Prothromplex total nf

Package leaflet: Information for the user

Prothromplex Total NF, 500 IU, powder and solvent for solution for injection
human prothrombin complex
Please read all of this leaflet carefully before this medicine is administered, because it contains
important information for the patient.

• Keep this leaflet, as you may need to read it again.
• If you have any further questions, ask your doctor or pharmacist.
• If you experience any side effects, including any not listed in this leaflet, tell your doctor or pharmacist. See section 4.

Contents of the leaflet

1. What Prothromplex Total NF is and what it is 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 pack and other information

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

Prothromplex Total NF is a medicine prepared from human plasma (the liquid part of blood). It contains blood clotting factors II, VII, IX, and X (vitamin K-dependent clotting factors), as well as protein C. These clotting factors are vitamin K-dependent and, like vitamin K, play an important role in blood coagulation. When one of these factors is deficient, blood does not clot as quickly as normal, leading to an increased tendency to bleed.

Prothromplex Total NF is used:

• for the treatment of bleeding,
• for the prevention of bleeding before and after surgery,
• in acquired and congenital deficiencies of clotting factors.

Acquired deficiency:
A deficiency of vitamin K-dependent clotting factors (acquired deficiency) may develop in patients, for example, as a result of treatment with drugs that reduce the effect of vitamin K (so-called vitamin K antagonists) or overdose of such drugs.
Congenital deficiency:
If the patient was born with a deficiency (congenital deficiency), this medicine may be administered just before or after surgery, especially when 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 clotting factors or to any of the other components of this medicine (listed in section 6).
• if the patient has or it is suspected that they may have heparin-induced thrombocytopenia (a decrease in platelet count related to heparin administration).

Warnings and precautions
Before starting treatment with Prothromplex Total NF, discuss the following with your doctor:

• since there is a rare possibility that the patient may develop a severe, sudden allergic reaction (anaphylactic reaction) to Prothromplex Total NF, as such allergic reactions have been reported during use of Prothromplex Total NF. Detailed information regarding early symptoms of such an allergic reaction can be found in section 4, "Possible side effects."
• if the patient has acquired deficiency of vitamin K-dependent clotting factors. This acquired deficiency may be caused by treatment with drugs that reduce blood clotting by inhibiting vitamin K. In such cases, Prothromplex Total NF should only be used in emergency situations requiring rapid correction of prothrombin complex factor levels, for example during severe bleeding or 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 medicines (drugs known as vitamin K antagonists). The patient may have an increased tendency to form blood clots, which may be intensified by infusion of human prothrombin complex concentrate.
• if the patient has a congenital deficiency of vitamin K-dependent clotting factors. The doctor will provide the patient with a concentrate of the specific clotting factor if available.
• if the patient is being treated with prothrombin complex concentrates, especially with repeated administration, because blood clots may form and enter the bloodstream (thromboembolism).
• due to the risk of blood clots in patients belonging to any of the following groups:
  • patients with coronary artery disease or myocardial infarction,
  • patients with liver disease,
  • patients before or after recent surgical procedures,
  • 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 against the potential risks of the complications listed above.

Traceability
It is strongly recommended that, with each administration of Prothromplex Total NF, the name and batch number of the product be recorded to maintain traceability of the batches used.

Viral safety
When medicines are manufactured from human blood or plasma, specific measures are taken to prevent transmission of infections to patients. These measures include:

• careful selection of blood and plasma donors to ensure exclusion of individuals from high-risk groups for infection,
• testing of individual blood samples and pooled plasma for viruses/infections,
• inclusion of virus inactivation or removal steps during the blood and plasma processing.

Despite these measures, when administering medicines derived from human blood or plasma, it cannot be completely ruled out that transmission of infection may occur. This also applies to unknown or newly emerging viruses and other infectious agents.

The measures taken are considered effective against enveloped viruses such as human immunodeficiency virus (HIV), hepatitis B virus, hepatitis C virus, and non-enveloped hepatitis A virus.

