Prothromplex Total Nf

Leaflet accompanying the packaging: information for the user

Prothromplex Total NF, 500 IU, powder and solvent for solution for injection
human prothrombin complex

Read the leaflet carefully before using the medicine, as it contains important information for the patient.

• Keep this leaflet, you may need to read it again.
• In case of any doubts, consult a doctor or pharmacist.
• If the patient experiences any side effects, including any not listed in this leaflet, they should inform their doctor or pharmacist. See section 4.

Table of contents of the leaflet

• 1. What is Prothromplex Total NF and what is it used for
• 2. Important information before using Prothromplex Total NF
• 3. How to use Prothromplex Total NF
• 4. Possible side effects
• 5. How to store Prothromplex Total NF
• 6. Contents of the packaging and other information

1. What is Prothromplex Total NF and what is it used for

Prothromplex Total NF is a medicine produced from human plasma (the liquid part of the blood). It contains factors II, VII, IX, and X of blood coagulation (prothrombin complex factors) as well as protein C.
These coagulation factors are vitamin K-dependent and, like vitamin K, play an essential role in blood coagulation. In the case of a deficiency of one of these factors, the blood does not clot as quickly as usual, which can lead to an increased tendency to bleed.
Prothromplex Total NF is used in:

• treatment of bleeding,
• prevention of bleeding immediately before and after surgery,
• treatment of acquired and congenital deficiency of coagulation factors.

Acquired deficiency:
The patient may develop a deficiency of vitamin K-dependent factors (acquired deficiency), for example, as a result of therapy with drugs that reduce the effect of vitamin K (so-called vitamin K antagonists) or overdose of such drugs.
Congenital deficiency:
If the patient is born with a deficiency (congenital deficiency), this medicine may be administered to them before or after surgery, if a concentrate of the specific single factor is not available.

2. Important information before using Prothromplex Total NF

When not to use Prothromplex Total NF:

• if the patient is allergic to coagulation factors or any of the other components of this medicine (listed in section 6).
• if the patient has or is suspected to have a decrease in platelet count (thrombocytopenia) associated with heparin administration (heparin-induced thrombocytopenia).

Warnings and precautions

Before starting treatment with Prothromplex Total NF, the patient should discuss the following with their doctor:

• because there is a rare possibility that the patient may develop a severe acute allergic reaction (anaphylactic reaction) to Prothromplex Total NF, as such allergic reactions have been reported during the use of Prothromplex Total NF. Detailed information on the early symptoms of such an allergic reaction can be found in section 4 "Possible side effects".
• if the patient has an acquired deficiency of vitamin K-dependent coagulation factors. This acquired deficiency may be caused by therapy with drugs that reduce blood coagulation by inhibiting vitamin K. In such cases, Prothromplex Total NF should only be used in case of urgent need to replenish prothrombin complex factor concentrations, for example, during severe bleeding or in emergency surgical procedures. In other cases, reducing the dose of vitamin K antagonists or administering vitamin K is usually sufficient.
• if the patient is taking anticoagulant medications (vitamin K antagonists). The patient may exhibit an increased tendency to form blood clots, which may be exacerbated by the administration of human prothrombin complex concentrate.
• if the patient has a congenital deficiency of vitamin K-dependent coagulation factors. The doctor will administer a concentrate of the specific factor to the patient if it is available.
• if the patient is being treated with prothrombin complex concentrates, especially in cases of repeated administration, as blood clots may form and be washed into the bloodstream (thromboembolism).
• due to the risk of blood clots in patients belonging to one of the following groups: patients with coronary artery disease or myocardial infarction, patients with liver disease, patients before or after recent surgery, newborns, patients at risk of thromboembolic disorders or disseminated intravascular coagulation (DIC).

In each of these cases, the doctor will carefully assess the benefits of using Prothromplex Total NF and the potential risk of the above complications.
Identifiability
It is strongly recommended that when administering a dose of Prothromplex Total NF, the name and batch number of the product be recorded to maintain information on the batches of the medicine used.
Virus safety
When medicines are produced from human blood or plasma, certain measures are taken to prevent the transmission of infections to patients. These measures include:

• careful selection of blood and plasma donors to ensure that individuals at risk of infection are excluded,
• testing of individual blood samples and plasma pools for viruses/infections,
• incorporation of procedures into the blood and plasma processing process that inactivate or remove viruses.

