Kepivance

1 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX I 
 

SUMMARY OF PRODUCT CHARACTERISTICS 

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1. NAME OF THE MEDICINAL PRODUCT 
 
Kepivance 6.25 mg powder for solution for injection 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
Each vial contains 6.25 mg of palifermin. 
 
Palifermin is a human keratinocyte growth factor (KGF), produced by recombinant DNA technology 
in Escherichia coli.  
 
Once reconstituted, Kepivance contains 5 mg/ml of palifermin. 
 
For the full list of excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Powder for solution for injection (powder for injection). 
 
White lyophilised powder. 
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
Kepivance is indicated to decrease the incidence, duration and severity of oral mucositis in adult 
patients with haematological malignancies receiving myeloablative radiochemotherapy associated 
with a high incidence of severe mucositis and requiring autologous haematopoietic stem cell support.  
 
4.2 Posology and method of administration 
 
Kepivance treatment should be supervised by a physician experienced in the use of anti-cancer 
therapy. 
 
Posology 
 
Adults 
The recommended dosage of Kepivance is 60 micrograms/kg/day, administered as an intravenous 
bolus injection for three consecutive days before and three consecutive days after myeloablative 
radiochemotherapy for a total of six doses. The duration between last dose of Kepivance before 
myeloablative radiochemotherapy and the first dose of Kepivance after myeloablative 
radiochemotherapy should be at least seven days. 
 
Pre- myeloablative radiochemotherapy:  
The first three doses should be administered prior to myeloablative therapy, with the third 
dose 24 to 48 hours before myeloablative radiochemotherapy. 
 
Post- myeloablative radiochemotherapy:  
The last three doses should be administered post myeloablative radiochemotherapy; the first of these 
doses should be administered after, but on the same day of haematopoietic stem cell infusion and at 
least seven days after the most recent Kepivance administration (see section 4.4).  
 
 

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Paediatric population 
The safety and efficacy of Kepivance in children aged 0 to 18 years have not been established. 
Currently available data are described in sections 5.1 and 5.2 but no recommendation on a posology 
can be made.  
 
Renal impairment 
Dose adjustment in patients with renal impairment is not necessary (see section 5.2). 
 
Hepatic impairment 
Safety and efficacy has not been evaluated in patients with hepatic impairment (see section 5.2). 
Caution should be used when dosing patients with hepatic impairment. 
 
Older people  
Safety and efficacy has not been evaluated in older people. Currently available data are described in 
section 5.2 but no recommendation on dose adjustment can be made. 
 
Method of administration 
 
Intravenous use. 
Kepivance should not be administered subcutaneously due to poor local tolerability. 
 
Reconstituted Kepivance should not be left at room temperature for more than one hour, and should 
be protected from light. Prior to administration, visually inspect the solution for discolouration and 
particulate matter before administration, see section 6.6. 
 
For instructions on reconstitution of the medicinal product before administration, see section 6.6. 
 
4.3 Contraindications 
 
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1, or to 
Escherichia coli-derived proteins. 
 
4.4 Special warnings and precautions for use 
 
Use with chemotherapy 
 
Kepivance should not be administered within 24 hours before, during infusion of, or within 24 hours 
after administration of cytotoxic chemotherapy. In a clinical trial, administration of Kepivance 
within 24 hours of chemotherapy resulted in an increased severity and duration of oral mucositis. 
 
Concomitant heparin use 
 
If heparin is used to maintain an intravenous line, sodium chloride solution should be used to rinse the 
line prior to and after Kepivance administration (see section 6.2). 
 
Visual acuity 
 
KGF receptors are known to be expressed on the lens of the eye. Cataractogenic effects of palifermin 
cannot be excluded (see section 5.1). Long term effects are not yet known. 
 
Long term safety 
 
The long-term safety of Kepivance has not been fully evaluated with respect to overall survival, 
progression free survival and secondary malignancies. 

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4 

 
 
Non-haematological malignancies 
 
Kepivance is a growth factor that stimulates the proliferation of KGF receptor expressing epithelial 
cells. The safety and efficacy of Kepivance has not been established in patients with KGF receptor 
expressing non-haematological malignancies. Palifermin should therefore not be given to patients 
with known or suspected non-haematological malignancies. 
 
Lack of efficacy and risk of infection with high dose melphalan conditioning regimen 
 
In a postmarketing clinical trial investigating multiple myeloma patients receiving 
melphalan 200 mg/m2 as conditioning regimen, palifermin administration with four days between the 
last pre dose and the first post dose did not show a therapeutic benefit in the frequency or duration of 
severe oral mucositis compared to placebo.  
 
