ANNEX I
SUMMARY OF PRODUCT CHARACTERISTICS
1.
ATryn 1750 IU powder for solution for infusion
2.
ATryn is presented as a powder for solution for infusion containing nominally 1750 IU
antithrombin alfa per vial.
The product contains approximately 175 IU/ml antithrombin alfa when reconstituted with 10
ml of Sterile Water for Injection (WFI).
Antithrombin alfa is a recombinant form of human antithrombin and is produced by
recombinant DNA technology in the milk of transgenic goats.
The potency (IU) is determined using the European Pharmacopoeial chromogenic assay. The
specific activity of ATryn is approximately 7 IU/mg protein.
For a full list of excipients, see section 6.1.
3.
Powder for solution for infusion. White to off-white powder.
4.
ATryn is indicated for the prophylaxis of venous thromboembolism in surgery of patients
with congenital antithrombin deficiency. ATryn is normally given in association with heparin
or low molecular weight heparin.
Treatment should be initiated under the supervision of a physician experienced in the
treatment of patients with congenital antithrombin deficiency.
Posology
Due to differences in pharmacokinetics of antithrombin alfa and plasma-derived antithrombin,
treatment with ATryn should follow the specific dosing recommendations described below. In
the treatment of congenital antithrombin deficiency, the dosage and duration of treatment
should be individualised for each patient taking into account the family history with regard to
thromboembolic events, the actual clinical risk factors, and the laboratory assessment.
The number of units of antithrombin alfa administered is expressed in International Units
(IU), which is related to the current WHO standard for antithrombin concentrate.
Antithrombin (AT) activity in plasma is expressed either as a percentage (relative to human
plasma) or in International Units (relative to the International Standard for antithrombin in
plasma). One International Unit (IU) of antithrombin activity is equivalent to that quantity of
antithrombin in one ml of normal human plasma. The calculation of the required dosage of
antithrombin alfa is based on pre-treatment plasma antithrombin activity and body weight.
2
The therapeutic goal of treatment with ATryn is to increase to, and maintain antithrombin
activity between 80 – 120% (0.8 – 1.2 IU/ml) for the duration of treatment.
Initial treatment starts with a loading dose of ATryn targeting an antithrombin activity level
of 100%. This initial loading dose is based on body weight and on the pretreatment
antithrombin activity level.
The required loading dose is determined using the following formula:
Loading Dose (IU) = [(100 – patient’s pre-treatment AT activity level in %) /2.28] x
Body Weight in kg
The usual loading dose in surgical patients (baseline AT activity 50%, bodyweight 75 kg)
with congenital antithrombin deficiency in clinical risk situations is 20-25 IU/kg bodyweight.
The loading dose should be given as a 15 minute infusion immediately followed by initiation
of the maintenance infusion.
The required maintenance dose for surgical patients is given as a continuous infusion and is
determined using the following formula:
Maintenance Dose (IU/hour) = [(100 – patient’s pre-treatment AT activity level in %)
/10.22] x Body Weight in kg
The usual maintenance dose in surgical patients with congenital antithrombin deficiency in
clinical risk situations is 4-5 IU/kg/h. During consumptive states (e.g. major surgery,
concomitant use of heparin) the actual dose may be higher. See therapeutic monitoring and
dose adjustment recommendations below.
Therapeutic Monitoring and Dose Adjustment
The dosage should be adjusted on the basis of laboratory measurements of antithrombin
activity. Response to ATryn may vary in individual patients, achieving different levels of in
vivo recovery and different half-lives. Frequent antithrombin activity assessments and dosing
adjustments may be necessary when starting treatment and just after surgery.
