)‫בטיחות‬
)‫מידע בטיחות‬
‫החמרה (( מידע‬
‫על החמרה‬
‫הודעה על‬
‫הודעה‬
_____26.9.10____ ‫תאריך‬
___Replenine-VF 500 & 1000____‫שם תכשיר באנגלית‬
_____ 122 97 29999 & 122 96 29998______‫מספר רישום‬
__________________Kamada Ltd_____‫שם בעל הרישום‬
‫השינויים בעלון מסומנים על רקע צהוב‬
‫רופא‬
‫בעלון ללרופא‬
‫בעלון‬
‫ים‬/‫ים המבוקש‬/‫פרטים על השינוי‬
‫טקסט חדש‬
‫טקסט נוכחי‬
Replenine® -VF, 50 IU/mL human factor IX, a powder for solution
Replenine® -VF
2.1
2.1
2.2
Qualitative composition
Replenine® -VF is a high purity factor IX. This product is
prepared from plasma from screened donors. Donors are
selected from the USA.
Quantitative composition
Replenine® -VF has a potency of, is presented as a sterile
powder for solution, containing nominally 500 IU or 1000
iuIU human coagulation factor IX per vial. against the
current WHO standard. The product has a specific
activity of not less than 100 iu per mg of protein. The
product contains approximately 50 IU/mL when
reconstituted with either 10 mL (500 IU vial) or 20 mL
(1000 IU vial) of Sterilised Water for Injections, (Ph.Eur.).
2.2
‫פרק בעלון‬
NAME OF THE MEDICINAL
PRODUCT
Qualitative composition
Replenine®-VF is a high purity factor IX. This product is
prepared from plasma from screened donors. Donors are selected
from the USA.
Quantitative composition
Replenine®-VF has a potency of, 500 or 1000 iu
per vial against the current WHO standard. The product has a
specific activity of not less than 100 iu per mg of protein.
1
QUALITATIVE AND
QUANTITATIVE
COMPOSITION
‫ים‬/‫ים המבוקש‬/‫פרטים על השינוי‬
‫טקסט חדש‬
‫טקסט נוכחי‬
‫פרק בעלון‬
One mL of Replenie-VF contains approximately 100 IU of
human coagulation factor IX after reconstitution at half
volume (see 6.6).
The potency (IU) is determined using the European
Pharmacopoeia one stage clotting test. The specific activity
of Replenine-VF is approximately 100 IU per mg of
protein.
For excipients, see section 6.1.
Replenine® -VF is a powder for solution, it is a freeze-dried
concentrate of factor IX for reconstitution with Sterilised
Water for Injections, Ph.Eur. After reconstitution with the
supplied sterile water diluents the product is administered
intravenously.
Replenine®-VF is a
freeze-dried concentrate of factor IX for reconstitution with
Sterilised Water for Injections, Ph.Eur. After reconstitution with
the supplied sterile water diluents the product is administered
intravenously.
4.1
Therapeutic indications
Treatment of bleeding and prophylaxis of bleeding in
patients with haemophilia B (congenital factor IX
deficiency).
4.1
Therapeutic indications
Treatment of bleeding and prophylaxis in patients with
haemophilia B (congenital factor IX deficiency).
4.2
Posology and method of administration
Treatment should be initiated under the supervision of a
physician experienced in the treatment of haemophilia.
4.2
Posology and method of administration
4.2.1
Posology
4.2.1
Posology
2
PHARMACEUTICAL FORM
CLINICAL
PARTICULARS
‫ים‬/‫ים המבוקש‬/‫פרטים על השינוי‬
‫טקסט חדש‬
Treatment should be under the supervision of a
physician experienced in the treatment of
haemophilia.
The dosage and duration of the substitution therapy
depend on the severity of the factor IX deficiency, on
the location and extent of the bleeding and on the
patient’s clinical condition.
On Demand treatment
The number of units of factor IX administered is
expressed in International Units (iuIU), which are
related to the current WHO standard for factor IX
products. Factor IX activity in plasma is expressed
either as a percentage (relative to normal human
plasma) or in International Units (relative to an
international standard for factor IX in plasma).
One International Unit (iuIU) of factor IX activity is
equivalent to that quantity of factor IX in one mlmL of
normal human plasma. The calculation of the required
dosage of factor IX is based on the empirical finding
®
that 1 International Unit (iuIU) Replenine -VF per kg
body weight raises the plasma factor IX activity by
1.3% 1.16% of normal activity. The required dosage is
determined using the following formula:
Required units = body weight (kg) x desired factor
‫טקסט נוכחי‬
Treatment should be under the supervision of a physician
experienced in the treatment of haemophilia.
The dosage and duration of the substitution therapy depend
on the severity of the factor IX deficiency, on the location
and extent of the bleeding and on the patient’s clinical
condition.
The number of units of factor IX administered is expressed in
International Units (iu), which are related to the current
WHO standard for factor IX products. Factor IX activity in
plasma is expressed either as a percentage (relative to normal
human plasma) or in International Units (relative to an
international standard for factor IX in plasma).
One International Unit (iu) of factor IX activity is equivalent
to that quantity of factor IX in one ml of normal human
plasma. The calculation of the required dosage of factor IX is
based on the empirical finding that 1 International Unit (iu)
Replenine®-VF per kg body weight raises the plasma factor
IX activity by 1.3% of normal activity. The required dosage
is determined using the following formula:
Required units = body weight (kg) x desired factor IX
rise (%) (iu/dl) x 0.8
The amount to be administered and the frequency of
administration should always be orientated to the
clinical effectiveness in the individual case. Factor IX
products rarely require to be administerd more than
3
‫פרק בעלון‬
‫ים‬/‫ים המבוקש‬/‫פרטים על השינוי‬
‫טקסט חדש‬
‫טקסט נוכחי‬
IX rise (%) (iuIU/dldL) x 0.8 0.85
The amount to be administered and the frequency of
administration should always be orientated to the
clinical effectiveness in the individual case. Factor IX
products rarely require to be administerd more than
once daily.
‫פרק בעלון‬
once daily.