Despite these measures, when medicines produced from human blood or plasma are administered, it is not possible to completely exclude the possibility of transmitting an infection. This also applies to unknown or newly discovered viruses and other types of infections.
The measures taken are considered effective against enveloped viruses, such as human immunodeficiency virus (HIV), hepatitis B virus, and hepatitis C virus, as well as non-enveloped hepatitis A virus.
The measures taken may have limited value against non-enveloped viruses, such as parvovirus B19. Parvovirus B19 infection can be serious

• in pregnant women (infection of the unborn child) and
• in individuals with weakened immune systems or with certain types of anemia (e.g., congenital spherocytosis or hemolytic anemia).

In patients regularly or repeatedly receiving prothrombin complex concentrates from human plasma, the doctor may recommend considering vaccination against hepatitis A and B.

Children and adolescents

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

Prothromplex Total NF and other medicines

The patient should inform their doctor or pharmacist about all medicines they are currently taking or have recently taken or plan to take.
The patient should inform their doctor if they are taking anticoagulant medications (vitamin K antagonists). In such cases, there may be an increased tendency to form blood clots, which may be exacerbated by the administration of human prothrombin complex concentrate.
Effect on laboratory tests
When performing coagulation tests that are sensitive to heparin, in patients receiving high doses of human prothrombin complex, the heparin content should be considered as a component of the administered product.

Pregnancy, breastfeeding, and fertility

If the patient is pregnant or breastfeeding, thinks they may be pregnant, or plans to have a child, they should consult their doctor or pharmacist before using this medicine.
Prothromplex Total NF should only be used during pregnancy and breastfeeding if clearly necessary.
There is no information on the effect of Prothromplex Total NF on fertility.

Driving and using machines

No studies have been conducted on the effect of Prothromplex Total NF on the ability to drive and use machines.

Prothromplex Total NF contains sodium and heparin

The medicine contains 68 mg of sodium per vial or 0.14 mg of sodium (the main component of table salt) per 1 international unit (IU). This corresponds to 3.4% of the maximum recommended daily sodium intake in the diet for adults.
Heparin can cause allergic reactions and a decrease in blood cell count, which can affect the coagulation system. Patients with a history of allergic reactions caused by heparin should avoid using heparin-containing medicines.

3. How to use Prothromplex Total NF

Treatment should be initiated, used, and monitored by a doctor with experience in treating coagulation disorders.
The required dose of Prothromplex Total NF and the duration of treatment depend on various factors, such as body weight, severity of the disease, location, and extent of bleeding or the need to prevent bleeding during surgical procedures.
The doctor will determine the appropriate dosage for the patient and regularly monitor the patient's coagulation and clinical condition (see "Information intended for healthcare professionals only").

Method of administration

Intravenous administration.
Administration of Prothromplex Total NF is performed under the supervision of a doctor.
After preparing the solution using the supplied sterile water for injections, Prothromplex Total NF is administered slowly into a vein (intravenously). The rate of administration depends on the patient's condition and should not exceed 2 ml per minute (60 IU/min).

Children and adolescents

There is insufficient data to recommend the use of Prothromplex Total NF in patients under 18 years of age.

Overdose of Prothromplex Total NF

In case of overdose, there is a risk of developing thromboembolic complications or coagulation disorders caused by excessive consumption of coagulation factors (consumption coagulopathy).
During the use of high doses of human prothrombin complex concentrates, cases of myocardial infarction, increased consumption of platelets and coagulation factors with enhanced thrombus formation in blood vessels (DIC, disseminated intravascular coagulation, consumption coagulopathy), venous thrombosis, and pulmonary embolism have been observed.
In case of any further doubts regarding the use of this medicine, the patient should consult their doctor.

4. Possible side effects

Like all medicines, Prothromplex Total NF can cause side effects, although not everybody gets them.
As with all therapies with medicines obtained from plasma, there is a possibility of an acute allergic reaction (anaphylactic reaction). In individual cases, this can lead to a severe hypersensitivity reaction, including shock.
Therefore, attention should be paid to potential early signs of an allergic reaction, such as:

• flushing (redness of the skin)
• rash
• appearance of hives on the skin
• itching in any part of the body
• swelling of the lips and tongue
• difficulty breathing/shortness of breath
• chest tightness
• general malaise
• dizziness
• drop in blood pressure

