Package Insert: Information for the Patient

Prothromplex Total 500 UI

Powder and solvent for injectable solution

Human prothrombin complex

Read this package insert carefully beforestarting to usethis medication, because it contains important information for you.

• Keep this package insert, as you may need to read it again.
• If you have any questions, consult your doctor or pharmacist.
• If you experience any adverse effects, consult your doctor or pharmacist, even if they are not listed in this package insert. See section 4.

1. What is Prothromplex Total and how is it used

2. What you need to know beforestarting touseProthromplex Total

3. How to use Prothromplex Total

4. Possible adverse effects

5. Storage of Prothromplex Total

6. Contents of the package and additional information

Prothromplex Totalis prepared from human plasma (the liquid part of blood). It contains the blood coagulation factorsII, VII, IX, and X (prothrombin complex factors) and protein C.

These coagulation factors depend on vitamin K and, like vitamin K, play an important role in blood coagulation. In the event of a deficiency of any of these factors, blood does not coagulate as quickly as usual, increasing the tendency to bleed.

Prothromplex Total is used for:

-treatment of hemorrhages

-prevention of hemorrhages immediately before or after a surgical operation.

• acquired deficiency and congenital deficiency of coagulation factors

Acquired deficiency:

You may develop a deficiency of vitamin K-dependent coagulation factors (acquired deficiency) caused, for example, by treatment or overdose of medications that reduce the effect of vitamin K (known as vitamin K antagonists).

Congenital deficiency:

If you were born with a deficiency (congenital deficiency), this medication may be administered immediately before or after a surgical operation when the individual factor concentrate is not available.

No use Prothromplex Total

• if he is allergicto clotting factors or any of the other components of this medication (listed in section 6).
• if heparin has caused or suspects that it has caused a decrease in platelets, the cells responsible for blood clotting (heparin-induced thrombocytopenia).

Warnings and Precautions

Consult your doctor before using Prothromplex Total

• since there is a rare possibility that he may develop a severe sudden allergic reaction (anaphylactic reaction) to Prothromplex Total because anaphylactic reactions of this type have been reported.

You can find detailed information about the first symptoms of this type of allergic reaction in section 4 “Possible Adverse Effects”

-if he has anacquired deficiencyof vitamin K-dependent clotting factors.

This acquired deficiency may becaused by treatment with medications that neutralize blood clotting through inhibition of vitamin K. In this case, Prothromplex Total should only be used when a rapid correction of the prothrombin complex levels is necessary, such as in cases of severe bleeding or emergency surgery. In other cases, it is sufficient to reduce the dose of the vitamin K antagonist or administer vitamin K

• if he receivesmedications to inhibit blood clotting(vitamin K antagonists). He may have a tendency to form blood clots that can be increased with the administration of human prothrombin complex concentrate.

• if he has acongenital deficiencyof specific vitamin K-dependent clotting factors, a product with the specific factor should be used if available.

• if he is being treated with human prothrombin complex concentrate, especially if it has been given repeatedly, as it may cause clots (thrombosis) and pass into the bloodstream (embolism).

• if he belongs to any of the following groups of patients, due to the possibility of clot formation:

• patients with coronary heart disease or who have had a heart attack
• patients with liver disease
• pre- or postoperative patients
• neonates
• patients at risk of thromboembolic complications or disseminated intravascular coagulation (DIC)

In all these situations, the doctor will carefully evaluate the benefits of treatment with Prothromplex Total against the possible risks of these complications.

Traceability

Each time Prothromplex Total is administered, it is recommended to record the name and batch number of the product to maintain control of the batches used.

Viral Safety

When administering medications derived from human plasma or blood, certain measures should be taken to prevent the transmission of infections to patients.

These measures include:

• a careful selection of donors, to exclude those who are at risk of being carriers of infectious diseases,
• analysis of specific infection markers inindividual donations and plasma mixtures,
• inclusion of stages in the manufacturing process to eliminate/inactivate viruses.