In addition, there was a higher incidence of infections in patients administered palifermin pre- and 
post-chemotherapy (49.5%) compared with patients who received placebo (24.6%). Compared with 
the placebo group, the pre/post-chemotherapy group had a higher incidence of herpes virus infection 
(9% vs 0%), oral fungal infection (7% vs 2%) and sepsis/septic shock (12% vs 2%). 
 
The efficacy and safety of palifermin have only been established in association with conditioning 
regimens for autologous haematopoietic stem cell support that comprise total body irradiation and 
high dose chemotherapy (cyclophosphamide and etoposide) (see section 5.1). Palifermin should not 
be used in association with myeloablative chemotherapy-only conditioning. 
 
4.5 Interaction with other medicinal products and other forms of interaction 
 
As a protein therapeutic, the risk for Kepivance to interact with other medicinal products is low. 
 
In-vitro and in-vivo data suggest that palifermin binds to unfractionated as well as low molecular 
weight heparins. In two studies in healthy volunteers, co-administration of Kepivance and heparin 
resulted in approximately 5 times higher systemic exposure to palifermin, due to a lower volume of 
distribution. The pharmacodynamic effect of palifermin, as measured by the change in Ki67 
expression, tended to be lower when administered with heparin but the clinical relevance of this 
finding is unclear. However, the administration of palifermin did not affect heparin´s anticoagulant 
effect in the experimental conditions (single dose, subtherapeutic dose regimen). Due to limited data 
in patients, heparins should be used with care in patients receiving palifermin and appropriate blood 
coagulation tests should be carried out to monitor their treatment. 
 
4.6 Fertility, pregnancy and lactation 
 
Pregnancy 
 
There are no adequate data from the use of Kepivance in pregnant women. Studies in animals have 
shown reproductive and developmental toxicity (see section 5.3). The potential risk to the human 
embryo or foetus is unknown. Kepivance should not be used during pregnancy unless clearly 
necessary. 
 
Breast-feeding 
 
It is not known whether Kepivance is excreted in human milk, therefore Kepivance should not be 
administered to women who are breast-feeding. 
 
Fertility 
 

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In studies in rats, no adverse effects on reproductivity/fertility parameters were observed at doses of 
up to 100 micrograms/kg/day. Systemic toxicity (clinical signs and/or changes in body weight) and 
adverse effects on male and female fertility parameters were seen at doses ≥ 300 micrograms/kg/day 
(5-fold higher than the recommended human dose).  
 
4.7 Effects on ability to drive and use machines 
 
Not relevant. 
 
4.8 Undesirable effects 
 
Safety data are based on patients with haematological malignancies enrolled in randomised, placebo-
controlled clinical studies, including one pharmacokinetic study, and post marketing experience. 
 
The most commonly reported adverse drug reactions (reported in > 1/10 patients) are reactions 
consistent with the pharmacologic action of Kepivance on skin and oral epithelium, e.g. oedema, 
including peripheral oedema, and hypertrophia of oral structures. These reactions were primarily mild 
to moderate in severity and were reversible. Median time to onset was approximately 6 days following 
the first of 3 consecutive daily doses of Kepivance, with a median duration of approximately 5 days. 
Pain and arthralgia are other common adverse reactions, consistent with Kepivance treated patients 
having received less opioid analgesia than placebo-treated patients (see Table 2). Hypersensitivity, 
including Anaphylactic reactions, has also been associated with palifermin. 
 
Table 1. Adverse reactions from clinical trials and spontaneous reporting 
 
The frequency listed below is defined using the following convention: very common (> 1/10), 
common (≥ 1/100 to < 1/10), not known (frequency cannot be estimated from available data). 
 
System organ class Frequency Adverse reactions 
   
Immune system disorders 
 
Nervous system disorders 
 
 

Not known: 
 
Very common: 
Common: 

Anaphylactic reaction/Hypersensitivity 
 
Dysgeusia 
Paraesthesia oral 
 

Gastrointestinal disorders 
 
 
 
 
 

Very common: 
 
 
Not known: 
 

Oral mucosal hypertrophy / Hypertrophy 
of tongue papillae,Oral mucosal 
discolouration / Tongue discolouration, 
Tongue disorder (e.g. redness, bumps), 
Tongue oedema 
 

Skin and subcutaneous tissue disorders 
 
 

Very common: 
Common: 
Not known: 