In the case of the following haemorrhagic events, the
factor IX activity should not fall below the given
plasma activity level (in iu/dl) in the corresponding
period. The following table can be used to guide
dosing in bleeding episodes and surgery:
In the case of the following haemorrhagic events, the
factor IX activity should not fall below the given
plasma activity level (in iuIU/dldL) in the
corresponding period. The following table can be used
to guide dosing in bleeding episodes and surgery:
Degree of
haemorrhae/
Type of
surgical
procedure
Factor IX
level
required
(%)
(IU/dldL)
Frequency of
doses (hours)/
Duration of
Therapy (days)
Factor IX
level required
(%)
(IU/dl)
Frequency of
doses (hours)/
Duration of
Therapy (days)
20-40
Repeat every 24
hours. At least 1
Haemorrhage
Haemorrhae
Early
Degree of
haemorrhage/
Type of
surgical
procedure
20-40
Repeat every 24
hours. At least 1
Early
haemarthrosis,
4
‫ים‬/‫ים המבוקש‬/‫פרטים על השינוי‬
‫טקסט חדש‬
haemarthrosi,
muscle bleed or
oral bleed
More extensive
haemarthrosi,
muscle bleed or
haematoma.
Life threatening
haemorrhages
bleeds such as
head surgery,
throat bleed,
severe abdominal
bleed.
30-60
60-100
‫טקסט נוכחי‬
day, until the
bleeding episode
as indicated by
pain is resolved
or healing is
achieved.
muscle bleed or
oral bleed
Repeat infusion
every 24 hours
for 3-4 days or
more until pain
and disability are
resolved.
More extensive
haemarthrosis,
muscle bleed or
haematoma.
30-60
Repeat infusion
every 24 hours
for 3-4 days or
more until pain
and disability are
resolved.
Repeat infusion
every 8 to 24
hours until threat
is resolved.
Life threatening
bleeds such as
head surgery,
throat bleed,
severe abdominal
bleed.
60-100
Repeat infusion
every 8 to 24
hours until threat
is resolved.
day, until the
bleeding episode
as indicated by
pain is resolved
or healing is
achieved.
30-60
Every 24 hours,
at least 1 day,
until healing is
Surgery
Surgery
Minor surgery
‫פרק בעלון‬
30-60
Every 24 hours,
Minor
Including tooth
extraction
5
‫ים‬/‫ים המבוקש‬/‫פרטים על השינוי‬
‫טקסט חדש‬
Including tooth
extraction
‫טקסט נוכחי‬
at least 1 day,
until healing is
achieved.
achieved.
80-100
Major
Major surgery
80-100
(preand
postoperat
ive)
Repeat infusion
every 8-24 hours
until adequate
wound healing,
then therapy for
at least another 7
days to maintain
a FIX activity of
30% to 60%
(IU/dldL).
Under certain circumstances larger amounts than
those calculated may be required, especially in the
case of the initial dose.
Posology in children
In the case of children, a dose of 1 iu/kg will
possibly give a reduced rise. There is insufficient
data to recommend the use of REPLENINE®-VF
in children less than 6 years old.
Prophylaxis
For long-term prophylaxis against bleeding in patients
‫פרק בעלון‬
(pre- and
postoperative)
Repeat infusion
every 8-24 hours
until adequate
wound healing,
then therapy for
at least another 7
days to maintain
a FIX activity of
30% to 60%
(IU/dl).
Under certain circumstances larger amounts than those
calculated may be required, especially in the case of the
initial dose.
Posology in children
In the case of children, a dose of 1 iu/kg will possibly give a
reduced rise. There is insufficient data to recommend the use
of REPLENINE®-VF in children less than 6 years old.
During the course of treatment, appropriate determination of
factor IX levels is advised to guide the dose to be
administered and the frequency of repeated infusions. In the
case of major surgical interventions in particular, precise
monitoring of the replacement therapy by means of
coagulation analysis (plasma factor IX activity) is
6
‫ים‬/‫ים המבוקש‬/‫פרטים על השינוי‬
‫טקסט חדש‬
‫טקסט נוכחי‬
with severe haemophilia B, the uaual doses are 20 to
40 IU of factor IX per kilogram of body weight at
intervals of 3 to 4 days.
indispensable. Individual patients may vary in their response
to factor IX, achieving different levels of in vivo recovery
and demonstrating different half-lives.
In some cases, especially in younger patients, shorter
dosage intervals or higher doses may be necessary.
Patients should be monitored for the development of factor
IX inhibitors. If the expected factor IX activity plasma levels
are not attained, or if bleeding is not controlled with an
appropriate dose, an assay should be performed to determine
if a factor IX inhibitor is present. If the inhibitor is present at
levels less than 10 Bethesda Units (BU) per ml,
administration of additional REPLENINE®-VF may
neutralise the inhibitor. In patients with titres above 10 BU or
with high anamnestic response, the use of (activated)
prothrombin complex concentrate (PCC) or recombinant
activated factor VII (rFVIIa) preparations has to considered.
These therapies should be directed by physicians with
experience in the care of patients with haemophilia.
DO NOT EXCEED THE RECOMMENDED DOSE.
Continuous infusion
Prior to surgery, a pharmacokinetic analysis should be
performed to obtain an estimate of clearance. The
initial infusion rate can be calculated as follows:
Clearance x Desired steady state level = Infusion
rate (IU/kg/h)
After the initial 24 hours of continuous infusion, the
clearance should be calculated again every day using
the steady state equation with the measured level and
the known rate of infusion (see also section 5.2).
See also 4.4.
During the course of treatment, appropriate
determination of factor IX levels is advised to guide
the dose to be administered and the frequency of
repeated infusions. In the case of major surgical
interventions in particular, precise monitoring of the
replacement substitution therapy by means of
7
‫פרק בעלון‬
‫ים‬/‫ים המבוקש‬/‫פרטים על השינוי‬
‫טקסט חדש‬
‫טקסט נוכחי‬
coagulation analysis (plasma factor IX activity) is
indispensable. Individual patients may vary in their
response to factor IX, achieving different levels of in
vivo recovery and demonstrating different half-lives.