The measures may have limited effectiveness against non-enveloped viruses such as parvovirus B19. Infection with parvovirus B19 may be dangerous:

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

For patients who regularly or repeatedly receive prothrombin complex concentrates derived 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
Inform your doctor or pharmacist about all medicines you are currently taking, have recently taken, or plan to take.

Inform your treating physician if you are taking anticoagulant medicines (vitamin K antagonists). In such cases, there may be an increased tendency to form blood clots, which may be intensified by administration of human prothrombin complex concentrate.

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

Pregnancy, breastfeeding, and fertility
If the patient is pregnant, breastfeeding, suspects she may be pregnant, or is planning to have a child, she should consult her doctor or pharmacist before using this medicine.

Prothromplex Total NF should be used during pregnancy and breastfeeding only if clearly indicated.

There is no information available regarding the effect of Prothromplex Total NF on fertility.

Driving and operating machinery
No studies have been conducted regarding the effect on the ability to drive vehicles or operate machinery.

Prothromplex Total NF contains sodium and heparin
This medicine contains 68 mg of sodium per vial or 0.14 mg of sodium (main component of table salt) per 1 international unit (IU). This corresponds to 3.4% of the maximum recommended daily dietary intake of sodium for adults.

Heparin may cause allergic reactions and reduction in blood cell counts, which may affect the coagulation system. Patients with a history of allergic reactions caused by heparin should avoid using medicines containing heparin.

3. How to use Prothromplex Total NF

Treatment should be initiated, administered, and monitored by a physician experienced in the management of coagulation disorders.
The required dose of Prothromplex Total NF and duration of treatment depend on various factors, such as body weight, severity of the condition, location and extent of bleeding, or the need to prevent hemorrhage during surgical procedures.
The physician will determine the appropriate dosage for the patient and will regularly monitor blood coagulation and the patient's clinical status (see section "Information intended exclusively for healthcare professionals").

Route of administration
Intravenous administration.
Administration of Prothromplex Total NF must be performed under medical supervision.
After reconstitution with the provided sterile water for injection, Prothromplex Total NF is administered slowly intravenously. The infusion rate depends on the patient's tolerance and should not exceed 2 ml per minute (60 IU/min).

Children and adolescents
There are insufficient data to recommend administration 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).
When high doses of human prothrombin complex concentrates are used, cases of myocardial infarction, increased platelet and coagulation factor consumption, enhanced intravascular clot formation (DIC, disseminated intravascular coagulation, consumption coagulopathy), venous thrombosis, and pulmonary embolism have been observed.
If you have any further questions regarding the use of this medicine, consult your physician.

4. Possible adverse reactions

Like any medicine, this medicine can cause adverse reactions, although they do not occur in every patient.
As with all plasma-derived medicinal therapies, there is a possibility of an acute allergic reaction (anaphylactic reaction). In individual cases, this may lead to a severe hypersensitivity reaction, including shock.
Therefore, potential early signs of an allergic reaction should be carefully monitored, such as:

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

If one or more of the above symptoms are observed, a physician must be notified immediately. The physician will decide whether to discontinue the infusion immediately. Severe symptoms require immediate emergency treatment.
When using prothrombin complex concentrates (including Prothromplex Total NF), patients may develop resistance (inhibitors) to one or more clotting factors, resulting in inactivation of blood clotting factors. The appearance of such inhibitors may manifest as inadequate response to treatment.
During treatment with prothrombin complex concentrates, blood clots may form and enter the bloodstream (embolism). This may lead to complications such as myocardial infarction, increased consumption of platelets and clotting factors with enhanced clot formation in blood vessels (consumption coagulopathy), blockage of veins by blood clots (venous thrombosis), and blockage of a pulmonary vessel by a blood clot (pulmonary embolism).
The following adverse reactions may occur in no more than 1 in 10 people receiving 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)
• sudden severe 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), skin redness (flushing)
• blockage of a pulmonary vessel by a blood clot (pulmonary embolism), difficulty breathing, shortness of breath (dyspnea), wheezing
• vomiting, nausea (feeling of sickness)
• hives all over the body, skin rash (erythematous rash), itching (pruritus)
• certain kidney function disorders with symptoms such as eyelid, facial and lower limb edema, weight gain, and loss of protein in urine (nephrotic syndrome)
• fever