After the start of the maintenance dose infusion, blood for AT activity levels should be drawn
at 45 minutes after the start of the loading dose infusion. In case the AT activity level is
between 80% and 120% (0.8 - 1.2 IU/ml), no dose adjustment is needed. In case the AT
activity level is less than 80%, increase the maintenance infusion rate by 50%. In case the AT
activity level is greater than 120% decrease the infusion rate by 30%. Check AT activity level
30 minutes after any change in infusion rate, or four hours after a value within the target
range. Subsequently, antithrombin activity should be checked 1-2 times a day and dose
adjustments made accordingly. The antithrombin activity level should be maintained above
80% for the duration of the treatment, unless clinical particulars would indicate a different
effective level.
It is possible that the surgical procedure will influence AT activity levels. Therefore, an
additional check of the AT activity level should be done after the surgery. In case the activity
level is below 80% a 15 minutes bolus infusion of AT can be given to quickly restore the AT
activity level. The dose can be calculated utilizing the post-surgical AT activity in the
loading dose formula above.
3
Method of administration:
Dissolve the preparation as described under 6.6. The product should be administered via the
intravenous route.
Paediatric Patients
There is no experience in children.
Hypersensitivity to any of the constituents.
Hypersensitivity to goat proteins or goat milk components.
As with any intravenous protein product, allergic type hypersensitivity reactions are possible.
Patients must be closely monitored and carefully observed for any symptoms throughout the
infusion period. 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 after administration, they should contact their
physician. In case of shock, standard medical treatment should be administered.
Patients treated with ATryn should be monitored for possible clinical immunological
reactions. Antibody status should be monitored and reported.
The experience from repeated treatment with ATryn is very limited. Close surveillance with
regard to immunological reactions is especially important in such situations.
Due to differences in pharmacokinetic characteristics of ATryn in pregnant versus non-
pregnant patients, recommendations for dosing in pregnancy or in the peripartum period
cannot be given.
Clinical and biological surveillance when antithrombin is used together with heparin, low
molecular weight heparin or other anticoagulants which potentiate the anticoagulant activity
of antithrombin:
-
In order to adjust dosage of the anticoagulant and to avoid excessive hypocoagulability,
controls of the extent of anticoagulation (APTT, and where appropriate anti-Factor Xa
activity) should be performed regularly, at close intervals and in particular in the first
minutes/hours following the start of antithrombin use.
-
Measure antithrombin levels daily, in order to adjust the individual dose. The risk of
diminution of antithrombin levels by prolonged treatment with a non-fractionated
heparin should be taken into account.
Antithrombin replacement during administration of anticoagulants that potentiate the
anticoagulant activity of antithrombin (e.g., heparin, low molecular weight heparin), may
increase the risk of bleeding. The half-life of recombinant antithrombin may be altered with
concomitant treatment with these anticoagulants due to an altered antithrombin turnover.
Thus, concurrent administration of antithrombin with heparin, low molecular weight heparin,
or other anticoagulants that potentiate the anticoagulant activity of antithrombin to a patient
with increased risk of bleeding must be monitored clinically and biologically.
4
No interaction studies have been performed.
Limited clinical data are available on the use of ATryn in pregnant women. Available data do
not suggest harmful effects to the mother or infant. However due to the difference in
pharmacokinetic characteristics of ATryn in pregnant vs. non-pregnant patients no
recommendation for dosing in pregnancy can be given at this time (see section 4.4). Animal
studies performed in rats did not indicate harmful effects on parturition, embryonal/foetal and
post-natal development.
Not relevant.
In clinical trials involving congenital antithrombin deficient patients (n=35) one mild
undesirable effect of “Application site pruritis” was reported as related to treatment with
ATryn. In other clinical trials with acquired antithrombin deficient cardiac surgery patients
(n=118) and healthy volunteers (n=102), undesirable effects reported to be related to
treatment with ATryn that were observed more than once are listed by System Organ Class in
the table below.
Common (1-10% of subjects)
Nervous system disorders
dizziness
headache
Vascular disorders
haemorrhage
Gastrointestinal disorders
nausea
General disorders and administration site conditions
venipuncture site haemorrhage
Injury and
poisoning
post procedural haemorrhage
wound secretion
Uncommon (0.1-1% of subjects)
General disorders and administration site conditions
Feeling hot
Infusion site erythema
Infusion site pain
Infusion site rash
Venipuncture site bruise
No antibodies to antithrombin alfa have been detected up to 90 days following treatment with
ATryn.