If one or more of these symptoms are noticed, the doctor should be informed immediately. The doctor will decide to stop the infusion immediately. Severe symptoms require immediate emergency treatment.
In the case of using prothrombin complex concentrates (including Prothromplex Total NF), patients may develop resistance (inhibitors) to one or more coagulation factors, which is associated with the inactivation of blood coagulation factors. The appearance of such inhibitors may manifest as an inadequate response to treatment.
During treatment with prothrombin complex concentrates, blood clots may form and be washed into the bloodstream (thromboembolism). This can lead to complications such as myocardial infarction, increased consumption of platelets and coagulation factors with enhanced thrombus formation in blood vessels (consumption coagulopathy), venous thrombosis, and pulmonary embolism.
The following side effects may occur in no more than 1 in 10 patients using Prothromplex Total NF:

• formation of blood clots throughout the body (disseminated intravascular coagulation), resistance (inhibitors) to one or more prothrombin complex factors (factors II, VII, IX, X)
• severe acute allergic reaction (anaphylactic shock), anaphylactic reaction, hypersensitivity
• stroke, headache
• heart attack (acute myocardial infarction), palpitations (tachycardia)
• arterial thrombosis, venous thrombosis, drop in blood pressure (hypotension), flushing (hot flashes)
• blockage of a pulmonary vessel by a blood clot (pulmonary thromboembolism), difficulty breathing, shortness of breath
• vomiting, nausea (feeling of nausea)
• hives all over the body, rash (erythematous rash), itching (pruritus)
• certain kidney function disorders with symptoms such as swelling of the eyelids, face, and lower legs, with weight gain and protein loss in the urine (nephrotic syndrome)
• fever

The following side effects have been observed during the use of other prothrombin complex concentrates:

• swelling of the face, tongue, and lips (angioedema), skin sensations such as burning, tingling, itching, numbness (sensory disturbances)
• reaction at the injection site
• lethargy
• restlessness

Reporting side effects

If side effects occur, including any not listed in the leaflet, the doctor should be informed. Side effects can be reported directly to the Department of Drug Safety Monitoring of the Office for Registration of Medicinal Products, Medical Devices, and Biocidal Products
Al. Jerozolimskie 181C
02-222 Warsaw
Phone: +48 22 49 21 301
Fax: +48 22 49 21 309
Website: https://smz.ezdrowie.gov.pl
Side effects can also be reported to the marketing authorization holder.
Reporting side effects will help to gather more information on the safety of the medicine.

5. How to store Prothromplex Total NF

Store in a refrigerator (2°C – 8°C). Do not freeze.
Store in the original packaging to protect from light.
Store out of sight and reach of children.
Do not use this medicine after the expiry date stated on the label and outer packaging after "EXP". The expiry date refers to the last day of the month.
During the stated shelf-life, the medicine can be stored at room temperature (up to 25°C) for a period of up to six months. The start and end of storage at room temperature should be noted on the packaging. After storage at room temperature, Prothromplex Total NF should not be returned to the refrigerator (2°C to 8°C) but should be used within those six months or discarded.
The prepared solution should be used immediately after preparation.
Medicines should not be disposed of via wastewater or household waste. The patient should ask their pharmacist how to dispose of medicines that are no longer needed. This will help protect the environment.

6. Contents of the packaging and other information

What Prothromplex Total NF contains

Powder:
The active substance of the medicine is human prothrombin complex, consisting of human coagulation factors II, VII, IX, and X, as well as protein C.

One vial contains at least 333 IU of protein C, copurified with coagulation factors.
Other ingredients are: sodium chloride, sodium citrate, sodium heparin (0.2 – 0.5 IU/IU factor IX), antithrombin III 12.5 – 25 IU/vial (0.75 – 1.5 IU/ml).
Solvent:
Sterile water for injections

What Prothromplex Total NF looks like and contents of the packaging

Powder and solvent for solution for injection.
Prothromplex Total NF is a white to slightly yellow lyophilized, brittle or compacted dry substance.
The pH of the solution after reconstitution is 6.5 to 7.5, and the osmolality is not less than 240 mOsm/kg.
The solution is clear or slightly opalescent.
The powder and solvent are supplied in single-dose vials made of glass (class II and class I, respectively). The vials are closed with butyl rubber stoppers.
Contents of the packaging

• 1 vial of Prothromplex Total NF 500 IU powder for solution for injection
• 1 vial of 17 ml sterile water for injections
• 1 Mix2Vial system for reconstitution

Package size
1 x 500 IU

Marketing authorization holder and manufacturer

Marketing authorization holder

Takeda Pharma sp. z o.o.
ul. Prosta 68
00-838 Warsaw

Manufacturer

Takeda Manufacturing Austria AG
Industriestrasse 67
1221 Vienna
Austria

This medicinal product is authorized in the Member States of the European Economic Area and in the United Kingdom (Northern Ireland) under the following names:

