ANNEX I
SUMMARY OF PRODUCT CHARACTERISTICS
1.
Kepivance 6.25 mg powder for solution for injection
2.
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 a full list of excipients, see section 6.1.
3.
Powder for solution for injection (powder for injection).
White lyophilised powder.
4.
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.
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
therapy for a total of six doses.
Pre-
myeloablative therapy:
The first three doses should be administered prior to myeloablative
therapy, with the third dose 24 to 48 hours before myeloablative
therapy.
Post-
myeloablative therapy:
The last three doses should be administered post myeloablative
therapy;
the first of these doses should be administered after, but on the same day of haematopoietic stem cell
infusion and more than four days after the most recent Kepivance administration (see section 4.4).
Paediatric population
The safety and efficacy of Kepivance in children aged 0 to 18 years have not been established.
Kepivance should not be used in children aged 0 to 18 years .
2
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.
Elderly
Safety and efficacy has not been evaluated in the elderly (see section 5.2)
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.
Hypersensitivity to the active substance or to any of the excipients, or to
Escherichia coli
-derived
proteins.
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. To date no evidence of an increase in
lens opacities has been observed in patients treated with Kepivance in clinical studies. 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.
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.
3
High dose melphalan conditioning regimen
In a postmarketing clinical trial investigating multiple myeloma patients receiving melphalan
200 mg/m
2
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. Palifermin should therefore not be used in association with
myeloablative chemotherapy-only conditioning.
No interaction studies have been performed. As a protein therapeutic, the risk for Kepivance to
interact with other medicinal products is low.
In-vitro
and
in-vivo
data suggests that palifermin binds to unfractionated as well as low molecular
weight heparins, which should be used with care in patients who are concomitantly administered
palifermin. The clinical relevance is unclear.
Pregancy
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
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).
Not relevant.
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.
4
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
Not known:
Anaphylactic reaction/Hypersensitivity
Nervous system disorders
Very common:
Common:
Dysgeusia
Paraesthesia oral
Gastrointestinal disorders
Very common:
Oral mucosal hypertrophy / Hypertrophy
of tongue papillae or (Oral mucosal
discolouration / tongue discolouration)
Tongue disorder (e.g. redness, bumps),
Tongue oedema
Not known:
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
Very common:
Arthralgia
Reproductive system and breast disorders
Not known
Vaginal oedema and vulvovaginal
erythema
General disorders and administration site
conditions
Very common:
Oedema, oedema peripheral, pain and
pyrexia
Lip swelling, eyelid oedema
Face oedema, oedema mouth
Common:
Not known:
Blood amylase increased and Lipase
Increased
1
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.
Very common:
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.
5
Investigations
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.
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
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), high-dose etoposide (60 mg/kg), and high-dose cyclophosphamide
(100 mg/kg) 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.
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
6
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 (25
th
, 75
th
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 (25
th
, 75
th
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 (25
th
, 75
th
percentile) days of
WHO Grade 2/3/4 oral mucositis
14 (11, 19)
8 (4, 12)
< 0.001
Opioid Analgesia for oral mucositis:
11 (8, 14)
7 (1, 10)
< 0.001
Median (25
th
, 75
th
percentile)
Days
Median (25
th
, 75
th
percentile)
535 (269,
1429)
212 (3, 558)
< 0.001
Cumulative Dose
(morphine mg equivalents)
Patient Incidence of Total Parenteral
Nutrition (TPN)
55%
31%
< 0.001
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/m
2
) 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. Treatment-emergent adverse events with respect
to infections were reported in 24.6%, 49.5% and 46.8% for the placebo, pre/post-CT and pre-CT
groups respectively.
7
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 V
ss
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 (cancer patients). Inter-subject
variability is high with a CV% of about 50% for CL and 60% for V
ss
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 paediatric and geriatric populations (age
above 70 years), or in patients with hepatic insufficiency, has not been assessed.
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.
6.
6.1 List of excipients
L-histidine
Mannitol
Sucrose
8
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
5 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 of the reconstituted medicinal product, see section 6.3.
6.5
Nature and contents of container
6.25mg 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.
Any unused product or waste material should be disposed of in accordance with local requirements.
9
7.
Biovitrum AB (publ)
SE-112 76 Stockholm
Sweden
8.
EU/1/05/314/001
9.
25/10/2005
Detailed information on this product is available on the website of the European Medicines Agency
10
ANNEX II
A.
MANUFACTURER OF THE BIOLOGICAL ACTIVE
SUBSTANCE AND MANUFACTURING AUTHORISATION
HOLDER RESPONSIBLE FOR BATCH RELEASE
B.
CONDITIONS OF THE MARKETING AUTHORISATION
11
A. MANUFACTURER OF THE BIOLOGICAL ACTIVE SUBSTANCE AND
MANUFACTURING AUTHORISATION HOLDER 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
Biovitrum AB (publ)
SE-112 76 Stockholm
Sweden
B. CONDITIONS OF THE MARKETING AUTHORISATION
•
Medicinal product subject to restricted medical prescription (See Annex I: Summary of Product
Characteristics, section 4.2).
