ATryn

1 

ANNEX I 

SUMMARY OF PRODUCT CHARACTERISTICS 

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This medicinal product is subject to additional monitoring. This will allow quick identification of new 
safety information. Healthcare professionals are asked to report any suspected adverse reactions. See section 
4.8 for how to report adverse reactions. 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
ATryn 1750 IU powder for solution for infusion. 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
One vial contains nominally 1750 IU* antithrombin alfa**. 

After reconstitution, 1 ml of solution contains 175 IU antithrombin alfa. 

 
The specific activity of ATryn is approximately 7 IU/mg protein.  
 
* potency (IU) determined using European Pharmacopoeial chromogenic assay. 
 
** recombinant human antithrombin produced in the milk of transgenic goats by recombinant DNA 
technology (rDNA).  
 
Excipient with known effect 
This medicine contains 38 mg (1.65 mmol) sodium per 10 ml vial. 
 
For the full list of excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Powder for solution for infusion  
The powder is white to off-white. 
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
ATryn is indicated for the prophylaxis of venous thromboembolism in surgery of adult patients with 
congenital antithrombin deficiency. It is normally given in association with heparin or low molecular weight 
heparin. 
 
4.2 Posology and method of administration 
 
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 
should follow the specific dose recommendations described below. In the treatment of congenital 
antithrombin deficiency, the dose 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.  
 

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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. 
 
The therapeutic goal of treatment with antithrombin alfa is to increase to, and maintain antithrombin activity 
between 80 – 120% of normal (0.8 – 1.2 IU/ml) for the duration of treatment. 
 
Initial treatment starts with a loading dose 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.  
Treatment should be continued until the risk for venous thromboembolisms is reduced and/or when effective 
follow-on anticoagulation has been established. 
 
Therapeutic Monitoring and Dose Adjustment 
 
The dose should be adjusted on the basis of laboratory measurements of antithrombin activity. Response 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. 
 
Paediatric population 

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The safety and efficacy of ATryn in children and adolescents (<18 years) have not been established.  No data 
are available.  Paediatric antithrombin levels may be different from adult levels, particularly in neonates.   
 
Method of administration 
For intravenous use. 
The loading dose should be given as a 15 minute infusion immediately followed by initiation of the 
maintenance infusion.  
 
For instructions on reconstitution of the medicinal product before administration, see section 6.6. 
 
4.3 Contraindications 
 
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. 
 
Hypersensitivity to goat proteins or goat milk components. 
 
4.4 Special warnings and precautions for use 
 
Hypersensitivity reactions 
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, generalized 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 this medicine should be monitored for possible clinical immunological reactions. 
Antibody status should be monitored and reported.  
 
The experience from repeated treatment with this medicine is very limited. Close surveillance with regard to 
immunological reactions is especially important in such situations.  
  
Pregnancy 
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. 
 
Use of concomitant anticoagulation 
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 properly adjust the dose 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. 

- Antithrombin levels should be measured 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. 

 
Sodium content 
This medicinal product contains 1.65 mmol (or 37.9 mg) sodium per vial. To be taken into consideration by 
patients on a controlled sodium diet. 
 
4.5 Interaction with other medicinal products and other forms of interaction 
 
No interaction studies have been performed. 
 

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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. 
 
4.6 Fertility, pregnancy and lactation 
 
Pregnancy 
Limited clinical data are available on the use of antithrombin alfa in pregnant women. Available data do not 
suggest harmful effects to the mother or infant. Animal studies performed in rats did not indicate harmful 
effects on parturition, embryonal/foetal and post-natal development. However due to the difference in 
pharmacokinetic characteristics of this medicine in pregnant versus non-pregnant patients no 
recommendation for dosing in pregnancy can be given at this time (see section 4.4). Antithrombin alfa 
should therefore not be used in pregnant women.  
 
Breast-feeding 
It is unknown whether antithrombin alfa or its metabolites are excreted in human milk. A risk to the suckling 
child cannot be excluded. A decision must be made whether to discontinue breast-feeding or to 
discontinue/abstain from ATryn therapy taking into account the benefit of breastfeeding for the child and the 
benefit of therapy for the woman. 
 
Fertility 
No information is available on the possible effects of antithrombin alfa on male and female fertility. 
 
4.7 Effects on ability to drive and use machines 
 
Not relevant. 
 
4.8 Undesirable effects 
 
Summary of the safety profile 
 
The most commonly reported adverse reactions observed in clinical trials are dizziness, headache, 
haemorrhage, nausea, venipuncture site haemorrhage, post procedural haemorrhage and wound secretion.  
The most serious reported adverse reactions observed in clinical trials are haemorrhage and post procedural 
haemorrhage. 
 
