ATryn - summary of medicine characteristics

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.

Cr

• * * 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 PARTICUL4.1 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.

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4.2 Posology and method of administration

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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.

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 lU/ml) for the duration of treatment.

Initial treatment starts with a loading dose targeting an antithrombin activity level of 100%. This init 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-treatm<    T activity level in %) /10.22] x Body

Weight in kg

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 uration 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.

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 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 pharmacokine recommendations for dosing in pregnancy or in the peripartum period cannot be given.

Use of concomitant anticoagu iq 'ion

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.

  
  

hrombin levels should be measured daily, in order to adjust the individual dose. The risk of ution of antithrombin levels by prolonged treatment with a non-fractionated heparin should be into account.

ium content

his 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.

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 f ft yuiiiHiHAi y         y<.pLt y pi

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 a dve, s e 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

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           x* _

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

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4.9 Overdose

No case of overdose has been reported.

5. PHARMACOLOGICAL PROPERTIES5.1 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 proteinaseinhibitor 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.

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 PARTICULARS6.1 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 lifeUnopened 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 réfrigéra« r (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).

ack 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.

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 conv administration.

Administration

Upon complete dissolution, the reconstituted product may be drawn up into a sterile dispo

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 shoul requirements.

• 7. MARKETING AUTHORISATION HOLDE

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Laboratoire Français du Fractionnement et des Bi

• 3 Avenue des Tropiques ZA de Courtaboeuf

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