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

These measures are considered effective for enveloped viruses such as human immunodeficiency virus (HIV), hepatitis B virus, and hepatitis C virus, and for non-enveloped viruses such as hepatitis A virus. The measures taken may have limited value against other non-enveloped viruses such as parvovirus B19. Parvovirus B19 infection can be severe for a pregnant woman (fetal infection) and for people whose immune system is depressed orin patients who have sometype of anemia (for example, sickle cell disease or hemolytic anemia).

Your doctor may recommend that you be vaccinated against hepatitis A and hepatitis B if you are regularly or repeatedly administered human prothrombin complex concentrates derived from human plasma.

It is strongly recommended that, each time Prothromplex Total is administered, the name of the medication and batch number administered be recorded in order tomaintain a record of the batches used.

Children and Adolescents

The safety and efficacy of using Prothromplex Total in patients under 18 years of age have not been established in clinical trials.

Other Medications and Prothromplex Total

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

Inform your doctor if you receive medications to inhibit blood clotting (vitamin K antagonists). You may have a tendency to form blood clots that can be increased with the administration of human prothrombin complex concentrate.

Interference with Biological Tests

When performing heparin-sensitive coagulation tests in patients receiving high doses of human prothrombin complex, the heparin contained in the administered product should be considered.

Pregnancy, Breastfeeding, and Fertility

If you are pregnant or breastfeeding, or if you think you may be pregnant, consult your doctor or pharmacist before using this medication. Prothromplex Total can be used during pregnancy and breastfeeding only in cases where it is clinically indicated.

No information is available regarding the effects of Prothromplex Total on fertility.

Driving and Operating Machines

No studies have been conducted on the ability to drive and operate machines.

Prothromplex Total contains sodium and heparin

This medication contains 68 mg of sodium per vial or 0.14 mg of sodium (main component of table salt/for cooking) per International Unit. This corresponds to 3.4% of the maximum daily sodium intake recommended for an adult.

Heparin may cause allergic reactions and a decrease in blood cell count that can affect blood clotting. Patients with a history of heparin-induced allergic reactions should avoid using medications that contain heparin.

The initiation, administration, and monitoring of treatment must be performed under the strict supervision of a doctor with experience in the treatment of coagulation disorders.

The dose and duration of treatment with Prothromplex Total will depend on various factors such as body weight, the severity of your disease, the location and intensity of bleeding or the need to prevent bleeding in surgical procedures.

Your doctor will calculate the dose according to your specific needs and will regularly monitor your coagulation and clinical condition (see section " This information is intended solely for healthcare professionals ").

Administration Form

Intravenous.

A doctor must supervise the administration of Prothromplex Total.

After reconstitution with the sterile water for injection provided, Prothromplex Total is administered slowly into a vein (intravenous). The rate of administration depends on your well-being and should not exceed 2 ml per minute (60 UI/min).

Use in Children and Adolescents

There are not enough data to recommend the administration of Prothromplex Total in patients under 18 years old.

If You Use More Prothromplex Total Than You Should

In case of overdose there is an increased risk of thromboembolic complications or consumption coagulopathy.

When high doses of human prothrombin complex concentrates have been administered, cardiac arrest, increased platelet consumption and coagulation factor consumption with elevated formation of blood clots in blood vessels (DIC, disseminated intravascular coagulation, consumption coagulopathy), deep vein thrombosis, and pulmonary embolism have been observed.

If you have any other questions about the use of this medication , ask your doctor.

Like all medicines, this medicine may cause side effects, although not everyone will experience them.

As with all treatments using plasma derivatives, there is a possibility that you may develop a sudden allergic reaction (anaphylactic reaction). In individual cases, it can develop from a severe hypersensitivity reaction to shock.

Therefore, you must pay attention to the early symptoms of an allergic reaction, such as:

• erythema (skin redness)
• skin eruption
• appearance of hives on the skin (urticaria)
• itching in any part of the body
• swelling of the lips and tongue
• difficulty breathing/dyspnea
• chest oppression
• generalized malaise
• dizziness
• fall in blood pressure

If you notice one or more of the mentioned symptoms, inform your doctor immediately, who will stop the infusion immediately. Severe symptoms require immediate emergency treatment.