Tabulated list of adverse reactions 
 
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. 
 
Adverse reactions are presented below by system organ class and absolute frequency. Frequencies are 
defined as: common (≥ 1/100 to < 1/10) and uncommon (≥1/1,000 to <1/100). 
 
MedDRA SOC Frequency 

category 
Adverse reactions 

Nervous system disorders Common Dizziness 
headache 

Vascular disorders Common Haemorrhage 

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Gastrointestinal disorders Common Nausea 
General disorders and administration site 
conditions 

Common Venipuncture site haemorrhage 

 Uncommon Feeling hot 
  Infusion site erythema 
  Infusion site pain 
  Infusion site rash 
  Venipuncture site bruise 
Injury and poisoning and procedural complications Common Post procedural haemorrhage 
  Wound secretion 
 
No antibodies to antithrombin alfa have been detected up to 90 days following treatment with ATryn.  
 
Reporting of suspected adverse reactions 
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows 
continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked 
to report any suspected adverse reactions via the national reporting system listed in Appendix V. 
 
4.9 Overdose 
 
No case of overdose has been reported. 
 
5. PHARMACOLOGICAL PROPERTIES 
 
5.1  Pharmacodynamic properties 
 
Pharmacotherapeutic Group: Antithrombotic agents: heparin group; ATC code: B01AB02. 
Mechanism of action 
 
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).  
 
Clinical efficacy and safety 
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 authorised 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 will review any new information which may become available every year and 
this SmPC will be updated as necessary. 
 

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http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


7 

5.2 Pharmacokinetic properties 
 
After intravenous administration of ATryn (intravenous 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) 
 
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. PHARMACEUTICAL PARTICULARS 
 
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 Shelf life 
 
Unopened vials: 4 years. 
 
After reconstitution, from a microbiological pointy of view, this medicinal product should be used 
immediately.  However, chemical and physical stability has been demonstrated for 3 hours after 
reconstitution and 8 hours after dilution at a temperature not above 25°C. 
 
6.4 Special precautions for storage 
 
Store in a refrigerator (2°C – 8°C). 
For storage conditions after reconstitution of the medicinal product, see section 6.3. 
 
6.5 Nature and contents of container  
  
Powder in glass vial (type I) with a stopper (siliconized bromobutyl rubber) and capped with a seal 
(aluminum) and flip-off cap (plastic).  
 
Pack sizes of 1, 10 or 25 vials. 
 
Not all pack sizes may be marketed. 
 
6.6 Special precautions for disposal and other handling 
 
This medicine is intended for single use only.  
 

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Reconstitution/dilution 
Vials should be brought at temperature not above 25°C prior to reconstitution.  The powder should be 
reconstituted with 10 ml of water for injections (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/or discolouration prior to 
administration. The solution should be slightly yellow, clear to slightly opalescent.  Do not use solutions that 
are cloudy or have deposits.  
 
The reconstituted solution should be used immediately and no longer than 3 hours after reconstitution. 
 
Normal sodium chloride solution 9 mg/ml (0.9%) may be added to dilute to a concentration convenient for 
administration.   
 
Administration 
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. The contents of the syringes should be administered 
immediately and no longer than 3 hours after reconstitution.  If diluted, the solution prepared in infusion bags 
should be administered immediately and no longer than 8 hours after dilution. Compatibility with PVC 
infusion lines with in-line filters has been established.  
 
Disposal 
Any unused medicinal product or waste material should be disposed of in accordance with local 
requirements. 
 
7. MARKETING AUTHORISATION HOLDER 
 
Laboratoire Français du Fractionnement et des Biotechnologies  
3 Avenue des Tropiques 
ZA de Courtaboeuf 
91940 Les Ulis 
France 
 
8. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/06/355/001-003 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation: 28 July 2006 
Date of latest renewal: 15 July 2016 
 
10. DATE OF REVISION OF THE TEXT 
 
Detailed information on this product is available on the website of the European Medicines Agency 
http://www.ema.europa.eu 
 
 
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http://www.ema.europa.eu/


9 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX II 
 

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

 
B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND 

USE 
 

C. OTHER CONDITIONS AND REQUIREMENTS OF THE 
MARKETING AUTHORISATION 

 
D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE 

SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT 
 

E. SPECIFIC OBLIGATION TO COMPLETE 
POST-AUTHORISATION MEASURES FOR THE MARKETING 
AUTHORISATION UNDER EXCEPTIONAL CIRCUMSTANCES 