In a clinical study in children under six years of age,
the median dose of Replenine-VF for prophylaxis was
29.3 IU/kg (95% confidence interval: 25.3 - 33.2
IU/kg) given up to twice weekly; the mean dose to
treat a bleed was 26.8 IU/kg (95% confidence interval:
15.7 - 37.9 IU/kg).
Patients should be monitored for the development of
factor IX inhibitors. If the expected factor IX activity
plasma levels are not attained, or if bleeding is not
controlled with an appropriate dose, an assay should be
performed to determine if a factor IX inhibitor is
present. In patients with high levels of inhibitor, factor
IX therapy may not be effective and other therapeutic
options should be considered. Management of such
patients should be directed by physicians with
rxperience in the care of patients with haemophilia.
If the inhibitor is present at levels less than 10
Bethesda Units (BU) per ml, administration of
additional REPLENINE®-VF may neutralise the
inhibitor. In patients with titres above 10 BU or
with high anamnestic response, the use of
8
‫פרק בעלון‬
‫ים‬/‫ים המבוקש‬/‫פרטים על השינוי‬
‫טקסט חדש‬
‫טקסט נוכחי‬
(activated) prothrombin complex concentrate
(PCC) or recombinant activated factor VII
(rFVIIa) preparations has to considered. These
therapies should be directed by physicians with
experience in the care of patients with haemophilia.
DO NOT EXCEED THE RECOMMENDED DOSE.
See also 4.4.
4.2.2
4.2.2
Method of administration
Reconstitute the product as described in 6.6. The
product should be administered via the intraveonous
route. The solution should be drawn from the vial
into a plastic disposable syringe (approved syringes
are made by Becton Dickinson) through the filter
needle supplied with the product. For
administration, a Number 23 "butterfly" needle
(Abbott venisystems) is approved for use with this
product. Although the material is unlikely to cause
side effects, The dose, especially the first dose, should
be given slowly (approximately 3 ml per minute).
The solution must not be stored and the slow
intravenous injection of each dose should be
completed within one hour of reconstitution.
®
REPLENINE -VF should be administered when
the first sign of bleeding occurs and should be
repeated as necessary to stop bleeding. Each
individual case must be assessed on its merits.
Method of administration
Reconstitute the product as described in 6.6. The solution
should be drawn from the vial into a plastic disposable
syringe (approved syringes are made by Becton Dickinson)
through the filter needle supplied with the product. For
administration, a Number 23 "butterfly" needle (Abbott
venisystems) is approved for use with this product. Although
the material is unlikely to cause side effects, The dose,
especially the first dose, should be given slowly
(approximately 3 ml per minute). The solution must not be
stored and the slow intravenous injection of each dose should
be completed within one hour of reconstitution.
REPLENINE®-VF should be administered when the first
sign of bleeding occurs and should be repeated as necessary
to stop bleeding. Each individual case must be assessed on
its merits.
9
‫פרק בעלון‬
‫ים‬/‫ים המבוקש‬/‫פרטים על השינוי‬
‫טקסט חדש‬
For continuous infusion during and after major
surgery, the product should be given intravenously and
undiluted by a syringe driver or syringe pump (see
4.2).
4.3
‫טקסט נוכחי‬
4.3
Contra-indications
Hypersensitivity to the active substance or to any of the
excipients.
The product should not be administered to patients showing
signs of Disseminated Intravascular Coagulation (DIC), or
patients suffering from acute liver failure. Patients with
impaired liver function require monitoring for signs of DIC.
(See 4.4 Special Warnings and Special Precautions for Use).
4.4
Special warnings and special precautions for use
As with any intravenous protein product, allergic type
hypersensitivity reactions are possible. Replenine®-VF
contains traces of human proteins other than FIX. Patients
should be informed of the early signs of hypersensitivity
reactions including hives, generalised urticaria, tightness of
the chest, wheezing, hypotension and anaphylaxis. If these
symptoms occur, they should be advised to discontinue use
of the product immediately and contact their physician. In the
case of shock current medical standards for shock-treatment
should be observed.
Contra-indications
Hypersensitivity to the active substance or to any of
the excipients.
The product should not be administered to patients
showing signs of Disseminated Intravascular
Coagulation (DIC), or patients suffering from acute
liver failure. Patients with impaired liver function
require monitoring for signs of DIC. (See 4.4
Special Warnings and Special Precautions for Use).
4.4 Special warnings and special precautions for use
As with any intravenous protein product, allergic type
hypersensitivity reactions are possible. Replenine ® -VF
contains traces of human proteins other than FIX.
Patients should be informed of the early signs of
hypersensitivity reactions including hives, generalised
urticaria, tightness of the chest, wheezing, hypotension
and anaphylaxis. If these symptoms occur, they should
be advised to discontinue use of the product
immediately and contact their physician. In the case of
shock current medical standards standard treatment
10
‫פרק בעלון‬
‫ים‬/‫ים המבוקש‬/‫פרטים על השינוי‬
‫טקסט חדש‬
‫טקסט נוכחי‬
for shock-treatment should be observed.
Standard measures to prevent infections resulting from
the use of medicinal products prepared from human
blood or plasma include selection of donors, screening
of individual donations and plasma pools for specific
markers of infection and the inclusion of effective
manufacturing steps for the inactivation/removal of
viruses. Despite this, when products prepared from
human blood or plasma are administered, the
possibility of transmitting infectious diseases due to
the transmission of infective agents cannot be totally
excluded. This also applies to unknown or emerging
viruses and other pathogens. of hitherto unknown
nature. The risk of transmission of infective agents
is however reduced by:
-
-
selection of donors by a medical interview and ,
screening of donations and for for specific markers
of infectionthe three major pathogenic viruses HIV,
HCV, HBV;
testing plasma pools for HCV genomic material;
removal/inactivation procedures included in the
production process that have been validated using
model viruses and are considered effective for HIV,
HCV, HAV, parvovirus B19 and HBV.