Date of last revision of the leaflet:

Information intended for healthcare professionals only:

Instructions for preparation and administration of the medicine

General instructions

• Only use the supplied reconstitution set for reconstitution of the product.
• Before reconstitution, check the expiry date and ensure that the Prothromplex Total NF powder and water for injections (solvent) are at room temperature. Do not use after the expiry date stated on the labels and carton.
• Use aseptic technique (clean and sterile conditions) and a flat work surface during reconstitution. Wash your hands and wear clean examination gloves (glove use is optional).
• Warm the closed vial of solvent (water for injections) to room temperature or body temperature (up to 37°C).
• Reconstitute Prothromplex Total NF immediately before administration. The solution should be clear or slightly opalescent. If the solution is cloudy or contains sediment, it should be discarded.

Instructions for reconstitution of the powder for solution for injection:

Steps Illustration

1

• Remove the protective caps from both the vial of powder and the vial of solvent.

2

• Disinfect the stopper of each vial with a separate, sterile swab moistened with alcohol (or another suitable sterile solution), wiping the stopper for a few seconds.
• Allow the rubber stopper to dry. Place the vials on a flat surface.

3

• Open the Mix2Vial system packaging by tearing off the cover, making sure not to touch the inside of the packaging.
• Do not remove the Mix2Vial system from the packaging.

Steps Illustration

4

• Invert the packaging containing the Mix2Vial system and place it over the vial of solvent.
• With a firm motion, push the blue plastic spike into the center of the solvent vial stopper, pressing straight down. Hold the protector at the edge and lift it off the Mix2Vial system.
• Be careful not to touch the clear plastic spike.
• The solvent vial is now connected to the Mix2Vial system and is ready to be connected to the Prothromplex Total NF vial.

5

• To connect the solvent vial to the Prothromplex Total NF vial, invert the solvent vial and place it over the Prothromplex Total NF vial.
• Insert the clear plastic spike fully into the Prothromplex Total NF vial stopper, pressing straight down. This should be done immediately to prevent contamination with microorganisms.
• Under the vacuum, the solvent will flow into the Prothromplex Total NF vial. Ensure that all the solvent has been transferred to the Prothromplex Total NF vial.
• Do not use if there is a loss of vacuum and the solvent does not flow into the Prothromplex Total NF vial.

6

• Gently rotate the connected vials until the powder is dissolved or leave the reconstituted product for 5 minutes, then gently rotate the vials to ensure the powder is fully dissolved.
• Do not shake. Shaking will negatively affect the product. Do not store in the refrigerator after reconstitution.

7

• Separate the two parts of the Mix2Vial system by holding one part of the clear plastic Mix2Vial system connected to the Prothromplex Total NF vial with one hand and the blue plastic part of the Mix2Vial system connected to the solvent vial with the other hand.
• Twist the blue plastic part in the opposite direction to the clockwise direction and carefully separate the two vials.
• Do not touch the end of the plastic connector on the vial containing the reconstituted Prothromplex Total NF.
• Place the vial containing Prothromplex Total NF on a flat work surface. Discard the empty solvent vial.

Steps Illustration

8

• Draw air into an empty, sterile, single-use plastic syringe by pulling the plunger.
• The amount of air should be the same as the amount of Prothromplex Total NF solution to be withdrawn from the vial.

9

• Holding the vial containing the reconstituted Prothromplex Total NF (with the product after reconstitution) on a flat work surface, connect the syringe to the clear plastic connector and twist the syringe in a clockwise direction.

10 •
While holding the vial with one hand, push all the air from the syringe into the vial with the other hand.

11 •
Invert the syringe connected to the vial containing Prothromplex Total NF so that the vial is at the top. Ensure the syringe plunger remains depressed. Slowly draw the Prothromplex Total NF solution into the syringe by slowly pulling the plunger.

• Do not push or draw the solution back and forth between the vial and syringe (and vice versa), as this may adversely affect the medicine.

12 •
Just before administering the infusion, disconnect the syringe from the vial by twisting it in the opposite direction to the clockwise direction. Inspect the syringe for the presence of solid particles; the solution should be clear and slightly opalescent.

• If the solution is cloudy or contains sediment, do not administer the solution.

Instructions for administration of the medicine
Before administration, inspect the prepared solution in the syringe for the presence of solid particles and changes in color (the solution should be clear, colorless, and free of solid particles).
The filter that is part of the Mix2Vial system completely removes such particles. Filtration does not affect the calculation of the dose. Do not administer the solution in the syringe if it is cloudy or contains flakes or other solid particles after filtration.

