Kepivance

Advise patients to report the following to healthcare providers:

• Rashes and reddening of skin [see ADVERSE REACTIONS]
• Itchiness [see ADVERSE REACTIONS]
• Swelling of tongue [see ADVERSE REACTIONS]
• Changes in mouth and tongue sensation [see ADVERSE REACTIONS]
• Alteration in taste [see ADVERSE REACTIONS]

Inform patients

• That the safety and efficacy of Kepivance have not been established in patients with nonhematologic malignancies [see INDICATIONS AND USAGE and WARNINGS AND PRECAUTIONS]
• Of the evidence of tumor growth and stimulation in cell culture and in animal models of nonhematopoietic human tumors [see WARNINGS AND PRECAUTIONS and CLINICAL PHARMACOLOGY]

Medications can interact with certain foods. In some cases, this may be harmful and your doctor may advise you to avoid certain foods. In the case of Kepivance, there are no specific foods that you must exclude from your diet when receiving this medication.

Before taking Kepivance, tell your doctor about all of your medical conditions. Especially tell your doctor if you:

• are allergic to Kepivance or to any of its ingredients
• are pregnant or plan to become pregnant
• are breastfeeding or plan to breastfeed

Tell your doctor about all the medicines you take including prescription and non-prescription medicines, vitamins, and herbal supplements.

Tell your doctor if you are pregnant or plan to become pregnant.

The FDA categorizes medications based on safety for use during pregnancy. Five categories - A, B, C, D, and X, are used to classify the possible risks to an unborn baby when a medication is taken during pregnancy

Kepivance falls into category C. Based on animal data, Kepivance may cause harm to your unborn baby. No well-controlled studies have been done in humans. Therefore, this medication may be used if the potential benefits to the mother outweigh the potential risks to the unborn child.

Tell your doctor if you are breastfeeding or plan to breastfeed.

It is not known if Kepivance crosses into human milk. Because many medications can cross into human milk and because of the possibility for serious adverse reactions in nursing infants with use of this medication, a choice should be made whether to stop nursing or stop the use of this medication. Your doctor and you will decide if the benefits outweigh the risk of using Kepivance.

Palifermin is a human keratinocyte growth factor (KGF) produced by recombinant DNA technology.

Palifermin is used to reduce the chance of developing sores and ulcers in the mouth and to shorten the time with sores or ulcers in patients with blood cancers who receive high doses of chemotherapy and radiation therapy before bone marrow transplants.

Palifermin may also be used for purposes other than those listed in this medication guide.

Follow your doctor's instructions about any restrictions on food, beverages, or activity.

Get emergency medical help if you have signs of an allergic reaction: hives; difficult breathing; swelling of your face, lips, tongue, or throat.

Call your doctor at once if you have:

• blurred vision, tunnel vision, eye pain, or seeing halos around lights.

Common side effects may include:

• fever;

• swelling or redness of your skin;

• itching or rash;

• changes in your sense of taste or sense of touch;

• unusual or unpleasant sensations in your mouth;

• numbness in or around your mouth;

• joint pain; or

• discolored or thickened tongue.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

Contraindications

• Known hypersensitivity to Escherichia coli-derived proteins, palifermin, or any ingredient in the formulation.1

Warnings/Precautions

Major Toxicities

Increased severity and duration of oral mucositis observed in patients receiving palifermin within 24 hours of chemotherapy administration, presumably because of increased sensitivity of rapidly dividing epithelial cells to chemotherapy after palifermin treatment.1 Do not administer during or within 24 hours before or after infusion of myelotoxic chemotherapy.1

General Precautions

Safety and efficacy not established in patients with nonhematological malignancies.1 Potential for stimulation of growth of nonhematologic tumors that express the keratinocyte growth factor receptor not established.1 Has been reported to stimulate growth of human epithelial tumor cell lines in vitro at concentrations >15-fold higher than average therapeutic concentrations in humans.1

Specific Populations

Category C.1

Not known whether distributed into milk.1 Use with caution.1

Safety and efficacy not established.1

Experience in patients ≥65 years of age insufficient to determine whether they respond differently than younger adults.1

Common Adverse Effects

Arthralgia,1 dysesthesia (hyperesthesia, hypoesthesia, paresthesia),1 edema,1 3 5 elevated serum amylase1 5 or lipase concentrations,1 5 erythema,1 3 5 fever,1 3 mouth or tongue thickness or discoloration,1 pain,1 pruritus,1 3 rash,1 3 5 taste alteration.1 3

Storage

Parenteral

Lyophilized powder and reconstituted solutions: 2–8°C; protect from light.1

Reconstituted solutions (5 mg/mL in sterile water for injection): Should be used immediately, but may be stored for ≤24 hours at 2–8°C.1

Prior to injection, allow solution to reach room temperature for ≤1 hour but protect from light.1 Discard solutions left at room temperature for >1 hour.1

Compatibility

For information on systemic interactions resulting from concomitant use, see Interactions.

Binds to heparin in vitro; if administered via an IV line maintained with heparin, flush line with 0.9% sodium chloride solution prior to and following palifermin administration.1

Use this medicine as ordered by your doctor. Read all information given to you. Follow all instructions closely.

• It is given as a shot into a vein.

What do I do if I miss a dose?

• Call your doctor to find out what to do.

If you think there has been an overdose, call your poison control center or get medical care right away. Be ready to tell or show what was taken, how much, and when it happened.

• If you need to store Kepivance at home, talk with your doctor, nurse, or pharmacist about how to store it.