5
4.9
No case of overdose has been reported.
5.
5.1 Pharmacodynamic properties
Pharmacotherapeutic Group: Antithrombotic agents: heparin group. ATC code: B01AB02.
Antithrombin, a 58 kD, 432 amino-acid glycoprotein, belongs to the serpin (serine protease
inhibitor) superfamily. It is one of the most important natural inhibitors of blood coagulation.
The factors most strongly inhibited are thrombin and Factor Xa, but also factors of contact
activation, intrinsic system and the Factor VIIa/tissue factor complex. Antithrombin activity is
greatly enhanced by heparin and the anticoagulant effects of heparin depend on the presence
of antithrombin.
Antithrombin contains two functionally important domains. The first contains the reactive
centre and provides a cleavage site for proteinases such as thrombin, a prerequisite for
forming a stable proteinase-inhibitor complex. The second is a glycosaminoglycan binding
domain responsible for the interaction with heparin and related substances, which accelerates
the inhibition of thrombin. The inhibitor-coagulation enzyme complexes are removed by the
reticulo-endothelial system.
Normal antithrombin activity in adults is 80 - 120% (0.8-1.2 IU/ml) and levels in neonates are
about 40 - 60
%
(0.4-0.6 IU/ml
).
In a formal clinical trial employing serial Duplex ultrasound examinations, antithrombin alfa
was shown to be effective in the prevention of thromboembolic events in fourteen congenital
antithrombin deficient patients in clinical high risk situations. Some additional data have been
obtained from a number of patients in a compassionate use programme.
This medicinal product has been authorized under “Exceptional Circumstances”. This means
that due to the rarity of the disease, it has not been possible to obtain complete information on
this medicinal product. The European Medicines Agency (EMEA) will review any new
information which may become available every year and this SPC will be updated as
necessary.
5.2 Pharmacokinetic properties
After intravenous administration of ATryn (IV bolus dose of 50 IU/kg or 100 IU/kg body
weight) to congenital antithrombin deficient patients without clinical symptoms of
thrombosis, and not using heparin, the incremental recovery was 2.07 ± 1.54 %/IU/kg body
weight (mean ± SD). Population pharmacokinetic parameters for ATryn derived from the
same study revealed (mean ± SD):
•
Area under the curve: 587.88 ± 1.63 (% x h)
•
Distribution half-life: 1.74 ± 1.28 h, elimination half-life: 10.16 ± 1.28 h.
•
Mean residence time (MRT): 8.57 ± 1.24 h
•
Clearance: 0.665 ± 0.0493 l/h (Mean ± SE)
6
5.3 Preclinical safety data
Non-clinical data reveal no special hazard for humans based on conventional studies of safety
pharmacology, repeated dose toxicity, genotoxicity and toxicity to reproduction.
6.
6.1 List of excipients
Glycine
Sodium citrate
Sodium chloride
6.2 Incompatibilities
In the absence of compatibility studies, this medicinal product must not be mixed with other
medicinal products.
6.3 Shelflife
Unopened vials: 3 years.
It is recommended to reconstitute the product immediately prior to use.
Reconstituted product should be used immediately after preparation.
6.4 Special precautions for storage
Store in a refrigerator (2°C – 8°C).
6.5 Nature and contents of container
Powder containing 1750 IU antithrombin alfa in a clear vial (type I glass) with a stopper
(siliconised bromobutyl rubber) and capped with a band (aluminium) and flip-off cap
(plastic).