•
CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND
EFFECTIVE USE OF THE MEDICINAL PRODUCT
Not applicable.
•
OTHER CONDITIONS
Pharmacovigilance system
The MAH must ensure that the system of pharmacovigilance, as described in version 2.0
presented in Module 1.8.1. of the Marketing Authorisation, is in place and functioning before
and whilst the product is on the market.
Risk Management Plan
The MAH commits to performing the studies and additional pharmacovigilance activities detailed in the
Pharmacovigilance Plan, as agreed in version 1.6 of the Risk Management Plan (RMP) presented in
Module 1.8.2. of the Marketing Authorisation and any subsequent updates of the RMP agreed by the
CHMP.
As per the CHMP Guideline on Risk Management Systems for medicinal products for human use, any
updated RMP should be submitted at the same time as the following Periodic Safety Update Report
(PSUR).
In addition, an updated RMP should be submitted:
•
When new information is received that may impact on the current Safety Specification,
Pharmacovigilance Plan or risk minimisation activities
•
Within 60 days of an important (pharmacovigilance or risk minimisation) milestone being
reached
•
At the request of the European Medicines Agency
12
PSURs
The MAH will continue to submit yearly PSURs, until otherwise specified by the CHMP.
13
ANNEX III
LABELLING AND PACKAGE LEAFLET
14
A. LABELLING
15
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
OUTER CARTON
1.
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.
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 REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight of children.
7.
OTHER SPECIAL WARNING(S), IF NECESSARY
8.
EXPIRY DATE
EXP
9.
SPECIAL STORAGE CONDITIONS
Store in a refrigerator
Do not freeze
Store in the original package in order to protect from light.
16
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
Biovitrum AB (publ)
SE-112 76 Stockholm
Sweden
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
17
MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS
VIAL
1.
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
18
B. PACKAGE LEAFLET
19
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.
-
Keep this leaflet. You may need to read it again.
-
If you have any further questions, ask your doctor or pharmacist.
-
If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet,
please tell your doctor or pharmacist.
In this leaflet
:
1.
What Kepivance is and what it is used for
2.
Before you use Kepivance
3.
How to use Kepivance
4.
Possible side effects
5.
How to store Kepivance
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 is similar to the protein called keratinocyte growth factor
(KGF) that is naturally made by your body in small amounts. Palifermin acts in the same way as
naturally occurring KGF by stimulating 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.
For the treatment of your blood cancer you are receiving chemotherapy in combination with
radiotherapy followed by autologous hematopoietic stem cell transplantation (cells from your own
body that produce blood cells). One of the side effects of this treatment is mucositis (soreness,
dryness and inflammation of the mouth). Kepivance is used to reduce the frequency, duration and
severity of oral mucositis and improve related symptoms.
Kepivance should only be used in adults over the age of 18 years.
2.
BEFORE YOU USE KEPIVANCE
Do not use Kepivance:
-
if you are allergic (hypersensitive) to palifermin, any other ingredients of Kepivance, or to
Escherichia coli
derived proteins.
Use in Children
Kepivance is not recommended in children (0 to 18 years).
Taking other medicines
Please tell your doctor or pharmacist if you are taking or have recently taken any other medicines,
including medicines obtained without a prescription. Kepivance might interact with a medicine called
heparin. Please inform your doctor if you are receiving or have recently received heparin.
20
6.
Further information
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 get pregnant.
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 any medicine.
3.
HOW TO USE KEPIVANCE
.
A doctor with experience in cancer treatment should supervise your Kepivance treatment.
The usual dose is 60 micrograms of Kepivance per kilogram of bodyweight per day. This is given as
an intravenous injection (into a vein) for three days in a row before chemotherapy and/or radiotherapy
and three days in a row after chemotherapy and/or radiotherapy for a total of six doses. The last of the
three doses given before chemotherapy/radiotherapy, must be given at least 24 to 48 hours before the
chemotherapy/radiotherapy. The first of the three doses given after the chemotherapy/radiotherapy
must be given more than four 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 Kepivance 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).
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;
21
•
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 any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please
tell your doctor or pharmacist.
5.
HOW TO STORE KEPIVANCE
Keep out of the reach and sight of children.
Do not use Kepivance after the expiry date which is stated on the carton and vial label, after EXP. The
expiry date refers to the last day of the month.
Store in a refrigerator (2°C – 8°C).
Do not freeze.
Store in the original carton, in order to protect from light.
6.
FURTHER 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
Biovitrum AB (publ)
SE-112 76 Stockholm
Sweden
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This leaflet was last approved in
Detailed information on this medicine is available on the European Medicines Agency web site:
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The following information is intended for medical or 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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Source: European Medicines Agency
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