Prospecto: information for the user

Kybernin P 500 UI powder and solvent for injectable solution and for infusion

Human Antithrombin III

Read this prospectus carefully before starting to use this medication, as it contains important information for you.

• Keep this prospectus, as you may need to read it again.
• If you have any doubts, consult your doctor or pharmacist.
• This medication has been prescribedonlyto you, and should not be given to other people even if they have the same symptoms as you, as it may harm them.
• If you experience adverse effects, consult your doctor or pharmacist,eveniftheyarenotlistedinthisprospectus. See section 4

1. What isKybernin Pand what it is used for

2. What you need to knowbeforestarting touseKybernin P

3. How to useKybernin P

4. Possible adverse effects

5. Storage ofKybernin P

6. Contents of the package and additional information

Kybernin Pis a powder and solvent for injectable solution and for infusion.

This medication belongs to the group of medications called antithrombotic agents.

Kybernin Pis used if you have a congenital deficiency of antithrombin, to preventthe formation and development of blood clots in the blood vessels of your legs (deep vein thrombosis) or in other blood vessels of your body (thromboembolism) during surgery or in the postpartum periodand in association with heparin if indicated.

Kybernin P also is used if you have acquired deficiency of antithrombin.

No use Kybernin P:

If you are allergic to the active ingredient or any of the other components of this medication (listed in section 6).

Warnings and precautions

As with any protein product for intravenous administration, allergic hypersensitivity reactions may occur. Close monitoring and careful observation of patients are required to detect any symptoms during the infusion period. Inform patients about the initial signs of hypersensitivity reactions, which include skin rashes that may progress to generalized urticaria, chest tightness, difficulty breathing, hypotension, and anaphylaxis. If these symptoms occur after administration, contact your doctor.

In case of shock, follow current recommendations for its treatment.

Viral safety

When administering human blood-derived or plasma-derived medications,certain measures must be taken to prevent infections from being transmitted to patients. These measures include:

• A careful selection of donors, excluding those at risk of being carriers of infectious diseases,
• Analysis of specific infection markers in individual donations and plasma mixtures,
• Inclusion of stages in the manufacturing process to eliminate/inactivate viruses.

Despite this, when administering human blood-derived or plasma-derived medications, the possibility of transmission of infectious agents cannot be entirely ruled out. This also applies to emerging or unknown viruses or other types of infections.

The measures taken are considered effective for enveloped viruses such as human immunodeficiency virus (HIV), hepatitis B virus (HBV), hepatitis C virus (HCV), and for non-enveloped viruses such as hepatitis A virus (HAV) and parvovirus B19.

Your doctor may recommend that you consider vaccination against hepatitis A and B if you regularly receive products containing human antithrombin.

It is highly recommended that each time Kybernin P is administered to a patient, the name of the medication and batch number administered be recorded to maintain a relationship between the patient and the product batch.

Monitoring of clinical and biological parameters in case of concomitant administration of antithrombin and heparin:

• To adjust the heparin dose and avoid excessive hypocoagulability, regular controls of anticoagulation range (APPT, and when appropriate, anti-FXa activity) should be performed at short intervals, especially in the first minutes/hours after starting antithrombin administration.
• Daily determination of antithrombin levels to adjust the individual dose, due to the risk of antithrombin level decrease as a consequence of prolonged treatment with unfractionated heparin.

Use of Kybernin P with other medications

Heparin: replacement of antithrombin during heparin administration at therapeutic doses increases the risk of bleeding. The antithrombin effect is significantly potentiated by heparin. The antithrombin half-life may decrease significantly due to concomitant treatment with heparin, due to accelerated antithrombin mobilization. Therefore, concomitant administration of heparin and antithrombin to a patient at high risk of bleeding should be clinically and biologically monitored.

Inform your doctor or pharmacist if you are using, have used recently, or may need to use any other medication.

Pregnancy, lactation, and fertility

The experience regarding the safety of human antithrombin products for use in human pregnancy is limited.

The safety of use of Kybernin P in human pregnancy has not been established in controlled clinical trials. Animal experimentation studies are insufficient to evaluate safety in relation to reproduction, embryonic or fetal development, gestation course, and peri- and postnatal development.