Pack sizes: 1, 10 or 25 vials.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal and other handling
Each vial of ATryn contains a lyophilised powder of 1750 IU antithrombin alfa and is
intended for single use only. Vials should be brought to room temperature prior to
reconstitution and kept no longer than 3 hours. The powder should be reconstituted with 10
ml of Sterile Water for Injection (WFI) injected along the side wall of the vial and gently
swirled (not shaken) to prevent foaming. The reconstituted product should be inspected
visually for particulate matter and discolouration prior to administration. The solution should
be clear or slightly opalescent. Do not use solutions that are cloudy or have deposits. Upon
complete dissolution, the reconstituted product may be drawn up into a sterile disposable
syringe. The reconstituted product should be administered by intravenous infusion using a
sterile disposable syringe or an infusion bag with a 0.22 micron pore size in-line filter.
Normal sodium chloride solution 9 mg/ml (0.9%) may be added to dilute to a concentration
convenient for administration. The contents of infusion syringes or diluted solution prepared
in infusion bags should be administered within 8 hours of preparation. Compatibility with
PVC infusion lines with in-line filters has been established.
7
Any unused product or waste material should be disposed of in accordance with local
requirements.
7.
GTC Biotherapeutics UK Limited
10 Norwich Street
London EC4A 1BD
United Kingdom
8.
EU/1/06/355/001-003
9.
28/07/2006
8
ANNEX II
A.
MANUFACTURER OF THE BIOLOGICAL
ACTIVE SUBSTANCE AND MANUFACTURING
AUTHORISATION HOLDER RESPONSIBLE FOR
BATCH RELEASE
B.
CONDITIONS OF THE MARKETING
AUTHORISATION
C.
9
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
Lonza Hopkinton, Inc.
97 South Street
Hopkinton, MA 01748-2204
USA
Name and address of the manufacturer responsible for batch release
LEO Pharma A/S
Industriparken 55
DK-2750 Ballerup
Denmark
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
The MAH must ensure that the system of pharmacovigilance is in place and functioning
before the product is placed on the market.
The MAH commits to performing the studies and additional pharmacovigilance activities
detailed in the Pharmacovigilance Plan.
An updated risk management plan should be provided as per the CHMP guideline on risk
management systems for medicinal products for human use.
C. SPECIFIC OBLIGATIONS TO BE FULFILLED BY THE MARKETING
AUTHORISATION HOLDER
The Marketing Authorisation Holder shall complete the following programme of studies
within the specified time frame, the results of which shall form the basis of the annual
reassessment of the benefit/risk profile.
10
Clinical aspects
1.Protocol GTC AT HD 012-04:
A Multicenter, Multinational Study to Assess the Safety and
Efficacy of Antithrombin alfa in Hereditary Antithrombin (AT) Deficient Patients in High-
Risk Situations for Thrombosis.
The results of ongoing study GTC AT HD 012-04 and in particular the results of
investigations in pregnant women treated during the peri-partum period have been submitted.
A marketing authorization variation will be submitted to seek to expand the indication and
dosing of pregnant women.
2. Post-marketing surveillance
a)
Prior to launch in any EU Member State, the MAH will set up a post-marketing
surveillance programme to collect the following information about congenital AT
deficient patients treated with ATryn
•
Demographics
•
Indication
•
Posology
•
Length of treatment
•
Prior treatment with ATryn
•
Use of anti-coagulants
•
Adverse drug reactions including lack of efficacy
•
Development of antibodies
Physicians should be encouraged to enrol patients in the surveillance programme and
results of the surveillance should be provided in the update to the EU-RMP or at the
time of the annual reassessment, whichever comes first.
b)
Prior to launch in any EU Member State, the MAH will set up an immunosurveillance
programme and provide antibody testing for anti-ATryn antibodies to physicians.
This antibody testing should be provided upon request of a physician and when the
MAH receives a report suggestive of a possible immune reaction or lack of efficacy.
c)
The MAH will ensure that material provided to physicians provides information on
the post-marketing surveillance programme and the immunosurveillance programme.
This post-marketing surveillance will run up until such time as 40 patients are enrolled.
11
ANNEX III
LABELLING AND PACKAGE LEAFLET
12
A. LABELLING
13
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
OUTER CARTON (1 VIAL)
1.
