.2 )] .

For injection: 5.16 mg lyophilized powder in single-dose vials. For injection: 5.16 mg lyophilized powder in single-dose vials ( 3 )

None None

Potential for stimulation of tumor growth — Kepivance is not indicated for non-hematologic tumors. The effects of Kepivance on stimulation of keratinocyte growth factor (KGF) receptor-expressing, non-hematopoietic tumors in patients are not known ( 1 , 5.1 )

5.1 Potential for Stimulation of Tumor Growth The safety and efficacy of Kepivance have not been established in patients with non-hematologic malignancies. The effects of Kepivance on stimulation of KGF receptor-expressing, 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 [see Clinical Pharmacology ( 12.1 )].

Most common adverse reactions (incidence ≥20% and 5%≥placebo) are rash, fever, elevated serum amylase, pruritus, erythema, and edema ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Swedish Orphan Biovitrum at 1-866-773-5274 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 Clinical Trial Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. The data described in Table 1 and the discussion below reflect exposure to Kepivance in 409 patients with hematologic malignancies who were enrolled in 3 randomized, placebo-controlled clinical trials and a pharmacokinetic study. Patients received Kepivance either before, or before and after, regimens of myelotoxic chemotherapy, with or without total body irradiation (TBI), followed by hematopoietic stem cell support. Kepivance was administered in daily doses ranging from 5 to 80 mcg/kg/day. The total dose of Kepivance ranged from 15 to 480 mcg/kg with a median of 360 mcg/kg. The population had a median age of 48 years (range: 41 to 60 years), 62% were male and 83% were White with 7.4 % Black and 6.2 % Hispanic. Non Hodgkin's lymphoma (NHL) was the most common malignancy followed by Hodgkin's disease, multiple myeloma, and leukemia. 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. 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. The most common serious adverse reaction attributed to Kepivance was skin rash, reported in less than 1% (3/409) of patients treated. Grade 3 skin rashes occurred in 3% of patients (9/409) receiving Kepivance and 2% (5/241) receiving placebo. Table 1. Incidence of Adverse Reactions Occurring with a Between-Group Difference of ≥ 5% BODY SYSTEM Adverse Reaction Kepivance (n = 409) % Placebo (n = 241) % BODY AS A WHOLE Edema 28 21 Pain 16 11 Fever 39 34 GASTROINTESTINAL Mouth/Tongue Thickness or Discoloration 17 8 MUSCULOSKELETAL Arthralgia 10 5 SKIN AND APPENDAGES Rash 62 50 Pruritus 35 24 Erythema 32 22 SPECIAL SENSES Taste Altered 16 8 CENTRAL NERVOUS SYSTEM / PERIPHERAL NERVOUS SYSTEM Dysesthesia – Hyperesthesia / hypoesthesia/ paresthesia 12 7 METABOLIC Elevated serum lipase All grades 28 23 Grade 3 and 4 11 5 Elevated serum amylase All grades 62 54 Grade 3 and 4 38 31 Cataracts: In a postmarketing safety study, the incidence of cataracts was numerically higher among patients receiving Kepivance than in the control population. (See 14 CLINICAL STUDIES ). Infections: In a randomized, double-blind, placebo-controlled post-approval study designed to determine the efficacy of Kepivance with a high-dose melphalan preparative regimen, the incidence of treatment-emergent infections was significantly greater in patients treated with Kepivance compared to placebo. A total of 281 patients were randomized to 3 arms: Kepivance before melphalan on days -6, -5, -4 and after melphalan on days 0, 1, and 2 (pre-post) (n=115); Kepivance before melphalan on days -6, -5, -4 (pre) (n=109); or placebo (n=57). The incidence of reported infections were pre-post – 50%; pre – 47%; and placebo – 25% [see Clinical Studies ( 14.2 )] . Laboratory Test Findings: Reversible elevations in serum lipase and amylase, which did not require treatment, were reported in 28% and 62% of patients receiving Kepivance and 23% and 54% of patients receiving placebo. In general, peak increases were observed during the period of cytotoxic therapy and returned to baseline by the day of hematopoietic stem cell infusion. Amylase was mainly salivary in origin.

6.2 Immunogenicity As with all therapeutic proteins, there is a potential for immunogenicity. The clinical significance of antibodies to Kepivance is unknown but may include decreased activity and/or cross reactivity with other members of the FGF family of growth factors. In clinical trials, serum samples from patients treated with Kepivance were tested for antibodies to Kepivance using an electrochemiluminescence-based binding assay. Twelve of 645 patients (2%) tested positive; none had evidence of neutralizing activity in a cell-based assay. 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.