The following adverse reactions have been observed during the use of other prothrombin complex concentrates:

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

Reporting of adverse reactions
If any adverse reactions occur, including those not listed in this leaflet, inform your doctor. Adverse reactions can be reported directly to the Department of Monitoring Adverse Drug Reactions, 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
Adverse reactions may also be reported to the responsible entity.
Reporting adverse reactions helps 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.
Keep in the original packaging to protect from light.
Store in a place inaccessible and not visible to children.
Do not use this medicinal product after the expiry date stated on the label and outer packaging
following “EXP”. The expiry date refers to the last day of the stated month.
During the stated shelf life, this medicinal product may be stored once at room temperature
(up to 25°C) for a period of up to six months. The start and end dates of storage at room
temperature should be recorded on the packaging. After storage at room temperature,
Prothromplex Total NF must not be returned to the refrigerator (2°C to 8°C), but must be used
within those six months or discarded.
The reconstituted solution should be used immediately after preparation.
Medicinal products should not be disposed of via wastewater or household waste. Ask a
pharmacist how to dispose of medicines no longer in use. Such measures help protect
the environment.

6. Contents of the pack and other information

What Prothromplex Total NF contains
Powder:
The active substance is human prothrombin complex consisting of human coagulation factors II, VII, IX, and X and protein C.

One vial contains at least 333 IU of protein C, co-purified with clotting factors.
Other components: sodium chloride, sodium citrate, sodium heparin (0.2 – 0.5 IU/IU of 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 pack
Powder and solvent for solution for injection.
Prothromplex Total NF is a white to slightly yellowish lyophilized, friable or amorphous dry substance.
The pH of the reconstituted solution is between 6.5 and 7.5 and 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 (respectively class II and class I). Vials are closed with butyl rubber stoppers.
Contents of the pack:

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

Pack size
1 x 500 IU
Marketing Authorisation Holder and Manufacturer
Marketing Authorisation Holder
Takeda Pharma sp. z o.o.
Prosta 68 Street
00-838 Warsaw
Manufacturer
Takeda Manufacturing Austria AG
Industriestrasse 67
1221 Vienna
Austria
This medicinal product is authorised for marketing in the European Economic Area and the United Kingdom (Northern Ireland) under the following names:

Information intended exclusively for healthcare professionals:
Instructions for preparation and administration of the medicinal product
General instructions

• Use only the provided kit for reconstitution of the product.
• Before preparation, check the expiry date and ensure that both the Prothromplex Total NF powder and the water for injections (diluent) are at room temperature. Do not use after the expiry date stated on the labels and cardboard box.
• Use aseptic technique (clean, microorganism-free conditions) and work on a flat surface during reconstitution. Wash hands and put on clean examination gloves (wearing gloves is optional).
• Warm the closed vial of diluent (sterile water for injections) to room temperature or body temperature (maximum 37 °C).
• Reconstitute Prothromplex Total NF immediately before administration. The resulting solution should be clear or slightly opalescent. If the solution is cloudy or contains a precipitate, discard it.

Instructions for reconstituting the powder for solution for injection:
Steps Illustration
1 • Remove protective caps from both the vial containing the powder

and the vial containing the diluent.
2 • Disinfect the stopper of each vial with a separate sterile

alcohol-impregnated swab (or another appropriate sterile solution), wiping each stopper for several seconds.

• Allow the rubber stoppers to dry. Place the vials on a flat surface.

3 • Open the Mix2Vial system package by peeling off the entire

lid without touching the inner surface of the packaging.

• Do not remove the Mix2Vial system from the package.

Steps Illustration
4 • Turn the package containing the Mix2Vial system upside

down and place it over the diluent vial.

• Firmly press the blue plastic spike of the device into the center of the diluent vial’s stopper by pushing straight down. Grasp the cover at the edge and lift it off the Mix2Vial system.
• Take care not to touch the transparent plastic spike.
• The diluent vial is now connected to the Mix2Vial system and is ready to be connected to the vial containing Prothromplex Total NF.