There are no negative experiences related to treatment during pregnancy and lactation.

Therefore, Kybernin P should be administered to pregnant or lactating women with antithrombin deficiency only if clearly indicated, taking into account that pregnancy confers an increased risk of thromboembolic episodes in these patients.

If you are pregnant or breastfeeding, think you may be pregnant, or intend to become pregnant, consult your doctor or pharmacist before using this medication. Your doctor will weigh the possible risk to the fetus and inform you if treatment with this medication is appropriate. Your doctor will only recommend this treatment if it is clearly indicated.

Driving and operating machinery

There is no indication that Kybernin P can affect the ability to drive vehicles or operate machinery.

KyberninP 500 UI contains sodium

Patients with low-sodium diets should note thatKyberninP 500 UIcontains up to 44.76 mg (1.947 mmol) of sodium per 500 UI.

Kybernin P is a hospital-use medication, so it will be administered in a hospital by the corresponding healthcare personnel.

Kybernin P is administered by preparing a previous solution, which is injected or infused slowly via intravenous route (maximum 4 ml/min).

Follow exactly the administration instructions of this medication indicated by your doctor or pharmacist.In case of doubt, consult your doctor or pharmacist again.

Your doctor will indicate how often and at what intervals Kybernin P should be administered.

Your doctor will indicate the duration of your treatment with Kybernin P.

If you use more Kybernin P than you should:

No symptoms of antithrombin overdose have been reported.

In case of overdose or accidental administration, consult the Toxicological Information Service. Phone 91 562 04 20.

If you forgot to use Kybernin P:

- Consult your doctor or pharmacist immediately.

- Do not administer a double dose to compensate for the missed doses.

Like all medications, this medication may produce adverse effects, although not all people will experience them.

The following adverse reactions are based on post-marketing experience. In cases where data is available, the following standard frequency categories have been used:

Very frequent>1/10

Frequent>1/100 to <1

Infrequent≥ 1/1,000 to <1

Rare≥ 1/10,000 to <1

Very rare<1>includingindividualcasesreported)

For information on viral safety, see “Warnings and Precautions” in section 2 of this prospectus.

Reporting Adverse Effects

If you experience any type of adverse effect, consult your doctor or pharmacist, even if it is an adverse effect that does not appear in this prospectus.You can also report them directly through theSpanish System for Pharmacovigilance of Medicines for Human Use: https://www.notificaram.es.By reporting adverse effects, you can contribute to providing more information on the safety of this medication.

Keep this medication out of the sight and reach of children.

Do not store at a temperature above 25 °C. Do not freeze.

Do not use this medication after the expiration date that appears on the packaging after EXP. The expiration date is the last day of the month indicated.

Do not use solutions that are turbid or present residues (deposits/particles).

After reconstitution, physical-chemical stability has been demonstrated for a time of 8 hours at room temperature (max. 25 °C). From a microbiological point of view and since Kybernin P does not contain preservatives, the reconstituted solution must be used immediately. If this is not possible, do not store for more than 8 hours at room temperature (maximum 25 °C).

The disposal of unused medication or waste material will be carried out in accordance with local regulations.

Medications should not be thrown away through drains or in the trash. Ask your pharmacist how to dispose of the packaging and medications that you no longer need. In this way, you will help protect the environment.

Composition of Kybernin P 500 UI

• The active principle is antithrombin III. Each vial of lyophilized contains 500 UI of antithrombin III. The reconstituted solution contains approximately 50 UI of antithrombin III/ml of antithrombin derived from human plasma when reconstituted with 10 ml of water for injectable preparations.

The potency (UI) is determined using the Chromogenic Substrate method in accordance with the European Pharmacopoeia. The specific activity of Kybernin P is approximately 5.3 UI/mg of protein.

• The other components are: glycine, sodium chloride, sodium citrate, hydrochloric acid or sodium hydroxide (to adjust the pH) and water for injectable preparations.

See section 2 for important information on some of the excipients.

Appearance of the product and contents of the package

Lyophilized powder and solvent for injectable solution and for infusion.