Rash, pruritus and erythema 
Skin hyperpigmentation 
Palmar-plantar erythrodysaesthesia 
syndrome (dysaesthesia, erythema, 
oedema on the palms and soles) 
 

Musculoskeletal and connective tissue 
disorders 
 
Reproductive system and breast disorders 
 
 

Very common: 
 
 
Not known 
 
 

Arthralgia 
 
 
Vaginal oedema and vulvovaginal 
erythema 
 

General disorders and administration site 
conditions 
 

Very common: 
 
Common: 

Oedema, oedema peripheral, pain and 
pyrexia 
Lip swelling, eyelid oedema 

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Investigations 

Not known: 
 
Very common: 

Face oedema, oedema mouth  
 
Blood amylase increased and Lipase 
Increased1 
 

1 Kepivance may cause increased lipase and amylase levels in some patients with or without 
symptoms of abdominal pain or backache. No overt cases of pancreatitis have been reported in this 
patient population. Fractionation of increased levels of amylase revealed the increase to be 
predominantly salivary in origin. 
 
Haematopoietic recovery following PBPC infusion was similar between patients who received 
Kepivance or placebo, and there were no observed differences in disease progression or survival. 
 
Dose limiting toxicities were observed in 36% (5 of 14) patients receiving 6 doses 
of 80 micrograms/kg/day administered intravenously over 2 weeks (3 doses preceding and three doses 
following myeloablative therapy). These events were consistent with those observed at the 
recommended dose but were generally more severe. 
 
Reporting of suspected adverse reactions 
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It 
allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare 
professionals are asked to report any suspected adverse reactions via the national reporting system 
listed in Appendix V. 
 
4.9 Overdose 
 
There is no experience with Kepivance doses greater than 80 micrograms/kg/day administered 
intravenously in patients over 2 weeks (3 doses preceding and 3 doses following myeloablative 
therapy).  
 
For information on dose limiting toxicities see section 4.8. 
 
A single dose of 250 micrograms/kg has been administered intravenously to 8 healthy volunteers 
without severe or serious adverse effects. 
 
 
5. PHARMACOLOGICAL PROPERTIES 
 
5.1  Pharmacodynamic properties 
 
Pharmacotherapeutic group: Detoxifying agents for antineoplastic treatment, ATC code: V03A F08. 
 
Palifermin is a 140 amino acid protein with a molecular weight of 16.3 kilodaltons. It differs from 
endogenous human KGF in that the first 23 N-terminal amino acids have been deleted to improve 
protein stability. 
 
Mechanism of action 
 
KGF is a protein that targets epithelial cells by binding to specific cell-surface receptors thereby 
stimulating proliferation, differentiation, and upregulation of cytoprotective mechanisms (e.g., 
induction of antioxidant enzymes). Endogenous KGF is an epithelial cell specific growth factor which 
is produced by mesenchymal cells and is naturally upregulated in response to epithelial tissue injury. 
 
Pharmacodynamic effects 
 

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http://www.whocc.no/atcddd/indexdatabase/index.php?query=V03AF


7 

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 palifermin at 40 micrograms/kg/day intravenously for 3 days, when measured 24 hours 
after the third dose. Dose-dependent epithelial cell proliferation was observed 48 hours post-dosing in 
healthy subjects given single intravenous doses of 120 to 250 micrograms/kg. 
 
Clinical efficacy and safety 
 
The palifermin clinical program in the setting of myelotoxic therapy requiring haematopoietic stem 
cell (HSC) support included 650 patients with haematologic malignancies enrolled in 3 randomised, 
placebo-controlled clinical studies and a pharmacokinetic study. 
 
Efficacy and safety of palifermin were established in a randomised, double-blind, placebo-controlled 
study in which patients received high-dose cytotoxic therapy consisting of fractionated total-body 
irradiation (12 Gy total dose; Day -8 to -5), high-dose etoposide (60 mg/kg; Day -4), and high-dose 
cyclophosphamide (100 mg/kg; Day -2) followed by PBPC support for the treatment of 
haematological malignancies ((Non-Hodgkin’s Lymphoma (NHL), Hodgkin’s disease, Acute Myeloid 
Leukaemia (AML), Acute Lymphocytic Leukaemia (ALL), Chronic Myeloid Leukaemia (CML), 
Chronic Lymphocytic Leukaemia (CLL), or multiple myeloma). In this study, 212 patients were 
randomised and received either palifermin or placebo. Palifermin was administered as a daily 
intravenous injection of 60 micrograms/kg for 3 consecutive days prior to initiation of cytotoxic 
therapy and for 3 consecutive days following infusion of peripheral blood progenitor cells with nine 
days between the last pre dose and first post dose. 
 