5 • To connect the diluent vial to the vial containing

Prothromplex Total NF, turn the diluent vial upside down and place it over the vial containing Prothromplex Total NF.

• Fully insert the transparent plastic spike into the stopper of the Prothromplex Total NF vial by firmly pushing straight down. Perform this step immediately to prevent microbial contamination of the liquid.
• Due to vacuum pressure, the diluent will flow into the vial containing Prothromplex Total NF. Ensure that all of the diluent has transferred into the product vial.
• Do not use if vacuum loss occurs and the diluent does not flow into the Prothromplex Total NF vial.

6 • Gently and evenly rotate the connected vials until the powder

is completely dissolved, or leave the reconstituted product for 5 minutes, then gently rotate the vials to ensure complete dissolution of the powder.

• Do not shake. Shaking may adversely affect the product. Do not refrigerate after reconstitution.

7 • Separate the two components of the Mix2Vial system,

holding with one hand the transparent plastic part of the Mix2Vial connected to the vial containing Prothromplex Total NF, and with the other hand the blue plastic part connected to the diluent vial.

• Rotate the blue plastic component counterclockwise and gently disconnect the two vials.
• Do not touch the tip of the plastic connector on the vial containing the reconstituted Prothromplex Total NF.
• Place the vial containing Prothromplex Total NF on a flat working surface. Discard the empty diluent vial.

Steps Illustration
8 • Draw air into an empty, sterile, single-use plastic

syringe by pulling the plunger.

• The volume of air drawn should equal the volume of reconstituted Prothromplex Total NF to be withdrawn from the vial.

9 • Holding the vial of Prothromplex Total NF

(containing the reconstituted product) on a flat working surface, connect the syringe to the transparent plastic connector and rotate the syringe clockwise to secure.

10 • While holding the vial with one hand, use the other hand to

fully push the air from the syringe into the vial.

11 • Turn the syringe connected to the vial containing

Prothromplex Total NF upside down so that the vial is on top. Ensure the syringe plunger remains depressed. Draw Prothromplex Total NF into the syringe by slowly pulling back the plunger.

• Do not repeatedly push and withdraw solution between the vial and syringe, as this may adversely affect the medicinal product.

12 • Immediately before infusion, disconnect the syringe from

the vial by rotating it counterclockwise. Inspect the syringe for particulate matter; the solution should be clear and slightly opalescent.

• Do not administer if the solution is cloudy or contains precipitate.

Instructions for administration of the medicinal product
Before administration, inspect the prepared solution in the syringe for particulate matter and discoloration (the solution should be clear, colorless, and free from particles).
The filter incorporated in the Mix2Vial system completely removes such particles. Filtration does not affect dose calculation. Do not administer the solution in the syringe if, after filtration, it is cloudy or contains flakes or other particulate matter.

1. Attach an infusion needle to the syringe containing the Prothromplex Total NF solution. For convenience, use of a butterfly needle set is recommended. Point the needle upward and gently tap the syringe to remove any air bubbles, then slowly and carefully expel air from the syringe and needle.
2. Apply a tourniquet and prepare the infusion site by carefully cleaning the skin with a sterile alcohol-impregnated swab (or another appropriate sterile solution).
3. Insert the needle into the vein and remove the tourniquet. Administer Prothromplex Total NF slowly. Do not administer faster than 2 mL per minute. Disconnect the empty syringe. Note: Do not remove the butterfly needle until administration from all syringes is complete, and do not touch the Luer connector that attaches to the syringe.
4. Remove the needle from the vein and apply pressure to the infusion site for several minutes using a sterile swab.

Do not recap the needle. Place the needle, syringe, and empty vials (from Prothromplex Total NF and diluent) into a hard-walled container for sharp medical waste to ensure proper disposal. Do not discard these materials into regular household waste bins.