It is recommended that patients are
vaccinated against (hepatitis A and
when products prepared from human blood or plasma are
administered, infectious diseases due to the transmission of
infective agents cannot be totally excluded. This also applies
to pathogens. of hitherto unknown nature. The risk of
transmission of infective agents is however reduced by:
selection of donors by a medical interview and , screening of
donations and for for specific markers of infectionthe three
major pathogenic viruses HIV, HCV, HBV;
testing plasma pools for HCV genomic material;
removal/inactivation procedures included in the production
process that have been validated using model viruses and are
considered effective for HIV, HCV, HAV, parvovirus B19
and HBV.
It is recommended that patients are vaccinated against
(hepatitis A and hepatitis B) as a precaution.
After repeated treatment with human coagulation factor IX
products, patients should be monitored for the development
of inhibitors that should be quantified in modified Bethesda
Units using appropriate biological testing.
There have been reports in the literature showing a
correlation between the occurrence of a factor IX inhibitor
11
‫פרק בעלון‬
‫ים‬/‫ים המבוקש‬/‫פרטים על השינוי‬
‫טקסט חדש‬
hepatitis B) as a precaution.
The measures taken are considered effective for
enveloped viruses such as HIV, HBV and HCV, and for
the non-enveloped viruses HAV and parvovirus B19.
It is strobgly recommended that every time that
Replenine-VF is administered to a patient, the name and
batch number of the product are recorded in order to
maintain a link between the patient and the batch of the
product.
After repeated treatment with human coagulation
factor IX products, patients should be monitored for
the development of neutralising antibodies (inhibitors)
that should be quantified in modified Bethesda Units
(BU) using appropriate biological testing.
There have been reports in the literature showing a
correlation between the occurrence of a factor IX
inhibitor and allergic reactions. Therefore, patients
experiencing allergic reactions should be evaluated for
the presence of an inhibitor. It should be noted that
patients with factor IX inhibitors may be at an
increased risk of anaphylaxis with subsequent
challenge with factor IX. Because of the risk of
allergic reactions with factor IX concentrates, the
initial administration of factor IX should, according to
the treating physician’s judgement, be performed
‫טקסט נוכחי‬
and allergic reactions. Therefore, patients experiencing
allergic reactions should be evaluated for the presence of an
inhibitor. It should be noted that patients with factor IX
inhibitors may be at an increased risk of anaphylaxis with
subsequent challenge with factor IX. Because of the risk of
allergic reactions with factor IX concentrates, the initial
administration of factor IX should, according to the treating
physician’s judgement, be performed under medical
observation where proper medical care for allergic reactions
could be provided.
The product should be used with caution in children less than
6 years, who have limited exposure to factor IX products.
Since the use of factor IX complex concentrates has historically
been associated with the development of thromboembolic
complications, the risk being higher in low purity preparations,
the use of factor IX containing products may be potentially
hazardous in patients with signs of fibrinolysis and in patients
with disseminated intravascular coagulation (DIC). Because of
the potential risk of thrombotic complications, clinical
surveillance for early signs of thrombotic and consumptive
coagulopathy should be initiated with appropriate biological
testing when administering this product to patients with liver
disease, to patients post-operatively, to neonates, or to patients
at risk of thromboembolic phenomena or disseminated
intravascular coagulation. In each of these situations, the
potential benefit of treatment with Replenine®-VF should be
weighed against the risk of these complications.
12
‫פרק בעלון‬
‫ים‬/‫ים המבוקש‬/‫פרטים על השינוי‬
‫טקסט חדש‬
‫טקסט נוכחי‬
under medical observation where proper medical care
for allergic reactions could be provided.
The product should be used with caution in
children less than 6 years, who have limited
exposure to factor IX products.
Since the use of factor IX complex concentrates has
historically been associated with the development of
thromboembolic complications, the risk being higher
in low purity preparations, the use of factor IX
containing products may be potentially hazardous in
patients with signs of fibrinolysis and in patients with
disseminated intravascular coagulation (DIC). Because
of the potential risk of thrombotic complications,
clinical surveillance for early signs of thrombotic and
consumptive coagulopathy should be initiated with
appropriate biological testing when administering this
product to patients with liver disease, to patients postoperatively, to neonates new-born infants, or to
patients at risk of thromboembolic phenomena or
disseminated intravascular coagulation DIC. In each
of these situations, the potential benefit of treatment
®
with Replenine -VF should be weighed against the
risk of these complications.
4.5
Interactions with other medicaments medicinal
products and other forms of interactions
4.5
Interactions with other medicaments and other forms of
interactions
13
‫פרק בעלון‬
‫ים‬/‫ים המבוקש‬/‫פרטים על השינוי‬
‫טקסט חדש‬
‫טקסט נוכחי‬
No interactions of REPLENINE®-VF human
coagulation plasma factor IX products with other
medicinal products are known so far.
No interactions of REPLENINE®-VF human plasma factor
IX with other medicinal products are known so far.
4.6
Pregnancy and lactation
No Animal reproduction and lactation studies have
®
not been conducted with REPLENINE -VF factor
IX. The safety of REPLENINE®-VF for use in
human pregnancy has not been established. Based
on the rare occurrence of haemophilia B in women,
experience regarding the use of factor IX during
pregnancy and breast-feeding is not available.
Therefore, Replenine® -VF should be administered to
pregnant lactating women used during pregnancy
and lactation only if clearly needed and the benefit
outweighs the risk indicated.
4.6
Pregnancy and lactation
No Animal reproduction and lactation studies have been
conducted with REPLENINE®-VF. The safety of
REPLENINE®-VF for use in human pregnancy has not been
established. Therefore, Replenine®-VF should be
administered to pregnant lactating women only if clearly
needed and the benefit outweighs the risk.
4.7
Effects on ability to drive and use machines
There are no indications that human plasma factor
IX may impair the ability to drive or to operate
machinery.
Replenine-VF has no influence on the ability to drive
and use machines.
4.7
Effects on ability to drive and use machines
There are no indications that human plasma factor IX may
impair the ability to drive or to operate machinery.