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

 
Name and address of the manufacturer(s) of the biological active substance(s) 
 
Therapure Biopharma Inc. 
2585 Meadowpine Blvd. 
Mississauga, Ontario, Canada L5N 8H9 
 
Name and address of the manufacturer(s) responsible for batch release 
 
LFB-BIOTECHNOLOGIES 
3 Avenue des Tropiques 
ZA de Courtaboeuf 
91940 Les Ulis 
France 
 
MedImmune Pharma BV 
Lagelandseweg 78 
6545 CG Nijmegen, The Netherlands 
 
The printed package leaflet of the medicinal product must state the name and address of the manufacturer 
responsible for the release of the concerned batch. 
 
B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE  
 
Medicinal product subject to restricted medical prescription (see Annex I: Summary of Product 
Characteristics, section 4.2). 
 
C.  OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION 
 
• Periodic Safety Update Reports 
 
The requirements for submission of periodic safety update reports for this medicinal product are set 
out in the list of Union reference dates (EURD list) provided for under Article 107c(7) of Directive 
2001/83/EC and any subsequent updates published on the European medicines web-portal. 
 
D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE 

OF THE MEDICINAL PRODUCT   
 
• Risk Management Plan (RMP) 

 
The MAH shall perform the required pharmacovigilance activities and interventions detailed in the 
agreed RMP presented in Module 1.8.2 of the Marketing Authorisation and any agreed subsequent 
updates of the RMP. 
 
An updated RMP should be submitted: 

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

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

 
• Additional risk minimisation measures 
 

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Prior to launch of Atryn in each Member State the MAH must agree about the content and format of the 
educational programme, including communication media, distribution modalities, and any other aspects of 
the programme, with the National Competent Authority. 
 
The educational material for healthcare professionals is aimed at increasing the awareness about the potential 
efficacy issues resulting from off-label use of Atryn. 
 
The MAH shall ensure that in each Member State where Atryn is marketed, all healthcare professionals who 
are expected to prescribe and use Atryn have access to/are provided with the following educational package: 
 

• Physician educational material (guide) 
• The Summary of Product Characteristics 

 
The Physician educational material shall contain the following key elements: 
 

• Information about the currently registered indications and population, including that the product is 
not indicated in the paediatric population. 

• Information regarding the resulting efficacy issues associated with off-label use of ATryn, especially 
in the paediatric population. 

 
E. SPECIFIC OBLIGATION TO COMPLETE POST-AUTHORISATION MEASURES FOR 

THE MARKETING AUTHORISATION UNDER EXCEPTIONAL CIRCUMSTANCES 
 
This being an approval under exceptional circumstances and pursuant to Article 14(8) of Regulation (EC) No 
726/2004, the MAH shall conduct, within the stated timeframe, the following measures: 
 

Description Due date 
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 completed 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. 
 

31/03/2020 

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 

31/03/2018 

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Description Due date 
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. 

  

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13 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX III 
 

LABELLING AND PACKAGE LEAFLET 
  

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14 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

A. LABELLING 
  

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PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
OUTER CARTON (1, 10 OR 25 VIALS) 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
ATryn 1750 IU powder for solution for infusion 
antithrombin alfa (rDNA) 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
One vial contains nominally 1750 IU antithrombin alfa*. After reconstitution, 1 ml of solution contains 
175 IU antithrombin alfa. 

* recombinant human antithrombin. 
 
3. LIST OF EXCIPIENTS 
 
Excipients: 
Glycine 
Sodium chloride 
Sodium citrate 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Powder for solution for infusion (1750 IU) 
1 vial  
10 vials 
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 SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
 
8. EXPIRY DATE 
 
EXP 
 
9. SPECIAL STORAGE CONDITIONS 
 
Store in a refrigerator. 

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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 medicinal product should be disposed of in accordance with local requirements. 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Laboratoire Français du Fractionnement et des Biotechnologies  
3 Avenue des Tropiques 
ZA de Courtaboeuf 
91940 Les Ulis 
France  
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/06/355/001 
EU/1/06/355/002 
EU/1/06/355/003 
 
 
13. BATCH NUMBER 
 
Batch 
 
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. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC:  
SN:  
NN:  
  

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MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 
 
Vial label 
 
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 
 
ATryn 1750 IU powder for solution for infusion 
antithrombin alfa (rDNA) 
For intravenous use. 
 