The main efficacy endpoint of the study was the number of days during which patients experienced 
severe oral mucositis (grade 3/4 on the World Health Organisation (WHO) scale). Other endpoints 
included the incidence, duration and severity of oral mucositis and the requirement for opioid 
analgesia. There was no evidence of a delay in time to haematopoietic recovery in patients who 
received palifermin as compared to patients who received placebo. The efficacy results are presented 
in Table 2. 
 
Table 2. Oral mucositis and related clinical sequelae - HSC transplant study 
 
 Placebo  

n = 106 
Palifermin  
(60 micrograms/kg/day) 
n = 106 

p-value* 

Median (25th, 75th percentile) days of 
WHO Grade 3/4 oral mucositis**  

9 (6, 13) 3 (0, 6) < 0.001 

Patient incidence of WHO 
Grade 3/4 oral mucositis 

98% 63% < 0.001 

Median (25th, 75th percentile) days of 
WHO Grade 3/4 oral mucositis in 
affected patients 

9 (6, 13) 
(n = 104) 

6 (3, 8) 
(n = 67) 

 

Patient incidence of WHO Grade 4 oral 
mucositis 

62% 20% < 0.001 

Median (25th, 75th percentile) days of 
WHO Grade 2/3/4 oral mucositis  

14 (11, 19) 8 (4, 12) < 0.001 

Opioid Analgesia for oral mucositis: 
 Median (25th, 75th percentile) 
 Days 

 
11 (8, 14) 

 
7 (1, 10) 

 
< 0.001 

 Median (25th, 75th percentile) 
 Cumulative Dose  
 (morphine mg equivalents) 

535  
(269, 1429) 

212 (3, 558) < 0.001 

Patient Incidence of Total Parenteral 
Nutrition (TPN) 

55% 31% < 0.001 

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 Placebo  
n = 106 

Palifermin  
(60 micrograms/kg/day) 
n = 106 

p-value* 

Patient Incidence of Febrile Neutropenia 92% 75% < 0.001 
*  Using Cochran-Mantel-Haenszel (CMH) test stratified for study centre. 
**  WHO Oral Mucositis Scale: Grade 1 = soreness/erythema; Grade 2 = erythema, ulcers, can 

eat solids; Grade 3 = ulcers, requires liquid diet only; Grade 4 = alimentation not possible 
 
In this Phase 3 clinical study, palifermin treated patients demonstrated significant benefits in 
patient-reported outcomes of mouth and throat soreness and its impact on swallowing, drinking, 
eating and talking. These patient-reported outcomes were highly correlated to the clinician grading of 
oral mucositis using the WHO scale. 
 
A randomised, placebo-controlled, double-blind study was conducted post-approval to evaluate the 
efficacy of palifermin given pre- or pre- and post- chemotherapy (CT). The study included three 
treatment arms and was designed to compare each of the palifermin arms (pre- and pre/post-) to 
placebo. 
In this study (n = 281), patients with multiple myeloma received conditioning with melphalan 
(200 mg/m2) prior to autologous haematopoietic stem cell transplantation.  
 
The incidence of ulcerative oral mucositis was 57.9% in the placebo arm, 68.7% in the pre/post CT 
group and 51.4% in the pre-CT group. Neither of the two dosing regimens demonstrated statistically 
significant results versus placebo. The incidence of severe (grades 3 and 4) oral mucositis in 
the 3 groups was 36.8%, 38.3% and 23.9% for the placebo, pre/post CT and pre-CT groups 
respectively, with no statistical significance being demonstrated.  
 
Cataractogenic effects of palifermin cannot be excluded following results of ophthalmologic 
examinations in a subset of patients (n = 66; 14 in the placebo group, 52 in the palifermin group) who 
were followed for 12 months after the acute phase of the above post-approval study. For the primary 
endpoint, which was incidence of cataract development or progression at 12 months (defined as an 
increase of ≥ 0.3 in the LOCS III score), a greater proportion of subjects experienced cataract 
development in the palifermin group compared with the placebo group (28.6 % in the placebo group 
vs 48.1% in the palifermin group). This difference was not statistically significant. Visual acuity was 
not affected at 6 or 12 months in either treatment group. There was an imbalance in age distribution 
with more elderly (> 65 years) patients in the palifermin group. 
 