ATryn 1750 IU powder for solution for infusion
Antithrombin alfa
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
Approximately 175 IU/ml antithrombin alfa when reconstituted with 10 ml of WFI.
3.
LIST OF EXCIPIENTS
Excipients:
Glycine
Sodium chloride
Sodium citrate
4.
1 Vial
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
For intravenous use.
Read the package leaflet before 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 {MM/YYYY)
9.
SPECIAL STORAGE CONDITIONS
Store in a refrigerator.
14
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
For single use only.
Any unused solution should be discarded.
GTC Biotherapeutics UK Limited
10 Norwich Street
London EC4A 1BD
United Kingdom
EU/1/06/355/001
13. BATCH NUMBER
Batch {number}
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
15
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
OUTER CARTON (10 VIALS)
1.
ATryn 1750 IU powder for solution for infusion
Antithrombin alfa
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
Approximately 175 IU/ml antithrombin alfa when reconstituted with 10 ml of WFI.
3.
LIST OF EXCIPIENTS
Excipients:
Glycine
Sodium chloride
Sodium citrate
4.
10 Vials
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
For intravenous use.
Read the package leaflet before 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 {MM/YYYY)
9.
SPECIAL STORAGE CONDITIONS
Store in a refrigerator.
16
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
For single use only.
Any unused solution should be discarded.
GTC Biotherapeutics UK Limited
10 Norwich Street
London EC4A 1BD
United Kingdom
EU/1/06/355/002
13. BATCH NUMBER
Batch {number}
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
17
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
OUTER CARTON (25 VIALS)
1.
ATryn 1750 IU powder for solution for infusion
Antithrombin alfa
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
Approximately 175 IU/ml antithrombin alfa when reconstituted with 10 ml of WFI.
3.
LIST OF EXCIPIENTS
Excipients:
Glycine
Sodium chloride
Sodium citrate
4.
25 Vials
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
For intravenous use.
Read the package leaflet before 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 {MM/YYYY)
9.
SPECIAL STORAGE CONDITIONS
Store in a refrigerator.
18
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
For single use only.
Any unused solution should be discarded.
GTC Biotherapeutics UK Limited
10 Norwich Street
London EC4A 1BD
United Kingdom
EU/1/06/355/003
13. BATCH NUMBER
Batch {number}
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
19
MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS
LABEL
1.
ATryn 1750 IU powder for solution for infusion
Antithrombin alfa
For intravenous use.
2.
METHOD OF ADMINISTRATION
3.
EXPIRY DATE
EXP {MM/YYYY)
4.
BATCH NUMBER
Batch {number}
5.
CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT
Approximately 175 IU/ml antithrombin alfa when reconstituted with 10 ml of WFI
6.
OTHER
Store in a refrigerator.
GTC Biotherapeutics UK Limited, United Kingdom.
20
B. PACKAGE LEAFLET
21
PACKAGE LEAFLET: INFORMATION FOR THE USER
ATryn 1750 IU powder for solution for infusion
Antithrombin alfa.
Read all of this leaflet carefully before you start using this medicine.
-
Keep this leaflet. You may need to read it again.
-
If any of the side effects get serious or if you notice any side effects not listed in the
leaflet, please tell your doctor.
In this leaflet
:
1.
What ATryn is and what it is used for
3.
How to use ATryn
4.
Possible side effects
5
How to store ATryn
6.
Further information
1.
WHAT ATryn IS AND WHAT IT IS USED FOR
ATryn is an anti-clotting agent and contains antithrombin alfa which is similar to human
antithrombin.
Antithrombin alfa
is produced by recombinant DNA technology from the milk
of goats. If you have congenital antithrombin deficiency, your blood level of antithrombin is
lower than normal, which may result in a reduced anti-clotting capacity of your blood. If your
anti-clotting capacity is reduced, there is an increased risk of the formation of clots in the
vessels of your legs (deep vein thrombosis) or in other vessels of your body
(thromboembolism) during major surgery. Therefore, it is important that your antithrombin
blood level be maintained at sufficient levels in these situations.