14
‫פרק בעלון‬
‫ים‬/‫ים המבוקש‬/‫פרטים על השינוי‬
‫טקסט חדש‬
4.8
‫טקסט נוכחי‬
Undesirable effects
The following adverse reactions have been reported
from patients in clinical studies and from postmarketing experience (Commom >1/100 to <1/10).
MedDRA
Standard
System
Organ
Class
Nervous
system
disorders
General
disorders
and
injection
site
changes
Adverese
reaction
Frequeny
Headachs
Commom
Injection
site
reaction
Commom
If there are any side effects these should be
controlled by stopping the infusion, followed by
specific treatment of the particular side effect.
Hypersensitivity or allergic reactions (which may
include angioedema, burning and stinging at the
infusion site, chills, flushing, generalised urticaria,
headache, hives, hypotension, lethargy, nausea,
restlessness, tachycardia, tightness of the chest,
4.8
Undesirable effects
If there are any side effects these should be controlled by
stopping the infusion, followed by specific treatment of the
particular side effect.
Hypersensitivity or allergic reactions (which may include
angioedema, burning and stinging at the infusion site, chills,
flushing, generalised urticaria, headache, hives, hypotension,
lethargy, nausea, restlessness, tachycardia, tightness of the
chest, tingling, vomiting, wheezing) have been observed
infrequently in patients treated with factor IX containing
products. In some cases, these reactions have progressed to
severe anaphylaxis, and they have occurred in close temporal
association with development of factor IX inhibitors (see also
4.4). The treatment required depends on the nature and
severity of the reaction.
Nephrotic syndrome has been reported following attempted
immune tolerance induction in haemophilia B patients with
factor IX inhibitors and a history of allergic reaction.
Increase in body temperature is observed in rare cases.
Patients with haemophilia B may develop antibodies
(inhibitors) to factor IX. If such inhibitors occur, the
condition will manifest as an insufficient clinical response. In
such cases, it is recommended that a specialised haemophilia
centre be contacted. There have been no reports of inhibitor
15
‫פרק בעלון‬
‫ים‬/‫ים המבוקש‬/‫פרטים על השינוי‬
‫טקסט חדש‬
tingling, vomiting, wheezing) have been observed
infrequently in patients treated with factor IX
containing products. In some cases, these reactions
have progressed to severe anaphylaxis, and they have
occurred in close temporal association with
development of factor IX inhibitors (see also 4.4). The
treatment required depends on the nature and
severity of the reaction.
Nephrotic syndrome has been reported following
attempted immune tolerance induction in haemophilia
B patients with factor IX inhibitors and a history of
allergic reaction.
‫טקסט נוכחי‬
development in patients treated with REPLENINE®-VF.
There is a potential risk of thromboembolic episodes
following the administration of factor IX products, with a
higher risk for low purity preparations. The use of low purity
factor IX products has been associated with instances of
myocardial infarction, disseminated intravascular
coagulation, venous thrombosis and pulmonary embolism.
The use of high purity factor IX is rarely associated with
such side effects.
Increase in body temperature is observed in rare
cases.
On rare occasions, fever has been observed.
Patients with haemophilia B may develop antibodies
(inhibitors) to factor IX. If such inhibitors occur, the
condition will manifest as an insufficient clinical
response. In such cases, it is recommended that a
specialised haemophilia centre be contacted. There have
been no reports of inhibitor development in patients
treated with REPLENINE®-VF. In a clinical study in
children aged less than six years, three previously
untrated patients were enrolled and remained inhibitor
negative after treatment with Replenine-VF for six
16
‫פרק בעלון‬
‫ים‬/‫ים המבוקש‬/‫פרטים על השינוי‬
‫טקסט חדש‬
‫טקסט נוכחי‬
‫פרק בעלון‬
months. Of the 67 previously treated patients in clinical
studies, one young child developed an inhibitor with a
titre of 3.6 Bethesda Units.
There is a potential risk of thromboembolic episodes
following the administration of factor IX products,
with a higher risk for low purity preparations. The use
of low purity factor IX products has been associated
with instances of myocardial infarction, disseminated
intravascular coagulation, venous thrombosis and
pulmonary embolism. The use of high purity factor IX
is rarely associated with such side effects.
For information on viral safety see 4.4
4.9
5.1
Overdose
No-case symptoms of overdose with human factor IX
have has been reported.
Pharmacodynamic properties
Pharmacotherapeutic group: Antihaemorrhagics: blood
coagulation factor IX, ATC code: B02B D04
Factor IX is a single chain glycoprotein with a molecular
mass of about 68,000 Daltons. It is a vitamin K-dependent
coagulation factor and it is synthesised in the liver.
4.9
Overdose
No symptoms of overdose with human factor IX have been
reported.
5.1
Pharmacodynamic properties
Pharmacotherapeutic group: Antihaemorrhagics: blood
coagulation factor IX, ATC code: B02B D04
Factor IX is a single chain glycoprotein with a molecular mass of
about 68,000. It is a vitamin K-dependent coagulation factor and
it is synthesised in the liver.
17
PHARMACOLOGICAL
PROPERTIES
‫ים‬/‫ים המבוקש‬/‫פרטים על השינוי‬
‫טקסט חדש‬
‫טקסט נוכחי‬
Factor IX is activated by factor XIa in the intrinsic
coagulation pathway and by the factor VII/tissue factor
complex in the extrinsic pathway. Activated factor IX,
in combination with activated factor VIII, activates
factor X. Activated factor X converts prothrombin into
thrombin. Thrombin then converts fibrinogen into
fibrin and a clot is formed.
Factor IX is activated by factor XIa in the intrinsic
coagulation pathway and by the factor VII/tissue factor
complex in the extrinsic pathway. Activated factor IX, in
combination with activated factor VIII, activates factor X.
Activated factor X converts prothrombin into thrombin.
Thrombin then converts fibrinogen into fibrin and a clot is
formed.
Haemophilia B is a sex-linked hereditary disorder of
blood coagulation due to decreased levels of factor IX
and results in profuse bleeding into joints, muscles or
internal organs, either spontaneously or as a result of
accidental or surgical trauma. By replacement therapy
the plasma level of factor IX is increased, thereby
enabling a temporary correction of the factor
deficiency and correction of the bleeding tendencies.