Paediatric population 
A phase I dose escalation study was conducted in paediatric patients aged 1-16 years. A total of 27 
paediatric patients with leukaemia were randomized to 40, 60 or 80 micrograms/kg/day of palifermin 
for 3 days pre- and post- hematopoietic stem cell transplantation (HSCT). The conditioning regimen 
consisted of total body irradiation (TBI), etoposide and cyclophosphamide. There was a lower 
incidence of severe oral mucositis in patients receiving 80 micrograms/kg/day but no effect on the 
incidence of acute graft-versus-host disease (GVHD). Although palifermin was safe at all doses tested 
the incidence of skin reactions increased with the dose. 
 
5.2 Pharmacokinetic properties 
 
The pharmacokinetics of palifermin were studied in healthy volunteers and patients with 
haematological malignancies. After single intravenous doses of 20 to 250 micrograms/kg (healthy 
volunteers) and 60 micrograms/kg (cancer patients), palifermin exhibited rapid extravascular 
distribution In patients with haematological malignancies mean Vss was 5 l/kg and mean clearance 
about 1300 ml/hour/kg with an average terminal half-life of approximately 4.5 hours. Approximately 
dose-linear pharmacokinetics were observed in healthy volunteers after single dose administration up 
to 250 micrograms/kg. No accumulation of palifermin occurred after 3 consecutive daily doses 
of 20 and 40 micrograms/kg (healthy volunteers) or 60 micrograms/kg (adult patients) or 40 to 80 

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9 

micrograms/kg (paediatric patients). Inter-subject variability is high with a CV% of about 50% for CL 
and 60% for Vss. 
 
No gender-related differences were observed in the pharmacokinetics of palifermin. Mild to moderate 
renal impairment (creatinine clearance 30-80 ml/min) did not influence palifermin pharmacokinetics. 
In patients with severe renal impairment (creatinine clearance < 30 ml/min), clearance was decreased 
by 22% (n = 5). In patients with end-stage renal disease (requiring dialysis) palifermin clearance was 
decreased by 10% (n = 6). The pharmacokinetic profile in patients with hepatic insufficiency has not 
been assessed. 
 
Older people 
In a single dose study the clearance of palifermin was approximately 30% lower in 8 healthy subjects 
aged 66-73 years after a dose of 90 micrograms/kg than in younger subjects (≤ 65 years) after a dose 
of 180 micrograms/kg. Based on these limited data no recommendation on dose adjustment can be 
made. 
 
Paediatric population 
In a small multiple-dose study in paediatric patients (1 to 16 years old) receiving 40, 60 or 
80 micrograms/kg/day for 3 days pre- and post- HSCT, there was no effect of age on the 
pharmacokinetics of palifermin although a large variability was observed in the estimated parameters. 
Systemic exposure did not appear to increase with the dose. 
 
5.3 Preclinical safety data 
 
Salient findings in toxicology studies in rat and monkey were generally attributable to the 
pharmacological activity of palifermin, specifically, proliferation of epithelial tissues. 
 
In fertility/general reproductive toxicity studies in rats, palifermin treatment was associated with 
systemic toxicity (clinical signs and/or changes in body weight) and adverse effects on male and 
female reproductive/fertility parameters at doses greater than or equal to 300 micrograms/kg/day. 
No adverse effects on reproductive/fertility parameters were observed at doses of up to 
100 micrograms/kg/day. These no observed adverse effect level (NOAEL) doses were associated with 
systemic exposures up to 2.5 times greater than anticipated clinical exposure.  
 
In embryo/foetal development toxicity studies in rats and rabbits, palifermin treatment was associated 
with developmental toxicity (increased post-implantation loss, reduced litter size, and/or reduced 
foetal weight) at doses of 500 and 150 micrograms/kg/day, respectively. Treatment with these doses 
was also associated with maternal effects (clinical signs and/or changes in body weight/food 
consumption), suggesting that palifermin was not selectively toxic to development in either species. 
No adverse developmental effects were observed in rats and rabbits at doses of up to 300 and 
60 micrograms/kg/day, respectively. These NOAEL doses were associated with systemic exposures 
(based on AUC) up to 9.7 and 2.1 times, respectively, anticipated clinical exposure. Peri- and 
postnatal development has not been studied. 
 
Palifermin is a growth factor that primarily stimulates epithelial cells through the KGF receptor. 
Haematologic malignancies do not express the KGF receptor. However, patients treated with 
chemotherapy and/or radiotherapy are at higher risk of developing secondary tumours some of which 
may express KGF receptors, and theoretically, be stimulated by KGF receptor ligands. In a study to 
assess potential carcinogenicity in transgenic rasH2 mice, no treatment related increases in the 
incidence of neoplastic lesions were observed. 
 