2.
BEFORE YOU USE ATryn
Do not use ATryn
If you are allergic (hypersensitive) to antithrombin alfa or any of the other ingredients of
ATryn.
Take special care with ATryn
If you are allergic to goat products, please tell your treating physician since you should not
use ATryn. As with any intravenous protein product, allergic reactions are possible. If you
experience hives, itchy welts or wheals all over the skin, tightness of the chest, wheezing
(difficulty breathing), you should immediately contact your physician since these might be
symptoms of a severe allergic reaction. To test for the occurrence of an allergic reaction,
blood will be collected and tested before and some time after you have been treated with
ATryn.
Using other medicines
Please tell your doctor if you are taking or have recently taken any other medicines, including
medicines obtained without a prescription.
When ATryn is used together with heparin (an anti-clotting drug), or some other anti-clotting
drugs, this may increase the risk of bleeding. Therefore your doctor will carefully monitor the
use of ATryn when administered together with these anti-clotting drugs.
22
-
If you have any further questions, ask your doctor.
2.
Before you use ATryn
Using ATryn with food and drink
No special precautions should be taken while eating or drinking.
Pregnancy
ATryn is not indicated for use in pregnant patients.
Breast-feeding
It is unknown whether ATryn is present in breast milk. Therefore it is not recommended to
breastfeed whilst being treated with ATryn.
Driving and using machines
Not relevant.
Important information about some of the ingredients of ATryn
Not relevant.
3.
HOW TO USE
ATryn
Your health care provider will prepare a solution of ATryn to be administered through an
infusion directly into a blood vessel. Blood levels of antithrombin will be regularly checked in
the blood and a change of dose may be necessary.
If you use more ATryn than you should
The doctor will treat you, as appropriate, if you have any particular ill effects.
If you stop using ATryn
Please discuss possibility of stopping the treatment with your doctor.
If you have any further questions on the use of this product, ask your doctor.
4.
POSSIBLE SIDE EFFECTS
Like all medicines, ATryn may cause side effects, although not everybody gets them.
Some side effects such as bleeding, bruises, redness, or pain at the site of injection, nausea,
headache, feeling hot, dizziness, bruising and increased bleeding may occur during treatment
with ATryn.
If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet,
please tell your doctor.
5.
HOW TO STORE ATryn
Keep out of the reach and sight of children.
Unopened vials:
Store in a refrigerator (2°C – 8°C).
Do not use ATryn after the expiry date stated on the labelling after the letters EXP.
Diluted solutions:
The product should be used immediately.
23
6.
FURTHER INFORMATION
What ATryn contains
-
The active substance is antithrombin alfa
-
The other ingredients are: glycine, sodium chloride, sodium citrate
What ATryn looks like and contents of the pack
Powder for solution for infusion.
White to off-white powder.
Package size: 1, 10 or 25 vials per carton. Each vial of ATryn contains a nominal value of
1750 IU of recombinant antithrombin alfa. The powder will be dissolved before it can be
infused.
Marketing Authorisation Holder and Manufacturer
Marketing authorisation Holder
GTC Biotherapeutics UK Limited, 10 Norwich Street, London EC4A 1BD, United Kingdom.
Manufacturer authorisation holder responsible for batch release
LEO Pharma A/S, Industriparken 55, DK-2750 Ballerup, Denmark.
This leaflet was last approved in
This medicinal product has been authorized under “Exceptional Circumstances”.
This means that due to the rarity of the disease, it has not been possible to obtain complete
information on this medicinal product.
The European Medicines Agency (EMEA) will review any new information which may
become available every year and this leaflet will be updated as necessary.