6.3 Postmarketing Experience The following adverse reactions have been identified during postapproval use of Kepivance in the stem cell transplant setting. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Vaginal edema and erythema; Palmar-plantar Erythrodysaesthesia Syndrome (also known as “hand-foot syndrome”)

In vitro and in vivo data showed that palifermin interacts with unfractionated as well as low molecular weight heparins with no noticeable effect on the pharmacodynamics of either drug. If heparin is used to maintain an intravenous line, rinse the line with saline prior to and after Kepivance administration [see Clinical Pharmacology ( 12.3 )] . Do not administer Kepivance within 24 hours before, during infusion of, or within 24 hours after administration of myelotoxic chemotherapy [see Dosage and Administration ( 2.1 ) and Clinical Studies ( 14 )]. In a clinical trial, administration of Kepivance within 24 hours of chemotherapy resulted in increased severity and duration of oral mucositis. Heparin increases systemic exposure; flush intravenous line between heparin and Kepivance. ( 7 ) Do not administer within 24 hours of myelotoxic chemotherapy. ( 7 , 14 )

Pregnancy: Based on animal data, may cause fetal harm ( 8.1 ) Lactation: Breastfeeding not recommended 8.2 )

8.1 Pregnancy Risk Summary Based on findings in animal studies, Kepivance may cause fetal harm when administered to pregnant women. There are no data available on Kepivance use in pregnant women to inform a drug-associated risk of major birth defects and miscarriage or adverse maternal or fetal outcomes. In animal reproduction studies, intravenous administration of palifermin to pregnant rabbits and rats during the period of organogenesis resulted in embryo-fetal mortality and alterations to growth [see Data ] . The estimated background risk of major birth defects and miscarriage for the indicated populations is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. Data Animal data In embryo-fetal development studies, palifermin was administered intravenously to pregnant rabbits and rats during the perid of organogenesis. Doses were 5, 60, and 150 μg/kg/day in rabbits (gestation days 6-18) and 100, 300, and 1000 μg/kg/day in rats (gestation days 6 through 17). Increased post-implantation loss and decreased fetal body weights occurred along with maternal toxicity (clinical signs and reductions in body weight gain and food consumption) at doses of 150 μg/kg/day in rabbits and 1000 μg/kg/day in rats. Increased skeletal variations was noted in rats at 1000 μg/kg/day. Doses of 150 μg/kg/day in rabbits and 1000 μg/kg/day in rats are approximately 5-times (rabbits) and 35-times (rats) the exposure (AUC) in patients receiving the recommended dose of 60 μg/kg/day.

8.2 Lactation Risk Summary There are no data on the presence of Kepivance in human milk, the effect on the breastfed child, or the effect on milk production. Since many drugs are secreted into human milk, and because of the potential for serious adverse reactions in a nursing child, breastfeeding should be discontinued during treatment and for at least 2 weeks after the last dose.

8.3 Females and Males of Reproductive Potential Infertility Based on findings from animal studies, palifermin may impair fertility in females and males of reproductive potential [see Nonclinical Toxicology ( 13.1 )] . The reversibility of the effects on fertility is unknown.

8.4 Pediatric Use Information on the dosing and safety of Kepivance in the pediatric population is limited. However, use of 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 of fractionated total body irradiation (TBI) (12 Gy total dose), high dose etoposide (1500 mg/m 2 ), and high dose cyclophosphamide (120 mg/kg) followed by allogeneic hematopoietic stem cell support. The dose intensity of this preparative regimen is comparable to the dose intensity of the Study 1 preparative regimen. See Clinical Studies [14.1]. Kepivance 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. 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 μg/kg cohort. The overall incidence of WHO grade 3 and 4 oral mucositis was 10/27 (37%). The pharmacokinetics of 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 of Kepivance. No accumulation was observed following 3 consecutive doses of Kepivance. Palifermin exposure did not increase linearly with increasing doses. The first dose AUC 0-inf (mean) of 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.

8.5 Geriatric Use Clinical studies of Kepivance did not include sufficient numbers of subjects aged 65 years and older to determine whether they responded differently from younger subjects [see Clinical Pharmacology ( 12.3 )].

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, mammary 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, Kepivance 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 (> 15-fold higher than average therapeutic concentrations in humans). In nude mouse xenograft models, three consecutive daily treatments of Kepivance 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 of 7 KGF receptor-expressing human tumor cell lines.