 

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10 

6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
L-histidine 
Mannitol 
Sucrose 
Polysorbate 20 
Diluted Hydrochloric acid 
 
6.2 Incompatibilities 
 
In the absence of compatibility studies, this medicinal product must not be mixed with other 
medicinal products. 
 
If heparin is used to maintain an intravenous line, sodium chloride solution should be used to rinse the 
line prior to and after Kepivance administration, since palifermin has been shown to bind to heparin 
in vitro. 
 
6.3 Shelf life 
 
6 years. 
 
After reconstitution: 24 hours at 2 °C – 8 °C, protected from light. 
 
6.4 Special precautions for storage 
 
Store in a refrigerator (2 °C – 8 °C). 
Do not freeze.  
 
Store in the original package in order to protect from light. 
 
For storage conditions after reconstitution of the medicinal product, see section 6.3. 
 
6.5 Nature and contents of container 
 
6.25 mg of powder in a vial (Type I glass) with a rubber stopper, an aluminium seal and a plastic flip-
off cap. 
 
Carton containing 6 vials. 
 
6.6 Special precautions for disposal and other handling 
 
Kepivance is a sterile but unpreserved product and is intended for single use only. 
 
Kepivance should be reconstituted with 1.2 ml water for injections. The diluent should be injected 
slowly into the Kepivance vial. The contents should be swirled gently during dissolution. Do not 
shake or vigorously agitate the vial.  
 
Generally, dissolution of Kepivance takes less than 5 minutes. Visually inspect the solution for 
discolouration and particulate matter before administration. Kepivance should not be administered if 
discolouration or particulates are observed. 
 
Before injection‚ Kepivance may be allowed to reach room temperature for a maximum of 1 hour but 
should be protected from light. Kepivance left at room temperature for more than 1 hour should be 
discarded. 

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11 

 
Any unused medicinal product or waste material should be disposed of in accordance with local 
requirements. 
 
 
7. MARKETING AUTHORISATION HOLDER 
 
Swedish Orphan Biovitrum AB (publ) 
SE-112 76 Stockholm 
Sweden  
 
 
8. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/05/314/001 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation: 25 October 2005 
Date of latest renewal: 23 September 2010 
 
 
10. DATE OF REVISION OF THE TEXT 
 
 
 
Detailed information on this medicinal product is available on the website of the European Medicines 
Agency http://www.ema.europa.eu 

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12 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX II 
 

A. MANUFACTURER OF THE BIOLOGICAL ACTIVE 
SUBSTANCE AND MANUFACTURER RESPONSIBLE FOR 
BATCH RELEASE 

 
B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY 

AND USE 
 

C. OTHER CONDITIONS AND REQUIREMENTS OF THE 
MARKETING AUTHORISATION 

 
D.  CONDITIONS OR RESTRICTIONS WITH REGARD TO 

THE SAFE AND EFFECTIVE USE OF THE MEDICINAL 
PRODUCT 

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A. MANUFACTURER OF THE BIOLOGICAL ACTIVE SUBSTANCE AND 
MANUFACTURER RESPONSIBLE FOR BATCH RELEASE 

 
Name and address of the manufacturer of the biological active substance 
 
Amgen Inc 
5550 Airport Boulevard 
Boulder, Colorado 80301 
United States of America 
 
Amgen Inc 
4000 Nelson Road 
Longmont, Colorado 80503 
United States of America  
 
Name and address of the manufacturer responsible for batch release 
 
Swedish Orphan Biovitrum AB (publ) 
SE-112 76 Stockholm 
Sweden 
 
 
B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE 
 
Medicinal product subject to restricted medical prescription (see Annex I: Summary of Product 
Characteristics, section 4.2). 
 
 
C.  OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 

AUTHORISATION 
 
• Periodic Safety Update Reports  
The marketing authorisation holder shall submit periodic safety update reports for this product in 
accordance with the requirements set out in the list of Union reference dates (EURD list) provided for 
under Article 107c(7) of Directive 2001/83/EC and published on the European medicines web-portal. 
 
 
D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 

EFFECTIVE USE OF THE MEDICINAL PRODUCT 
 
• Risk Management Plan (RMP) 
The MAH shall perform the required pharmacovigilance activities and interventions detailed in 
the agreed RMP presented in Module 1.8.2 of the Marketing Authorisation and any agreed 
subsequent updates of the RMP. 
 