None

Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenicity: No treatment-related increase in the incidence of neoplastic lesions occurred in transgenic rasH2 mice treated with 9 weekly intravenous doses of palifermin, at 167-fold higher than the recommended human dose (on a mcg/kg basis).

Mutagenicity: No clastogenic or mutagenic effects of palifermin were observed in mammalian chromosomal aberration or Ames genotoxicity assays.

Impairment of Fertility: Reproductive performance, fertility, and sperm assessment parameters were not affected when palifermin was administered intravenously to male and female rats prior to and during mating at doses up to 100 mcg/kg/day. Decreased epididymal sperm counts, and increased post-implantation losses were observed at doses ≥ 300 mcg/kg/day (5-fold higher than the recommended human dose, on a mcg/kg basis). Increased pre-implantation loss and a decreased fertility index were observed at a palifermin dose of 1000 mcg/kg/day.

Reproductive and Developmental Toxicology

In animal reproductive toxicity studies, palifermin is 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 occurred 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 efficacy 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 of 212 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 irradiation (TBI) (12 Gy total dose), high-dose etoposide (60 mg/kg), and high-dose cyclophosphamide (100 mg/kg) followed by hematopoietic stem cell support. Patients were randomized to receive either Kepivance (n = 106) or placebo (n = 106). Kepivance 60 mcg/kg 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 efficacy 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.

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 (12cGy total dose), high-dose etoposide (60 mg/kg), and high-dose cyclophosphamide (75100 mg/kg) followed by hematopoietic stem cell support. The results for Study 1 were supported by results observed in the subset of patients in Study 2 who received the same dose and schedule of Kepivance administered in Study 1. One arm 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 of TBI prior to etoposide, and for 3 consecutive days following infusion of hematopoietic stem cells was prematurely closed by the Safety Committee for lack of efficacy 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 (2.1) and Drug Interactions (7)].

Lack of Efficacy: Autologous transplantation preparative regimen using high dose melphalan

In a post approval study, Study 3, designed to determine the efficacy 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 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 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 multiple myeloma receiving high dose melphalan followed by autologous peripheral blood stem cell transplantation. For the primary cataract endpoint of incidence of cataract 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) (difference of 17 [95% CI: -11, 46]) [see Adverse Reactions (6.1)].

Lack of Efficacy: Allogeneic Transplantation

In a post approval study, designed to determine the efficacy of Kepivance in decreasing the incidence of severe acute graft versus host disease (aGVHD) in patients with hematologic malignancies undergoing allogeneic transplantation, the incidence , duration and severity of oral mucositis was also measured. Multiple conditioning regimens were used. Patients were randomized to placebo (n=78) or to Kepivance (n=77) 60 micrograms/kg for 3 doses prior to the conditioning regimen and 180 micrograms/kg at least 24 hours from the last dose of chemotherapy and at least 24 hours before the first dose of post transplant methotrexate. There was no difference in the incidence of severe aGVHD Kepivance (16%) compared to placebo (17%). In addition to the lack of efficacy in preventing severe aGVHD, the incidence of WHO grade 3 and 4 mucositis was nominally higher in patients treated with Kepivance (81%) compared to placebo (73%).

Advise patients to report the following to healthcare providers:

• Rashes and reddening of skin [see Adverse Reactions (6.1)]
• Itchiness [see Adverse Reactions (6.1)]
• Swelling of tongue [see Adverse Reactions (6.1)]
• Changes in mouth and tongue sensation [see Adverse Reactions (6.1)]
• Alteration in taste [see Adverse Reactions (6.1)]

Inform patients

• That the safety and efficacy of Kepivance have not been established in patients with non-hematologic malignancies [see Indications and Usage (1) and Warnings and Precautions (5.1)]
• Of the evidence of tumor growth and stimulation in cell culture and in animal models of non-hematopoietic human tumors [see Warnings and Precautions (5.1) and Clinical Pharmacology (12.1)]

sobi
SWEDISH ORPHAN BIOVITRUM
Manufactured by:
Swedish Orphan Biovitrum AB (publ)
SE-112 76 Stockholm, Sweden
U.S. License No. 1859

© Swedish Orphan Biovitrum AB (publ). All rights reserved.

Principal Display Panel - 6.25 mg/1.2 mL Carton Label

6 x 6.25 mg/vial Single Use Vials

sobi

Kepivance®
(palifermin)

For Injection

6.25 mg/vial

Dosage - See Package Insert

No U.S. Standard of Potency

US Patent Numbers:

6,420,531 B1; 5,824,643; and 5,677,278

Principal Display Panel - 6.25 mg/1.2 mL Carton Label

3 x 6.25 mg/vial Single Use Vials

sobi

Kepivance®
(palifermin)

For Injection

6.25 mg/vial

Dosage - See Package Insert

No U.S. Standard of Potency

US Patent Numbers:

6,420,531 B1; 5,824,643; and 5,677,278

Usual Adult Dose for Mucositis:

60 mcg/kg IV bolus daily for 6 doses administered on 3 consecutive days prior to and 3 consecutive days after myelotoxic therapy

Prior to myelotoxic therapy, administer the third dose no later than 24 to 48 hours prior to initiation of myelotoxic therapy.

Following myelotoxic therapy, administer the first dose no sooner than 4 days after the most recent Kepivance administration and on the same day of hematopoietic stem cell infusion.

Call your doctor for instructions if you miss an appointment for your Kepivance injection.

Follow your doctor's instructions about any restrictions on food, beverages, or activity.