2. METHOD OF ADMINISTRATION 
 
 
 
3. EXPIRY DATE 
 
EXP 
 
4. BATCH NUMBER 
 
Batch 
 
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 
 
1750 IU of antithrombin alfa 
 
6. OTHER 
 
Store in a refrigerator. 
 
Laboratoire Français du Fractionnement et des Biotechnologies, Les Ulis, France 
  

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B. PACKAGE LEAFLET 

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Package leaflet: Information for the user 
 

ATryn 1750 IU powder for solution for infusion 
antithrombin alfa (rDNA) 

 
This medicine is subject to additional monitoring. This will allow quick identification of new safety 

information. You can help by reporting any side effects you may get. See the end of section 4 for how to 
report side effects. 
 
Read all of this leaflet carefully before you start using this medicine because it contains important 

information for you. 
- Keep this leaflet. You may need to read it again.  
- If you have any further questions, ask your doctor. 
- If you get any side effects, talk to your doctor. This includes any possible side effects not listed in this 

leaflet. See section 4. 
 
 
What is in this leaflet 
 
1. What ATryn is and what it is used for  
2. What you need to know before you use ATryn  
3. How to use ATryn  
4. Possible side effects  
5. How to store ATryn  
6. Contents of the pack and other information 
 
 
1. What ATryn is and what it is used for 
 
ATryn contains antithrombin alfa which is similar to the naturally occurring human antithrombin. In the 
body, antithrombin blocks thrombin, a substance that plays a central role in the process of blood clotting. 
 
If you have an inborn deficiency of antithrombin, your blood level of antithrombin is lower than normal. 
This may result in a higher tendency to form clots in your blood vessels. This may be in the vessels of your 
legs (deep vein thrombosis) or in other vessels of your body (thromboembolism). Around major surgical 
procedures this tendency to clot is even more increased. Therefore, it is important that your antithrombin 
blood level be maintained at sufficient levels in these situations.  
 
This medicine is used in patients who have ‘congenital antithrombin deficiency’ (inherited low levels of the 
protein antithrombin). It is used when the patients are having surgery, to prevent problems due to the 
formation of blood clots in the vessels. It is normally given in association with heparin or low molecular 
weight heparin (another medicine that helps to prevent blood clots). 
 
 
2. What you need to know before you use ATryn  
 
Do not use ATryn: 
- if you are allergic to antithrombin alfa or any of the other ingredients of this medicine (listed in section 

6).  
- if you are allergic to goat products as antithrombin alfa is produced in the milk of transgenic goats by 

recombinant DNA technology (rDNA). 
 
Warnings and precautions  
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 

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allergic reaction. To test whether you developed an allergic reaction, blood may be collected and tested 
before and some time after you have been treated with ATryn. 
 
Children and adolescents 
 
No information on the use of ATryn in patients less than 18 years is available. This medicine should 
therefore not be used if you are less than18 years. 
 
Other medicines and ATryn 
Tell your doctor if you are taking, have recently taken or might take any other medicines. 
When ATryn is used together with heparin (an anti-clotting medicine), or some other anti-clotting medicines, 
this may increase the risk of bleeding. Therefore your doctor will carefully monitor the use of this medicine 
when administered together with these anti-clotting medicines. 
 
Pregnancy and breast-feeding 
ATryn is not indicated for use in pregnant women.  It is unknown whether it is present in breast milk. 
Therefore it is not recommended to breastfeed whilst being treated with this medicine. 
 
ATryn contains sodium 
This medicinal product contains 1.65 mmol (or 37.9 mg) sodium per vial. To be taken into consideration by 
patients on a controlled sodium diet. 
 
 
3. How to use ATryn 
 
Your treatment will be initiated under the supervision of a physician experienced in the care of patients with 
an inborn deficiency of antithrombin.  
Your health care provider will prepare a solution of antithrombin alfa to be administered to you through your 
vein. To protect you from developing blood clots the medicine will continue to be administered to you until 
your doctor determines it safe to stop treatment. 
 
If you use more ATryn than you should 
 
The doctor will treat you, as appropriate, if you have any particular side 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 medicine, ask your doctor. 
 
 
4. Possible side effects 
 
Like all medicines, this medicine can cause side effects, although not everybody gets them. 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. 
 