Detailed information is available on the European Medicines Agency (EMEA) web site:
http://www.emea.europa.eu
---------------------------------------------------------------------------------------------------------------------
The following information is intended for medical or healthcare professionals only:
Each vial of ATryn contains a lyophilised powder of 1750 IU antithrombin alfa and is
intended for single use only. Vials should be brought to room temperature prior to
reconstitution and kept no longer than 3 hours. The powder should be reconstituted with 10
ml of Sterile Water for Injection (WFI) injected along the side wall of the vial and gently
swirled (not shaken) to prevent foaming. The reconstituted product should be inspected
visually for particulate matter and discolouration prior to administration. The solution should
be clear or slightly opalescent. Do not use solutions that are cloudy or have deposits. Upon
complete dissolution, the reconstituted product may be drawn up into a sterile disposable
syringe. The reconstituted product should be administered by intravenous infusion using a
sterile disposable syringe or an infusion bag with an in-line filter e.g. a methylcellulose filter
with a 0.2 micron pore size. Normal sodium chloride solution 9 mg/ml (0.9%) may be added
to dilute to a concentration convenient for administration. The contents of infusion syringes
on diluted solution prepared in infusion bags should be administered within 8 hours of
preparation. Compatibility with PVC infusion lines with in-line filters has been established.
24
Any unused product or waste material should be disposed of in accordance with local
requirements.
The therapeutic goal of treatment with ATryn is to increase to, and maintain antithrombin
activity between 80 – 120% (0.8 – 1.2 IU/ml) for the duration of treatment.
Initial treatment starts with a loading dose of ATryn targeting an antithrombin activity level
of 100%. This initial loading dose is based on body weight and on the pretreatment
antithrombin activity level.
The required loading dose is determined using the following formula:
Loading Dose (IU) = [(100 – patient’s pre-treatment AT activity level in %) /2.28] x
Body Weight in kg
The usual loading dose in surgical patients (baseline AT activity 50%, bodyweight 75 kg)
with congenital antithrombin deficiency in clinical risk situations is 20-25 IU/kg bodyweight.
The loading dose should be given as a 15 minute infusion immediately followed by initiation
of the maintenance infusion.
The required maintenance dose for surgical patients is given as a continuous infusion and is
determined using the following formula:
Maintenance Dose (IU/hour) = [(100 – patient’s pre-treatment AT activity level in %)
/10.22] x Body Weight in kg
The usual maintenance dose in surgical patients with congenital antithrombin deficiency in
clinical risk situations is 4-5 IU/kg/h. During consumptive states (e.g. major surgery,
concomitant use of heparin) the actual dose may be higher. See therapeutic monitoring and
dose adjustment recommendations below.
Therapeutic Monitoring and Dose Adjustment
The dosage should be adjusted on the basis of laboratory measurements of antithrombin
activity. Response to ATryn may vary in individual patients, achieving different levels of in
vivo recovery and different half-lives. Frequent antithrombin activity assessments and dosing
adjustments may be necessary when starting treatment and just after surgery.
After the start of the maintenance dose infusion, blood for AT activity levels should be drawn
at 45 minutes after the start of the loading dose infusion. In case the AT activity level is
between 80% and 120% (0.8- 1.2 IU/ml), no dose adjustment is needed. In case the AT
activity level is less than 80%, increase the maintenance infusion rate by 50%. In case the AT
activity level is greater than 120% decrease the infusion rate by 30%. Check AT activity level
30 minutes after any change in infusion rate, or four hours after a value within the target
range. Subsequently, antithrombin activity should be checked 1-2 times a day and dose
adjustments made accordingly. The antithrombin activity level should be maintained above
80% for the duration of the treatment, unless clinical particulars would indicate a different
effective level.
It is possible that the surgical procedure will influence AT activity levels. Therefore, an
additional check of the AT activity level should be done after the surgery. In case the activity
level is below 80% a 15 minutes bolus infusion of AT can be given to quickly restore the AT
activity level. The dose can be calculated utilizing the post-surgical AT activity in the
loading dose formula above.
25
There is no experience in children.
26
Source: European Medicines Agency
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