KEPIVANCE

1 INDICATIONS AND USAGE 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 )] .

2 DOSAGE AND ADMINISTRATION Administer as an intravenous bolus injection at a dose of 60 mcg/kg/day for 3 consecutive days before and 3 consecutive days after myelotoxic therapy for a total of 6 doses ( 2.1 ) Administer the first 3 doses prior to myelotoxic therapy with the third dose 24 to 48 hours before myelotoxic therapy ( 2.1 ) Administer the last 3 doses after myelotoxic therapy is complete with the first of these doses on the day of hematopoietic stem cell infusion after the infusion is completed, and at least 7 days after the most recent administration of Kepivance ( 2.1 ) 2.1 Recommended Dosage Regimen The recommended dose of Kepivance is 60 mcg/kg/day, administered as an intravenous bolus injection for 3 consecutive days before and 3 consecutive days after myelotoxic therapy, for a total of 6 doses. The recommended dose of Kepivance is 60 mcg/kg/day, administered as an intravenous bolus injection for 3 consecutive days before and 3 consecutive days after myelotoxic therapy, for a total of 6 doses. Administer the first 3 doses prior to myelotoxic therapy. Administer the third dose 24 to 48 hours prior to beginning myelotoxic therapy Administer the first 3 doses prior to myelotoxic therapy. Administer the third dose 24 to 48 hours prior to beginning myelotoxic therapy [see Drug Interactions ( 7 )]. Administer the last 3 doses after myelotoxic therapy is complete; administer the first of these doses on the day of hematopoietic stem cell infusion after the infusion is completed, and at least 7 days after the most recent administration of Kepivance [see Drug Interactions ( 7 )]. 2.2 Preparation and Administration Preparation Prepare the solution for infusion, using aseptic technique, as follows: Reconstitute Kepivance lyophilized powder with Sterile Water for Injection, USP (not supplied) by slowly injecting 1.2 mL of Sterile Water for Injection, USP to yield a final concentration of 5 mg/mL. Swirl the contents gently during dissolution. Do not shake or vigorously agitate the vial. Dissolution of Kepivance can take up to 3 minutes. Visually inspect the solution for discoloration and particulate matter before administration. The reconstituted solution should be clear and colorless. Do not administer Kepivance if discoloration or particulates are observed. Do not filter the reconstituted solution during preparation or administration. Do not freeze the reconstituted solution. Protect from light. Administration Administer Kepivance by intravenous bolus injection. If heparin is used to maintain an intravenous line, rinse the line with saline prior to and after Kepivance administration [see Drug Interactions ( 7 )]. The reconstituted solution contains no preservatives and is intended for single use only. Discard any unused portion. Following reconstitution, it is recommended that the product be used immediately. If not used immediately, the reconstituted solution of Kepivance may be stored refrigerated in its carton at 2° to 8°C (36° to 46°F) for up to 24 hours. Prior to injection, allow Kepivance to reach room temperature for a maximum of 1 hour protected from light. Discard Kepivance left at room temperature for more than 1 hour.

4 CONTRAINDICATIONS None None

5 WARNINGS AND PRECAUTIONS 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 )].

7 DRUG INTERACTIONS 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 )

6 ADVERSE REACTIONS 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”)

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.