The commercial packaging contains a type II glass injection vial (according to Farm. Eur.), colorless and sealed with a rubber stopper, plastic disk and aluminum capsule containing the lyophilized, a vial with 10 ml of water for injectable preparations (solvent for the preparation of the solution) and a transfer device.

Presentations:

Individual packaging of Kybernin P 500 UI:

1 vial of lyophilized

1 vial with 10 ml of water for injectable preparations

1 transfer device

Clinical packaging of Kybernin P 500 UI:

10 vials of lyophilized

10 vials with 10 ml of water for injectable preparations

10 transfer devices

Only some package sizes may be marketed.

Marketing authorization holder and responsible manufacturer

Marketing authorization holder

CSL Behring, S.A.

c/ Tarragona 157, 18th floor

08014 Barcelona - Spain

Responsible manufacturer

CSL Behring GmbH

Emil-von-Behring-Str. 76

35041 Marburg - Germany

Last review date of this leaflet:November 2020

The detailed and updated information on this medicine is available on the website of the Spanish Agency for Medicines and Medical Devices (AEMPS)http://www.aemps.gob.es

This information is intended solely for healthcare professionals:

Dosage

In congenital deficiency, the dose must be individualized for each patient, taking into account the family history of thromboembolic episodes, the patient's clinical risk factors and laboratory tests.

The dosage and duration of therapy in acquired deficiency depend on the level of plasma antithrombin, the presence of increased mobilization signs, the underlying disorder and the severity of the clinical condition of the patient. The dose and administration frequency must be based on clinical efficacy and laboratory tests in each case in particular.

The number of antithrombin units administered is expressed in International Units (UI), in relation to the World Health Organization (WHO) standard for antithrombin in force at the time. Plasma antithrombin activity is expressed as a percentage (in relation to normal human plasma) or in International Units (in relation to an international standard for antithrombin in plasma).

One international unit (UI) of antithrombin activity is equivalent to the amount of antithrombin in 1 ml of normal human plasma. The calculation of the required dose of antithrombin is based on the empirical finding that 1 International Unit (UI) of antithrombin per kg of body weight increases plasma antithrombin activity by approximately 1.5%.

The initial dose is determined by the following formula:

Required units = body weight [kg] x (100 - current antithrombin activity [%]) x 2/3.

The antithrombin activity to be achieved initially depends on the clinical condition. When it is established that antithrombin substitution is indicated, the dose should be sufficient to achieve the desired antithrombin activity and to maintain an effective level. The dose must be determined and monitored in accordance with laboratory tests of antithrombin activity, which will be performed at least twice a day until the patient stabilizes, and then once a day, preferably immediately before the next infusion. The adjustment of the dose must take into account both the signs of increased antithrombin production according to laboratory tests and the clinical evolution. Antithrombin activity must be maintained above 80% during treatment, unless the clinical condition indicates a different level of efficacy.

The usual initial dose in congenital deficiency is 30-50 UI/kg.

Therefore, the dose and administration frequency, as well as the duration of treatment, must be adjusted to the patient's biological data and clinical situation.

Pediatric population:

Kybernin P is not recommended for use in children under 6 years due to the scarcity of data.

Based on clinical experience, it cannot be recommended to use antithrombin in the treatment of RDS (Respiratory Distress Syndrome) in premature infants.

Instructions for correct administration of the preparation

General instructions

The lyophilized powder must be completely reconstituted, under aseptic conditions, with the accompanying solvent.A transparent or slightly opalescent solution is obtained.

The appropriate diluent is a 5% human albumin solution. To prepare dilutions of up to 1:5, the following may also be used: Ringer lactate solution, physiological saline solution, 5% glucose solution or polygelin.

The use of hydroxyethyl starch is not recommended as a solvent (for infusion), as a loss of antithrombin activity has been observed.

This medicine must not be mixed with other medications in the syringe/infusion equipment. Dopamine, dobutamine and furosemide must not be administered through the same venous access.

The product must be administered intravenously. Maximum infusion rate: 4 ml/min.

Reconstitution

To handle the Transofix®double-pointed device correctly, follow the steps below: