- 1. NAME OF THE MEDICINAL PRODUCT
- 2. QUALITATIVE AND QUANTITATIVE COMPOSITION
- 3. PHARMACEUTICAL FORM
- 4. CLINICAL
- 4.1 Therapeutic indications
- 4.2 Posology and method of administration
- 4.3 Contraindications
- 4.4 Special warnings and precautions for use
- 4.5 Interaction with other medicinal products and other forms of interaction
- 4.6 Fertility, pregnancy and lactation
- 4.7 Effects on ability to drive and use machines
- 4.8 Undesirable effects
- 4.9 Overdose
- 5. PHARMACOLOGICAL PROPERTIES
- 6. PHARMACEUTICAL PARTICULARS
- 7. MARKETING AUTHORISATION HOLDER
- 8. MARKETING AUTHORISATION NUMBER(S)
- 9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
- 10. DATE OF REVISION OF THE TEXT
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.
Powder for solution for infusion
The powder is white to
4. CLINICAL PARTICULARS
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.
4.2Posology and method of administration
Treatment should be initiated under the supervision of a physician experienced in the treatment of patients with congenital antithrombin deficiency.
Due to differences in pharmacokinetics of antithrombin alfa and
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
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
The usual loading dose in surgical patients (baseline AT activity 50%, bodyweight 75 kg) with congenital antithrombin deficiency in clinical risk situations is
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
The usual maintenance dose in surgical patients with congenital antithrombin deficiency in clinical risk situations is
Treatment should be continued until the risk for venous thromboembolisms is reduced and/or when effective
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
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
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
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.
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
Hypersensitivity to goat proteins or goat milk components.
4.4Special warnings and precautions for use
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.
Due to differences in pharmacokinetic characteristics of ATryn in pregnant versus
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
-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
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.
4.5Interaction with other medicinal products and other forms of interaction
No interaction studies have been performed.
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
4.6Fertility, pregnancy and lactation
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
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
No information is available on the possible effects of antithrombin alfa on male and female fertility.
4.7Effects on ability to drive and use machines
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).
Nervous system disorders
General disorders and administration site
Venipuncture site haemorrhage
Infusion site erythema
Infusion site pain
Infusion site rash
Venipuncture site bruise
Injury and poisoning and procedural complications
Post procedural haemorrhage
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.
No case of overdose has been reported.
Pharmacotherapeutic Group: Antithrombotic agents: heparin group; ATC code: B01AB02. Mechanism of action
Antithrombin, a 58 kD, 432
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
Normal antithrombin activity in adults is 80 - 120%
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.
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)
•Mean residence time (MRT): 8.57 ± 1.24 h
•Clearance: 0.665 ± 0.0493 l/h (Mean ± SE)
5.3Preclinical safety data
6.1List of excipients
In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.
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.
6.4Special precautions for storage
Store in a refrigerator (2°C – 8°C).
For storage conditions after reconstitution of the medicinal product, see section 6.3.
6.5Nature and contents of container
Powder in glass vial (type I) with a stopper (siliconized bromobutyl rubber) and capped with a seal (aluminum) and
Pack sizes of 1, 10 or 25 vials.
Not all pack sizes may be marketed.
6.6Special precautions for disposal and other handling
This medicine is intended for single use only.
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 clear or 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.
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
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
7.MARKETING AUTHORISATION HOLDER
GTC Biotherapeutics UK Limited
10 Norwich Street
London EC4A 1 BD
8.MARKETING AUTHORISATION NUMBER(S)
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