In studies with ATryn the following side effects were reported: 
Common side effects (may affect up to 1 in 10 people) are:  

• itching at the site of infusion  
• dizziness 
• headache 
• bleeding (at site of infusion or after surgery) 
• nausea 

Uncommon side effects (may affect up to 1 in 100 people) are:  

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• feeling hot 
• infusion site reactions such as pain, bruising and redness 

 
Reporting of side effects 
If you get any side effects, talk to your doctor. This includes any possible side effects not listed in this leaflet. 
You can also report side effects directly via the national reporting system listed in Appendix V. By reporting 
side effects you can help provide more information on the safety of this medicine. 
 
 
5. How to store ATryn 
 
Keep out of the sight and reach of children. 
 
Unopened vials: 
Store in a refrigerator (2°C – 8°C). 
Do not use  this medicine after the expiry date stated which is stated on the carton and vial label after EXP. 
The expiry date refers to the last date of that month. 
 
Reconstituted/diluted solutions: 
After reconstitution, from a microbiological pointy of view, this medicinal product should be used 
immediately. However, chemical and physical stability has been demonstrated for 3 hours after 
reconstitution and 8 hours after dilution at a temperature not above 25°C. 
 
 
6. Contents of the pack and other information 
 
What ATryn contains  
 
The active substance is antithrombin alfa*: 1750 IU. After reconstitution, 1 ml of solution contains 175 IU 
antithrombin alfa. 
 
The specific activity of ATryn is approximately 7 IU/mg protein.  
 
* recombinant human antithrombin produced in the milk of transgenic goats by recombinant DNA 
technology (rDNA). 
 
The other ingredients are: glycine, sodium chloride, sodium citrate  
 
What ATryn looks like and contents of the pack 
 
ATryn is supplied as a powder for solution for infusion (1750 IU powder in vial).   
 
The powder is white to off-white. 
 
Pack sizes of 1, 10 or 25 vials.   
 
Marketing Authorisation Holder and Manufacturer 
 
Marketing Authorisation Holder 
Laboratoire Français du Fractionnement et des Biotechnologies, 3 Avenue des Tropiques, ZA de 
Courtaboeuf, 91940 Les Ulis, France 
  
Manufacturer  
LFB-BIOTECHNOLOGIES, 3 Avenue des Tropiques, ZA de Courtaboeuf, 91940 Les Ulis, France 
 
MedImmune Pharma BV Lagelandseweg 78 6545 CG Nijmegen, The Netherlands. 

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This leaflet was last revised in 
 
This medicine has been authorised under ‘exceptional circumstances’. This means that because of the rarity 
of this disease it has been impossible to get complete information on this medicine. 
The European Medicines Agency will review any new information on this medicine every year and this 
leaflet will be updated as necessary. 
 
Detailed information on this medicine is available on the European Medicines Agency web site: 
http://www.ema.europa.eu.   
 
<-----------------------------------------------------------------------------------------------------------------------------> 
 
The following information is intended for healthcare professionals only: 
 
This medicine is intended for single use only.  
 
Reconstitution/dilution 
Vials should be brought at temperature not above 25°C prior to reconstitution.  The powder should be 
reconstituted with 10 ml of water for injections (WFI) injected along the side wall of the vial and gently 
swirled (not shaken) to prevent foaming.  
 
The reconstituted solution should be inspected visually for particulate matter and/or discolouration prior to 
administration. The solution should be slightly yellow, clear to slightly opalescent.  Do not use solutions that 
are cloudy or have deposits.  
 
The vials should be used immediately and no longer than 3 hours after reconstitution. 
 
Normal sodium chloride solution 9 mg/ml (0.9%) may be added to dilute to a concentration convenient for 
administration.   
 
Administration 
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. The contents of the syringes should be administered 
immediately and no longer than 3 hours after reconstitution.  If diluted, the solution prepared in infusion bags 
should be administered immediately and no longer than 8 hours after dilution. Compatibility with PVC 
infusion lines with in-line filters has been established.   
 
Disposal 
Any unused medicinal product or waste material should be disposed of in accordance with local 
requirements. 
 
The therapeutic goal of treatment with antithrombin alfa 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 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. 
 

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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.  
Treatment should be continued until the risk for venous thromboembolisms is reduced and/or when effective 
follow-on anticoagulation has been established. 
 
Therapeutic Monitoring and Dose Adjustment 
 
The dose should be adjusted on the basis of laboratory measurements of antithrombin activity. Response 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. 
 
Paediatric population 
The safety and efficacy of ATryn in children and adolescents (<18 years) have not been established.  No data 
are available.  Paediatric antithrombin levels may be different from adult levels, particularly in neonates.   
 
Method of administration 
For intravenous use. 
The loading dose should be given as a 15 minute infusion immediately followed by initiation of the 
maintenance infusion.  
 

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