An updated RMP should be submitted: 

• At the request of the European Medicines Agency;  
• Whenever the risk management system is modified, especially as the result of new 

information being received that may lead to a significant change to the benefit/risk 
profile or as the result of an important (pharmacovigilance or risk minimisation) 
milestone being reached. 

 
If the dates for submission of a PSUR and the update of a RMP coincide, they can be submitted 
at the same time.

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14 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX III 
 

LABELLING AND PACKAGE LEAFLET 

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15 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

A. LABELLING 

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16 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
OUTER CARTON 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Kepivance 6.25 mg powder for solution for injection 
Palifermin  
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each vial contains 6.25 mg of palifermin 
Reconstituted Kepivance contains 5 mg/ml of palifermin 
 
 
3. LIST OF EXCIPIENTS 
 
L-histidine, mannitol, sucrose, polysorbate 20 and diluted hydrochloric acid 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
6 vials containing powder for solution for injection 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
For single use only 
Read the package leaflet before use. 
For intravenous use  
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP 
 
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9. SPECIAL STORAGE CONDITIONS 
 
Store in a refrigerator 
Do not freeze 
Store in the original package in order to protect from light. 
Once reconstituted, store in a refrigerator and use within 24 hours. 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Swedish Orphan Biovitrum AB (publ) 
SE-112 76 Stockholm 
Sweden  
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/05/314/001  
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
Medicinal product subject to medical prescription. 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Justification for not including Braille accepted 
 

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MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 
 
VIAL  
 
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 
 
Kepivance 6.25 mg powder for injection 
Palifermin  
IV 
 
 
2. METHOD OF ADMINISTRATION 
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Lot 
 
 
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 
 
6.25 mg 
 
 
6. OTHER 
 

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B. PACKAGE LEAFLET 

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Package leaflet: Information for the user 
 

Kepivance 6.25 mg powder for solution for injection 
palifermin 

 
 
Read all of this leaflet carefully before you start using this medicine because it contains 

important information for you. 
- Keep this leaflet. You may need to read it again. 
- If you have any further questions, ask your doctor or pharmacist. 
- If you get any side effects, talk to your doctor or pharmacist. This includes any possible side 

effects not listed in this leaflet. See section 4. 
 

 
What is in this leaflet: 
1. What Kepivance is and what it is used for 
2. What you need to know before you use Kepivance 
3. How to use Kepivance 
4. Possible side effects 
5. How to store Kepivance 
6. Contents of the pack and other information 
 
 
1. What Kepivance is and what it is used for 
 
Kepivance contains the active substance palifermin which is a protein produced by biotechnology in a 
bacteria called Escherichia coli. Palifermin stimulates the growth of specific cells called epithelial 
cells that form the tissue lining of your mouth and digestive tract, as well as other tissues such as skin. 
Palifermin works in the same way as keratinocyte growth factor (KGF) which is made naturally by 
your body in small amounts. 
 
Kepivance is used to treat oral mucositis (soreness, dryness and inflammation of the mouth) which 
has occurred as a side effect of treatments for your blood cancer. 
 
To treat your blood cancer you may be receiving chemotherapy, radiotherapy and autologous 
hematopoietic stem cell transplantation (cells from your own body that produce blood cells). One of 
the side effects of these treatments is oral mucositis. Kepivance is used to reduce the frequency, 
duration and severity of oral mucositis symptoms. 
 
Kepivance should only be used in adults over the age of 18 years. 
 
 
2. What you need to know before you use Kepivance 
 
Do not use Kepivance: 
- if you are allergic to palifermin, Escherichia coli derived proteins or any other ingredients of 

this medicine (listed in section 6). 
 
Children 
Kepivance is not recommended in children (0 to 18 years). 
 
Other medicines and Kepivance 
Tell your doctor or pharmacist if you are taking, have recently taken or might take any other 
medicines. Kepivance might interact with a medicine called heparin. Please inform your doctor if you 
are receiving or have recently received heparin. 
 

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Pregnancy and breast-feeding 
Kepivance has not been tested in pregnant women. It is important to tell your doctor if you: 
- are pregnant; 
- think you may be pregnant; or  
- plan to have a baby. 
 
If you are pregnant you should not use Kepivance unless clearly necessary. 
 
It is not known whether Kepivance is present in human milk. Do not use Kepivance if you are breast-
feeding. 
 
Ask your doctor or pharmacist for advice before taking this medicine. 
 
 
3. How to use Kepivance 
 
 Kepivance will be given to you by a doctor or nurse with experience in cancer treatment. 
 