Haemophilia B is a sex-linked hereditary disorder of blood
coagulation due to decreased levels of factor IX and results in
profuse bleeding into joints, muscles or internal organs, either
spontaneously or as a result of accidental or surgical trauma.
By replacement therapy the plasma level of factor IX is
increased, thereby enabling a temporary correction of the
factor deficiency and correction of the bleeding tendencies.
From clinical trial experience, young children using
prophylactic Replenine-VF experienced less bleeds than
those only using it on demand. For dosed in children see
4.2.
5.2
Pharmacokinetic properties
Infusion of REPLENINE®-VF into patients with
haemophilia B results in recoveries of greater than
70% of the plasma factor IX activity. The plasma
half-life of factor IX ranges from 16-30 hours, with
an average of 24 hours.
In a clinical study of 15 adult patients with
5.2
Pharmacokinetic properties
Infusion of REPLENINE®-VF into patients with
haemophilia B results in recoveries of greater than 70% of
the plasma factor IX activity. The plasma half-life of factor
IX ranges from 16-30 hours, with an average of 24 hours.
18
‫פרק בעלון‬
‫ים‬/‫ים המבוקש‬/‫פרטים על השינוי‬
‫טקסט חדש‬
‫טקסט נוכחי‬
haemophilia B, the mean pharmacokinetic properties
of Replenine-VF were as follows:
Incremental Recovery:
AUC0-56 hrs:
Terminal Half-life:
Alpha Half-life:
Beta Half-life:
Mean Residence Time:
Clearance:
Volume of Distribution:
1.16 IU/dL per IU/kg
15.2 IU.mL/hour
19.0 hours
4.8 hours
20.9 hours
24.9 hours
4.52 mL/hour/kg
122.1 ML/kg
From clinical studies in 48 adult patients with
haemophilia B, most of whom had several assessments
of incremental recovery, all based on the maximum
FIX:C in the first 1 hour (ISTH, 2001), the overall
results were as follows:
Mean:
1.25 (95%CI 1.16 - 1.33) IU/dL per IU/kg
Median: 1.17 IU/dL per IU/kg
In a clinical trial, of Replenine-VF given by continuous
infusion to cover for major surgery, an initial bolus
dose was given to raise the factor IX activity to about
100 IU/dL. Continuous infusion was then started at 6
IU/kg/hour (given undeiluted by syringe pump or
syringe driver). Subsequently, the rate of infusion was
adjusted according to the following formula:
19
‫פרק בעלון‬
‫ים‬/‫ים המבוקש‬/‫פרטים על השינוי‬
‫טקסט חדש‬
‫טקסט נוכחי‬
New Rate = Latest Rate x Target FIX level (IU/mL)
(IU/kg/hour) (IU/kg/hour) Recently recorded FIX
level (IU/mL)
The median clearance was fastest during the first 24
hours peri-operatively (Day 1). Thereafter, median
clearance declined as follows: Day 1, 7.3 mL/kg/h;
Day 2, 4.2 mL/kg/h; Day 3, 4.4 mL/kg/h; Day 4, 3.4
mL/kg/h; Day 5, 3.2 mL/kg/h; Day 6, 1.3 mL/kg/h.
The formula describing the reduction in clearance from
post-operative Days 2 to 8 was as follows:
Factor IX clearance (mL/h/kg) = 5.05 – (0.36 x day)
There was inter-patient variability in clearance so,
when covering surgery by continuous infusion,
monitoring of plasma factor IX activity is required (see
section4.2).
Additional data from the study of comtinuous infusion
in major surgery provided the following mean
pharmacokinetic values for the period on continuous
infusion (by one-compartment multidose analysis):
Half-life:
Mean Residence Time:
Clearance:
Volume of Distribution:
14.8 hours
31.3 hours
3.8 mL/hour/kg
107.0 mL /kg
20
‫פרק בעלון‬
‫ים‬/‫ים המבוקש‬/‫פרטים על השינוי‬
‫טקסט חדש‬
5.3
Preclinical safety data
Human plasma coagulation factor IX (as contained
in Replenine® -VF) is a normal constituent of the
human plasma and acts like the endogenous factor
IX. Single dose toxicity testing is of no relevance
since higher doses result in overloading.
‫טקסט נוכחי‬
5.3
Preclinical safety data
Human plasma coagulation factor IX (as contained in
Replenine®-VF) is a normal constituent of the human
plasma and acts like the endogenous factor IX. Single
dose toxicity testing is of no relevance since higher doses
result in overloading.
Repeated dose toxicity testing in animals is
impracticable due to interference with developing
antibodies to heterologous protein. Since clinical
experience provides no evidence for tumourigenic
and mutagenic effects of human plasma coagulation
factor IX, experimental studies, particularly in
heterologous species, are not considered necessary.
Repeated dose toxicity testing in animals is impracticable
due to interference with developing antibodies to
heterologous protein. Since clinical experience provides
no evidence for tumourigenic and mutagenic effects of
human plasma coagulation factor IX, experimental
studies, particularly in heterologous species, are not
considered necessary.
Single dose toxicity studies in rats and mice have
established greater than a 20 fold safety margin.
Thrombogenicity testing in rabbits and rats showed
no evidence of thrombogenicity at doses of 200-300
iuIU/kg body weight.
Single dose toxicity studies in rats and mice have
established greater than a 20 fold safety margin.
Thrombogenicity testing in rabbits and rats showed no
evidence of thrombogenicity at doses of 200-300 iu/kg
body weight.
21
‫פרק בעלון‬
‫ים‬/‫ים המבוקש‬/‫פרטים על השינוי‬
‫טקסט חדש‬
6.1
List of excipients
Replenine® -VF solution contains the following
excipients:
Factor IX, factor II, factor X, protein, glycine,
L-lysine monohydrochloride,
trisodium citrate,
citric acid,
disodium phosphate dihydrate,
sodium chloride,
polysorbate 80 and
tri-n-butyl phosphate.
6.2
Incompatibilities
®
REPLENINE -VF should This medicinal product
must not be mixed with other medicinal products.