When using prothrombin complex concentrates (including Prothromplex Total), patients may develop resistance (inhibitors) to one or more coagulation factors, resulting in inactivation of blood coagulation factors. The appearance of these inhibitors may manifest as an insufficient response to treatment.

During treatment with prothrombin complex concentrates, blood clots (thrombi) may form and be carried into the bloodstream (embolism). This may cause complications such as heart attack, increased platelet consumption and coagulation factor consumption with elevated clot formation in blood vessels (consumption coagulopathy), or occlusion of veins by a blood clot (venous thrombosis) and occlusion of a pulmonary vessel by a blood clot (pulmonary infarction).

The following side effects may affect up to 1 in 10 people when using Prothromplex Total:

• blood clot formation throughout the body (disseminated intravascular coagulation), resistance (inhibitors) to one or more of the prothrombin complex factors (factors II, VII, IX, X)
• severe and sudden allergic reaction (anaphylactic shock), anaphylactic reaction, hypersensitivity, stroke, headache
• heart attack (acute myocardial infarction), heart palpitations (tachycardia)

• arterial thrombosis, venous thrombosis, fall in blood pressure (hypotension), skin redness (flushing)
• occlusion of a pulmonary vessel by a blood clot (pulmonary embolism),difficulty breathing, lack of breathing (dyspnea), panting
• vomiting, sensation of vomiting (nausea)
• hives all over the body (urticaria), skin eruption (erythematous eruption), itching (pruritus)
• a certain kidney disorder with symptoms such as swelling of the eyelids, face, and lower legs with weight gain, as well as protein loss through urine (nephrotic syndrome)
• fever (pyrexia).

The following side effects have been observed with other prothrombin complex concentrates:

• swelling of the face, tongue, and lips (angioedema), skin sensation like burning, tingling, itching, or prickling (paresthesia)
• reaction at the injection site
• lethargy
• restlessness

Reporting of side effects

If you experience any type of side effect, consult your doctor, even if it is a possible side effect that does not appear in this prospectus. You can also report them directly through the Spanish System for Pharmacovigilance of Medicines for Human Use: www.notificaRAM.es.

By reporting side effects, you can contribute to providing more information on the safety of this medicine.

Store in the refrigerator (between 2°C and 8°C). Do not freeze.

Store the medication in its original packaging to protect it from light.

Keep this medicationout of the sight and reach of children.

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

During the validity period, the product can be stored at room temperature (max. 25°C) for a period of up to 6 months. The start and end dates of storage at room temperature must be noted on the medication packaging.

After storage at room temperature, Prothromplex Total must not be returned to the refrigerator (2 °C to 8 °C) and must be discarded if not used within the 6 months.

Use the solution immediately after reconstitution.

Medications should not be disposed of through drains or in the trash. Ask your pharmacist how to dispose of unused packaging and medications. This will help protect the environment.

Composition of Prothromplex Total

Dry Powder:

The active principle is human prothrombin complex, composed of human coagulation factors II, VII, IX, and X, and protein C.

A vial contains at least 333 UI of protein C co-purified with blood coagulation factors.

The other components are: sodium chloride, sodium citrate, sodium heparin (0.2-0.5 UI/UI of factor IX), and antithrombin III 12.5-25 UI per vial (0.75-1.5 UI/ml).

Vehicle:Sterile Water for Injection.

Appearance of the Product and Contents of the Container

Dry powder and vehicle for injectable solution.

Prothromplex Total is a white or slightly yellowish, lyophilized or compact dry substance.

After reconstitution, the solution has a pH ranging from 6.5 to 7.5 and an osmolality of not less than 240 mosm/kg. The solution is transparent or slightly opalescent.

The powder and vehicle are contained in single-dose glass vials (Type I and Type II glass, respectively) and sealed with butyl rubber stoppers.