The usual dose of Kepivance is 60 micrograms of Kepivance per kilogram of bodyweight per day. 
This dose will be given to you as an intravenous injection (into a vein). 
 
When you will be given Kepivance 
You will be given Kepivance for three days in a row before chemotherapy and radiotherapy and for 
three days in a row after chemotherapy and radiotherapy for a total of six doses.  
 
The last of the three doses given before chemotherapy andradiotherapy, must be given at 
least 24 to 48 hours before the chemotherapy and radiotherapy starts. The first of the three doses 
given after the chemotherapy and radiotherapy must be given at least 7 days after the most recent 
Kepivance administration. 
 
For information on preparation and administration of Kepivance, please see information for 
healthcare professionals at the end of this leaflet. 
 
 
4. Possible side effects 
 
Like all medicines, this medicine can cause side effects, although not everybody gets them. 
 
Very common (affects more than 1 user in 10) side effects are: 
• skin rash, itching and redness (pruritus and erythaema); 
• an increase in the thickness in the mouth or tongue; 
• change in colour of the mouth or tongue; 
• generalised swelling (oedema); 
• swelling of hands, ankles or feet; 
• pain; 
• fever; 
• aching joints (arthralgia);  
• altered taste; 
• increase in lipase and amylase levels (digestive enzymes) in the blood (which do not require 

treatment and usually return to normal after stopping treatment with Kepivance). 
 

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Common (affects 1 to 10 users in 100) side effects are: 
• tingling of the mouth; 
• darkening of an area of skin (hyperpigmentation); 
• eyelid swelling; 
• lip swelling. 
 
Not known (frequency cannot be estimated from available data): 
• redness, bumps or swelling of the tongue; 
• swelling (oedema) of the face or mouth; 
• swelling or redness of the vagina; 
• hand-and-foot skin-reaction (palms of the hands or soles of the feet tingle, become numb, 

painful, swollen or red);  
• allergic reactions. 
 
If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects 
not listed in this leaflet. 
 
Reporting of side effects 
If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects 
not listed in this leaflet. You can also report side effects directly via the national reporting system 
listed in Appendix V. By reporting side effects you can help provide more information on the safety 
of this medicine. 
 
 
5. How to store Kepivance 
 
Keep this medicine out of the sight and reach of children. 
 
Do not use this medicine after the expiry date which is stated on the carton and vial label, after EXP. 
The expiry date refers to the last day of that month. 
 
Store in a refrigerator (2 °C – 8 °C). 
 
Do not freeze. 
 
Store in the original carton, in order to protect from light. 
 
 
6. Contents of the pack and other information 
 
What Kepivance contains  
- The active substance is palifermin. Each vial contains 6.25 mg of palifermin.  
- The other ingredients are mannitol, sucrose, L-histidine, polysorbate 20 and diluted 

hydrochloric acid. 
 
What Kepivance looks like and contents of the pack 
Kepivance is a white powder supplied in vials. Each pack contains 6 vials. 
 
Marketing Authorisation Holder and Manufacturer 
Swedish Orphan Biovitrum AB (publ) 
SE-112 76 Stockholm 
Sweden 
 
 
 

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This leaflet was last revised in  
 
Detailed information on this medicine is available on the European Medicines Agency web site: 
http://www.ema.europa.eu 
 
--------------------------------------------------------------------------------------------------------------------------- 
 
The following information is intended for healthcare professionals only: 
 
Kepivance is a sterile but unpreserved product and is intended for single use only. 
 
Kepivance should be reconstituted with 1.2 ml water for injections. The diluent should be injected 
slowly into the Kepivance vial. The contents should be swirled gently during dissolution. Do not 
shake or vigorously agitate the vial.  
 
Generally, dissolution of Kepivance takes less than 5 minutes. Visually inspect the solution for 
discolouration and particulate matter before administration. Kepivance should not be administered if 
discolouration or particulates are observed. 
 
Before injection‚ Kepivance may be allowed to reach room temperature for a maximum of 1 hour but 
should be protected from light. Kepivance left at room temperature for more than 1 hour should be 
discarded. 
 
Any unused product or waste material should be disposed of in accordance with local requirements. 

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	SUMMARY OF PRODUCT CHARACTERISTICS
	A. MANUFACTURER OF THE BIOLOGICAL ACTIVE SUBSTANCE AND MANUFACTURER RESPONSIBLE FOR BATCH RELEASE
	B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE
	C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION
	D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT
	A. LABELLING
	B. PACKAGE LEAFLET