• 1. Attach a needle for infusion to the syringe containing the Prothromplex Total NF solution. For convenience, it is recommended to use a butterfly needle set. Point the needle upwards and gently tap the syringe with your finger to remove any air bubbles, then slowly and carefully push the air out of the syringe and needle.
• 2. Apply a tourniquet and prepare the infusion site, carefully wiping the skin with a sterile swab moistened with alcohol (or another suitable sterile solution).
• 3. Insert the needle into a vein and remove the tourniquet. Administer Prothromplex Total NF slowly. Do not administer the product at a rate faster than 2 ml per minute. Remove the empty syringe.

Warning:

Do not remove the butterfly needle until the administration of all syringes is complete and do not touch the Luer connector that connects to the syringe.

• 4. Remove the needle from the vein and apply pressure to the infusion site with a sterile swab for a few minutes.

Do not re-sheath the needle. Place the needle, syringe, and empty vials of Prothromplex Total NF and solvent in a puncture-resistant container for medical sharp waste to ensure their proper disposal. Do not dispose of these materials in ordinary household waste.
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Dosage and administration

Dosage

Except for the treatment of bleeding and prevention of bleeding during surgery in patients treated with vitamin K antagonists, the following are only general recommendations for dosing.
Treatment should be initiated under the supervision of a doctor with experience in treating coagulation disorders.
The dosage and duration of substitution treatment depend on the degree of coagulation disorder, the location and extent of bleeding, and the patient's clinical condition.
The dose and frequency of administration should be calculated individually for each patient.
The intervals between doses must be determined taking into account the different half-lives of the individual prothrombin complex factors.
Determining individual dosing, according to the patient's needs, is only possible during regular monitoring of the levels of the relevant coagulation factors in the patient's plasma or regular determination of the levels of these coagulation factors or tests evaluating the overall level of all prothrombin complex factors (e.g., Quick test, prothrombin time, INR) and constant monitoring of the patient's clinical condition.
In the case of major surgical procedures, precise monitoring of substitution treatment is necessary using coagulation tests (determination of coagulation factors and (or) tests evaluating the overall level of all prothrombin complex factors).
Bleeding or prevention of bleeding during surgery in patients treated with vitamin K antagonists:
In severe bleeding or before surgical procedures with a high risk of bleeding, it is recommended to aim for normalization of coagulation parameters (Quick test 100%, INR 1.0).
There is a practical rule that 1 IU of factor IX per kg of body weight increases the Quick test value by about 1%.
If the administration of Prothromplex Total NF is based on INR measurement, the dose will depend on the INR value before starting treatment and the desired INR.
According to the recommendation by Makris et al. 2001, the following dosing recommendations should be followed.

One international unit (IU) of coagulation factor activity is equivalent to the content in one milliliter of normal human plasma. For example, the calculation of the required dose of factor X is based on the empirical finding that 1 IU of factor X per kg of body weight increases the factor X activity in plasma by about 0.017 IU/ml.
The required dose is determined using the following formula:

Required dose = body weight (kg) x desired increase in factor X activity (IU/ml) x 60

where 60 (ml/kg) is the reciprocal of the estimated recovery value.
If the individual recovery value is known, it should be used for calculations.
Maximum single dose:
To correct INR, there is no need to exceed a dose of 50 IU/kg. If the severity of bleeding requires higher doses, the treating doctor should assess the risk-benefit ratio.
Children and adolescents
The safety and efficacy of Prothromplex Total NF in children and adolescents have not been established in clinical trials.

Interactions with other medicines and other types of interactions

When performing coagulation tests that are sensitive to heparin, in patients receiving high doses of human prothrombin complex, the heparin content should be considered as a component of the administered product.

Incompatibilities

Do not mix the medicinal product with other medicinal products except for the supplied solvent.
As with other medicinal products containing coagulation factors, the efficacy and tolerability of the medicinal product may be reduced when mixed with other medicinal products. Before and after administration of Prothromplex Total NF, it is recommended to flush the common venous access with isotonic sodium chloride solution.

Special precautions for storage and handling

Only use the supplied reconstitution set for reconstitution of the product.
Prothromplex Total NF should be reconstituted immediately before administration. The solution should then be used immediately (the solution does not contain preservatives).
The solution is clear or slightly opalescent. Before administration, always check the solution visually for the presence of undissolved particles and changes in color. If the solution is cloudy or contains sediment, it should be discarded.

Product name and batch number

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