Contents of the Container

• 1 vial with Prothromplex Total 500 UI in powder
• 1 vial with 17 ml of Sterile Water for Injection
• 1 Mix2Vial for reconstitution

Size of the Container1 x 500 UI

Marketing Authorization Holder and Responsible Manufacturer

Marketing Authorization Holder:

Baxalta Innovations GmbH

Industriestrasse 67

1221 Vienna

Austria

Responsible Manufacturer:

Takeda Manufacturing Austria AG

Industriestrasse, 67

A-1221 Vienna, Austria

Local Representative:

Takeda Farmacéutica España S.A.

Calle Albacete, 5, planta 9ª

Edificio Los Cubos

28027 Madrid

Spain

Tel: +34 91 790 42 22

This Medicinal Product is Authorized in the Member States of the European Economic Area and in the United Kingdom (Northern Ireland) with the Following Names:

Last Review Date of this Leaflet:March 2023

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

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This information is intended solely for healthcare professionals:

Instructions for Preparation and Administration

General Instructions

• For reconstitution, use only the reconstitution equipment supplied.
• Check the expiration date and ensure that Prothromplex Total powder and Sterile Water for Injection (vehicle) are at room temperature before preparation. Do not use after the expiration date indicated on the labels and the container.
• Use aseptic technique (cleaning conditions and low bacterial content) and a flat work surface during the reconstitution procedure. Wash hands and put on clean examination gloves (the use of gloves is optional).
• Warm the vial without opening that contains the vehicle (sterile water for injection) to room temperature or body temperature (maximum 37°C).
• Prothromplex Total should only be reconstituted immediately before administration. The solution is transparent or slightly opalescent. Do not use cloudy or particulate solutions.

Instructions for Reconstitution of Powder for Injectable Solution:

Instructions for Administration

Examine the prepared solution in the syringe for particles and color changes before administration. The solution should be transparent, colorless, and free of particles. The filter included in the Mix2Vial device eliminates all particles. Filtration does not affect the dose calculation.The solution in the syringeshould not be used if it is cloudy or contains flakes or particles after filtration.

1.Connect the infusion needle to a syringe containing Prothromplex Total solution. For greater convenience, it is recommended to use an infusion set with wings (mariposa). Point the needle upwards and eliminate any air bubbles by gently tapping the syringe with your finger and slowly pushing the air out of the syringe and needle.

2.Apply a tourniquet and prepare the infusion site by thoroughly cleaning the skin with a sterile cotton swab soaked in alcohol (or another suitable sterile solution).

3.Insert the needle into the vein and remove the tourniquet. Infuse Prothromplex Total slowly. Do not infuse more than 2 ml per minute. Disconnect the empty syringe.

Nota:Do not remove the mariposa needle until all syringes have been infused and do not touch the Luer port that connects to the syringe.

4.Remove the needle from the vein and use a sterile gauze to apply pressure to the infusion site for several minutes.

Do not re-cap the needle. Place the needle, syringe, and empty Prothromplex Total and vehicle vials in a rigid-walled puncture container for proper disposal. Do not dispose of these supplies in ordinary household trash.

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Dosage and Administration

Posology

The following are only general guidelines for dosing, except for the treatment of hemorrhages and perioperative bleeding prophylaxis during treatment with vitamin K antagonists.

Treatment should be initiated under the supervision of a physician experienced in the treatment of coagulation disorders. The dose and duration of treatment depend on the severity of the disorder, the location and intensity of the hemorrhage, and the patient's clinical condition.

The amount and frequency of administration should be calculated individually for each patient. The dosing intervals should be adapted to the different circulating half-lives of the various coagulation factors in the prothrombin complex.

Individual patient requirements can only be identified based on periodic determinations of plasma levels of the relevant coagulation factors or on global analysis of prothrombin complex levels (e.g., Quick test, INR, prothrombin time) and continuous monitoring of the patient's clinical condition.

In the case of major surgery, it is essential to perform precise monitoring of the substitution treatment by means of coagulation analysis (specific tests for the specific coagulation factors and/or global analysis to measure the levels of the prothrombin complex).