Only approved injection/infusion sets should be used
with the reconstituted product because treatment
failure may occur as a consequence of human factor
IX adsorption to the internal surface of some
unapproved infusion equipment.
6.3
Shelf-life
When unopened, shelf-life is 36 months at 2°C to
8°C, up to 3 months at normal ambient temperature
(25°C) within this period is not detrimental to the
product. The expiry date is printed on the label.
‫טקסט נוכחי‬
6.1
6.2
6.3
‫פרק בעלון‬
List of excipients
Replenine® -VF solution contains:
Factor IX, factor II, factor X, protein, glycine, L-lysine
monohydrochloride, trisodium citrate, citric acid, disodium
phosphate dihydrate, sodium chloride, polysorbate 80 and tri-nbutyl phosphate.
Incompatibilities
®
REPLENINE -VF should not be mixed with other
medicinal products.
Only approved injection/infusion sets should be used with
the reconstituted product because treatment failure may
occur as a consequence of human factor IX adsorption to the
internal surface of some unapproved infusion equipment.
Shelf-life
When unopened, shelf-life is 36 months at 2°C to 8°C, up to
3 months at normal ambient temperature (25°C) within this
period is not detrimental to the product. The expiry date is
printed on the label.
22
PHARMACEUTICAL
PARTICULARS
‫ים‬/‫ים המבוקש‬/‫פרטים על השינוי‬
‫טקסט חדש‬
‫טקסט נוכחי‬
When opened, store at 2°C to 25°C and use within one
hour. Warm to ambient temperature (25°C) before
injection.
When opened, store at 2°C to 25°C and use within one hour.
Warm to ambient (25°C) before injection.
Sterilised Water for Injections, Ph.Eur. should be stored between
2°C and 25°C.
Sterilised Water for Injections, Ph.Eur. should be stored
between 2°C and 25°C.
The Transfer Device (Mix2VialTM) can be stored in the
original carton with Replenine-VF at 2°C to 8°C.
6.4
Special precautions for storage
Store Replenine® -VF in the dark in its carton to protect
from light at the temperature specified on the packaging.
DO NOT FREEZE. Do not use beyond the expiry date on
the label. When the product is for home use a domestic
refrigerator is suitable for storage.
6.4
Special precautions for storage
Store Replenine® -VF in the dark in its carton at the
temperature specified on the packaging. DO NOT
FREEZE. Do not use beyond the expiry date on the label.
When the product is for home use a domestic refrigerator is
suitable for storage.
6.5
Nature and contents of container
Replenine® -VF is a freeze-dried plug of high purity
factor IX supplied in a single dose vial of either, 500
iuIU or 1000 iuIU (nominal). The product is contained
in glass (type I Ph.Eur.) bottles stoppered with a
halobutyl stopper. The bung is over-sealed with a
snap-off polypropylene cap and a clear lacquered
aluminium skirt.
6.5
Nature and contents of container
Replenine® -VF is a freeze-dried plug of high purity factor IX
supplied in a single dose vial of either, 500 iu or 1000 iu
(nominal). The product is contained in glass (type I Ph.Eur.)
bottles stoppered with a halobutyl stopper. The bung is oversealed with a snap-off polypropylene cap and a clear lacquered
aluminium skirt.
Supplied with the product is a Transfer Device called
23
‫פרק בעלון‬
‫ים‬/‫ים המבוקש‬/‫פרטים על השינוי‬
‫טקסט חדש‬
‫טקסט נוכחי‬
Mix2VialTM to allow needle free, easy and safe
reconstitution of the product with the Sterilised Water for
Injectios, Ph.Eur.
6.6
Instructions for use, and handling and disposal
Reconstitute the product with the Sterilised Water for
Injections, Ph.Eur., supplied (10 mlmL for 500 iuIU
and 20 mlmL for 1000 iuIU). Do not use the water if
beyond the expiry date or if signs of particulate
matter are visible. Do not inject Sterilised Water for
Injections, Ph.Eur., on its own.
®
Reconstitute REPLENINE -VF as follows:
The container of concentrate and the Sterilised Water
for Injections, Ph. Eur., should be brought to between
20°C and 30°C, prior to the removal of the 'flip-off'
closures.
Remove the caps from the concentrate and
Sterilised Water for Injections, Ph.Eur., and
clean stoppers with a an spirit swab. Either of the
following methods of reconstitution can then be
used:
a) Using a sterile disposable needle and syringe
draw up the required volume of Sterilised Water
for Injections, Ph.Eur. and transfer to the vial of
the factor IX. On piercing the seal of the factor
IX vial, the water will be drawn into the vial
which is under vacuum.
NB: THE FILTER NEEDLE PROVIDED MUST
6.6
Instructions for use, handling and disposal
Reconstitute the product with the Sterilised Water for
Injections, Ph.Eur., supplied (10 ml for 500 iu and 20 ml
for 1000 iu). Do not use the water if beyond the expiry date
or if signs of particulate matter are visible. Do not inject
Sterilised Water for Injections, Ph.Eur., on its own.
®
Reconstitute REPLENINE -VF as follows:
The container of concentrate and the Sterilised Water for
Injections, Ph. Eur., should be brought to between 20°C and
30°C, prior to the removal of the 'flip-off' closures.
Remove the caps from the concentrate and Sterilised
Water for Injections, Ph.Eur., and clean stoppers with a an
spirit swab. Either of the following methods of
reconstitution can then be used:
a) Using a sterile disposable needle and syringe draw up the
required volume of Sterilised Water for Injections, Ph.Eur.
and transfer to the vial of the factor IX. On piercing the
seal of the factor IX vial, the water will be drawn into the
vial which is under vacuum.