Dosage and method of administration
Dosage
Except for the treatment of bleeding and perioperative bleeding prophylaxis during treatment with vitamin K antagonists, the following are only general dosage recommendations.
Treatment should be initiated under the supervision of a physician experienced in managing coagulation disorders.
The dosage and duration of replacement therapy depend on the severity of the coagulation disorder, the location and extent of bleeding, and the patient’s clinical condition.
The dose and frequency of administration must be individually calculated for each patient.
Intervals between doses must be determined considering the different half-lives of the individual prothrombin complex factors.
Individualized dosing, tailored to the patient’s needs, can only be achieved through regular monitoring of the appropriate coagulation factor levels in the patient’s plasma, regular measurement of specific coagulation factor levels, or tests assessing overall prothrombin complex factor levels (e.g., Quick index, prothrombin time, INR), along with continuous monitoring of the patient’s clinical status.
Precise monitoring of replacement therapy using coagulation tests (measurement of coagulation factors and/or tests assessing overall prothrombin complex factor levels) is essential during major surgical procedures.
Bleeding or perioperative bleeding prophylaxis during treatment with vitamin K antagonists:
In severe hemorrhage or prior to surgical procedures with high bleeding risk, normalization of coagulation parameters should be achieved (Quick index 100%, INR 1.0).
A practical rule applies: 1 IU of factor IX per kg body weight increases the Quick index by approximately 1%.
If administration of Prothromplex Total NF is based on INR measurement, the dose will depend on the INR value before treatment initiation and the desired INR.
According to the recommendation published by Makris et al. 2001, the dosing recommendations in the table below should be followed.

The correction of vitamin K antagonist-induced coagulation disorders lasts for approximately 6–8 hours. However, the effect of concurrently administered vitamin K is usually achieved within 4–6 hours. Therefore, repeated administration of human prothrombin complex concentrate is generally not necessary when vitamin K has been given.

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

Bleeding or perioperative bleeding prophylaxis in congenital deficiency of any vitamin K-dependent clotting factor, when a specific factor concentrate is not available:

The required treatment dose is calculated based on empirical data indicating that approximately 1 IU of factor IX per kg of body weight increases plasma factor IX activity by about 0.015 IU/mL; and 1 IU of factor VII per kg increases plasma factor VII activity by about 0.024 IU/mL. One IU of factor II or X per kg of body weight increases plasma factor II or X activity by approximately 0.021 IU/mL.

The dose of a given clotting factor is expressed in international units (IU), which refer to the current WHO standard for each clotting factor. The activity of a specific clotting factor in plasma is expressed either as a percentage (relative to normal plasma) or in international units (relative to the international standard for that clotting factor). One international unit (IU) of clotting factor activity is equivalent to the content found in one millilitre of normal human plasma. For example, the calculation of the required therapeutic dose of factor X is based on the empirical observation that 1 international unit (IU) of factor X per kg of body weight increases plasma factor X activity by approximately 0.017 IU/mL.

The required dose should be calculated using the following formula:

Required number of units = body weight (kg) × desired increase in factor X activity (IU/mL) × 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:

For correction of INR, there is no need to exceed a dose of 50 IU/kg. If the severity of bleeding requires higher doses, the treating physician should assess the risk-benefit ratio.

Children and adolescents:

The safety and efficacy of Prothromplex Total NF have not been established in clinical studies in children and adolescents.

Interactions with other medicinal products and other forms of interaction:

When performing coagulation tests sensitive to heparin in patients receiving high doses of prothrombin complex concentrate, the heparin content present in the administered product should be taken into account.

Pharmaceutical incompatibilities

Do not mix the medicinal product with other medicinal products except with the provided diluent.

As with other medicinal products containing clotting factors, the efficacy and tolerability of the medicinal product may be reduced if mixed with other medicinal products. It is recommended to flush the common intravenous line with isotonic saline solution before and after administration of Prothromplex Total NF.

Special precautions for storage and preparation for use

Use only the provided reconstitution kit.

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

The solution is clear or slightly opalescent. Before administration, the solution should always be visually inspected for insoluble particles and discoloration. If the solution is cloudy or contains a precipitate, it must be discarded.

Name and batch number of the medicinal product

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