Hemorrhage and perioperative bleeding prophylaxis during treatment with vitamin K antagonists:

In severe hemorrhages or before undergoing operations with a high risk of bleeding, normal levels (Quick test 100%, INR 1.0) should be achieved.

The following rule applies: 1 UI of factor IX per kg of body weight increases the Quick test value by approximately 1%.

If the administration of Prothromplex Total is based on INR values, the dose will depend on the INR value before treatment and the target INR value.

Follow the doses described in the following table according to the recommendations published by Makris et al. 20011.

1Makris M, Watson HG: The Management of Coumarin-Induced Over-Anticoagulation Br. J. Haematol.2011; 114:271-280

Correction of the vitamin K antagonist that induces a deterioration of hemostasis persists for approximately 6-8 hours. However, the effects of vitamin K, if administered at the same time, are usually achieved within 4-6 hours. Therefore, it is not necessary to repeat the treatment with human prothrombin complex when vitamin K has been administered.

As these recommendations are empirical and the recovery and duration of effect may vary,INR monitoring during treatment is mandatory.

Treatment of hemorrhages and perioperative bleeding prophylaxis in congenital deficiency of one of the vitamin K-dependent coagulation factors, when a purified product of the specific coagulation factor is not available:

The dose required for treatment is based on the empirical data that approximately 1 UI of factor VII or factor IX per kg of body weight increases the plasma activity of factor IX by around 0.015 UI/ml; and 1 UI per kg of body weight of factor VII by around 0.024 UI/ml. One UI of factor II or X per kg of body weight increases the plasma activity of factor II or X by around 0.021 UI/ml2

2Ostermann H, Haertel S, Knaub S, Kalina U, Jung K, Pabinger I. Pharmacokinetics of Beriplex P/N prothrombin complex concentrate in healthy volunteers.Thromb Haemost. 2007;98(4):790-797

The dose of a specific factor administered is expressed in International Units (UI), which are related to the current WHO standard for each factor. Plasma activity of a specific coagulation factor is expressed either as a percentage (relative to normal plasma) or in International Units (relative to the international standard for the specific coagulation factor).

One International Unit (UI) of activity of a coagulation factor is equivalent to the amount contained in 1 ml of normal human plasma. For example, the calculation of the required dose of factor X is based on the empirical data that 1 International Unit (UI) of factor X per kg of body weight increases the plasma activity of factor X by around 0.017 UI/ml. The required dose is determined using the following formula:

Required Units = body weight (kg) x desired increase in factor X (UI/ml) x 60

where 60 (ml/kg) is the reciprocal of the estimated recovery.

If the individual recovery is known, this value should be used in the calculation.

Maximum Single Dose

To correct the INR value, it is not necessary to exceed a dose of 50 UI/kg. If the severity of the hemorrhage requires a higher dose, the physician must evaluate the risk/benefit.

Pediatric Population

The safety and efficacy of the use of Prothromplex Total in the pediatric population have not been established in clinical trials.

Interaction with Other Medications and Other Forms of Interaction

If high doses of Prothromplex Total are administered, the heparin contained in the product should be taken into account when performing coagulation analyses sensitive to heparin.

Incompatibilities

This medicinal product should not be mixed with other medications, except with the vehicle supplied.

As with all coagulation factor medications, the efficacy and tolerance of the medication may be affected if mixed with other medications. It is recommended to clarify a common venous access with isotonic saline solution before and after administration of Prothromplex Total.

Special Precautions for Disposal and Other Manipulations

Only the reconstitution equipment supplied should be used for reconstitution.

Prothromplex Total should be reconstituted immediately before administration. The solution should be used immediately after (the solution does not contain preservatives).

The solution should be visually inspected before administration to verify the absence of foreign particles or discoloration. Do not use cloudy or particulate solutions.

Name and Batch Number of the Medicinal Product

It is strongly recommended that each time Prothromplex Total is administered to a patient, the name and batch number of the product be recorded to maintain a link between the patient and the product batch.