NB: THE FILTER NEEDLE PROVIDED MUST NOT BE
USED TO DRAW UP THE WATER FOR INJECTIONS.
or
b) Remove the cover guard from one end of a double ended
transfer needle and insert through the stopper into the vial
24
‫פרק בעלון‬
‫ים‬/‫ים המבוקש‬/‫פרטים על השינוי‬
‫טקסט חדש‬
NOT BE USED TO DRAW UP THE WATER
FOR INJECTIONS.
or
b) Remove the cover guard from one end of a
double ended transfer needle and insert through
the stopper into the vial of Sterilised Water for
Injections, Ph.Eur. Remove the other end of the
needle guard, invert the water vial over the
product vial and insert the free end of the needle
through the stopper into the vial of factor IX. On
piercing the seal of the product vial, the water
will be drawn into the vial which is under
vacuum. A small amount of water will remain in
the water vial.
If the water to be used for reconstitution is not
drawn into the vial containing factor IX, this
indicates loss of vacuum. If the vial does not
contain a vacuum or if the reconstituted factor
IX forms a gel or a clot, the vial must not be
used.
The container should be agitated to wet the
product and the vacuum then released by either:
a) Removing the syringe from the needle before
removing the needle from the product vial.
or
b) Disconnecting the two vials by first removing the
transfer needle from the water vial and then
removing the transfer needle from the product
vial.
‫טקסט נוכחי‬
of Sterilised Water for Injections, Ph.Eur. Remove the
other end of the needle guard, invert the water vial over the
product vial and insert the free end of the needle through
the stopper into the vial of factor IX. On piercing the seal
of the product vial, the water will be drawn into the vial
which is under vacuum. A small amount of water will
remain in the water vial.
If the water to be used for reconstitution is not drawn into
the vial containing factor IX, this indicates loss of vacuum.
If the vial does not contain a vacuum or if the reconstituted
factor IX forms a gel or a clot, the vial must not be used.
The container should be agitated to wet the product and the
vacuum then released by either:
a) Removing the syringe from the needle before removing the
needle from the product vial.
or
b) Disconnecting the two vials by first removing the transfer
needle from the water vial and then removing the transfer
needle from the product vial.
REPLENINE®-VF dissolves rapidly and requires only
very gentle agitation to ensure complete dissolution. A
clear or slightly opalescent solution should be obtained
within 5 minutes. If a gel or clot forms discard the vial.
Discard any unused Sterilised Water for Injections, Ph.Eur.
and unused product by approved means.
25
‫פרק בעלון‬
‫ים‬/‫ים המבוקש‬/‫פרטים על השינוי‬
‫טקסט חדש‬
‫טקסט נוכחי‬
REPLENINE®-VF dissolves rapidly and
requires only very gentle agitation to ensure
complete dissolution. A clear or slightly
opalescent solution should be obtained within 5
minutes. If a gel or clot forms discard the vial.
You can dissolve your product in two ways using the
Transfer Device called Mix2VialTM:
(A)
Dissolving in Full Volume or
(B)
Dissolving with Half Volume
(A) Dissolving in Full Volume
The Mix2VialTM Transfer Device is provided with the
product for needle-free, easy and safe use.
Step 1:
Step 2:
Step 3:
Remove the caps from the product vial and
clean the top of the stopper with an alcohol
swab. Repeat this step with the sterile water
vial. Peel back the top of the Transfer Device
package but leave the device in the package.
Place the blue end of the Transfer Device on
the water vial and push straight down until the
spike penetrates the rubber stopper and snap
into place. Remove the plastic outer packaging
from the Transfer Device and discard it, taking
care not to touch the exposed end of the
device.
Turn the water vial upside down with the
Transfer Device still attached.
26
‫פרק בעלון‬
‫ים‬/‫ים המבוקש‬/‫פרטים על השינוי‬
‫טקסט חדש‬
Step 4:
Step 5:
Step 6:
‫טקסט נוכחי‬
Place the clear end of the Transfer Device on
the product vial and push straight down until
the spike penetrates the rubber stopper and
snaps into place.
The sterile water will be pulled into the
product vial by the vacuum contained within it.
Gently swirl the vial to make sure the product
is thoroughly mixed. Do not shake the vial. A
clear or slightly pearl-like solution should be
obtained, usually in about 2 to 2 1/2 minutes (5
minutes maximum).
Seporate the empty water vial and blue part
from the clear part unscrewing anti-clockwise.
Draw air into the syringe by pulling the
plunger to the volume of water added. Connect
the syringe to the white filter and push the air
into the vial.
Immediatly invert the vial of solution which
will be drawn into the syringe. Disconnect the
filled syringe from the device. Follow normal
safety practices to administer your medicine.
Note:
If you have more than one vial to make up your
dose, repeat Steps 1 through 6 withdrawing the solutionin
the vial into the same syringe.
The Transfer Device supplied with the product is sterile
and cannot be used more than once. When the
27
‫פרק בעלון‬
‫ים‬/‫ים המבוקש‬/‫פרטים על השינוי‬
‫טקסט חדש‬
‫טקסט נוכחי‬
reconstitution process is complete, dispose of it in the
'sharps box'.
(B) Dissolving with half Volume
This Transfer Device is provided with the product for easy
and safe reconstitution.
 Firstly remove the cap from the Replenine-VF product
vial and clear the top of the stopper with an alcohol
swab. Repeat this step with the sterile water vial.
To use the Transfer Device for dissolving Replenine-VF in
half volumes, it is first necessary to remove and discard
half the water volume from the sterile water vial.
 Pierce the stopper of the sterile water vial with a
needle and syringe and draw up half the volume of
sterile water.
 Check that the correct amount is withdrawn, the
needle and syringe can now be safely disposed of (in
the 'sharp box).
 The remaining sterile water in the vial will be used for
reconstitution (half the original volume).
 To complete the dissolving process, follow steps 1 to 6
in Section A above.
 The product is then ready for administration.
Discard any unused Sterilised Water for Injections,
28
‫פרק בעלון‬
‫ים‬/‫ים המבוקש‬/‫פרטים על השינוי‬
‫טקסט חדש‬
‫טקסט נוכחי‬
Ph.Eur. and unused product by approved means.
Any unused product or wate material should be disposed
of in accordance with local requirements.
The solution should be clear or slightly opalescent. Do
not use solutions that are cloudy or have deposits.
Reconstituted products should be inspected visually for
particulate matter and discolouration prior to
administration.
29
‫פרק בעלון‬