Prothromplex Total Nf

Leaflet accompanying the packaging: patient information

Prothromplex Total NF, 600 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.
• If the patient experiences any side effects, including any side effects 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 II, VII, IX, and X blood clotting factors (prothrombin complex factors), as well as protein C.
These clotting factors are vitamin K-dependent and, like vitamin K, play an essential role in blood clotting. In the case of a deficiency of one of these factors, the blood does not clot as quickly as usual, leading to an increased tendency to bleed.
Prothromplex Total NF is used in:

• treatment of bleeding,
• prevention of bleeding before and after surgery
• acquired and congenital deficiency of clotting factors

Acquired deficiency:
The patient may develop a deficiency of vitamin K-dependent clotting factors (acquired deficiency), for example, as a result of therapy with medications that reduce the effect of vitamin K (so-called vitamin K antagonists) or overdose of such medications.
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 clotting 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 any of the other components of this medicine (listed in section 6).
• if the patient has or is suspected to have a reduced platelet count (thrombocytopenia) associated with heparin administration (heparin-induced thrombocytopenia).

Warnings and precautions

Identifiability
It is strongly recommended that each administration of Prothromplex Total NF be recorded with the product name and batch number, in order to maintain information on the batches used.
Before starting treatment with Prothromplex Total NF, the patient should consult a 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 clotting factors. This acquired deficiency may be caused by therapy with medications that reduce blood clotting by inhibiting vitamin K. In such cases, Prothromplex Total NF should only be used in case of an urgent need to replenish prothrombin complex factor levels, for example, during severe bleeding or emergency surgery. In other cases, reducing the dose of vitamin K antagonists or administering vitamin K is usually sufficient.
• if the patient is taking medications that inhibit blood clotting (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 clotting factors. The doctor will administer a concentrate of the specific clotting factor, if available.
• if the patient is being treated with prothrombin complex concentrates, especially in the case of repeated administration, as blood clots may form in 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.
Viral 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 dangerous

• 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 currently or recently taken/or being taken or planned to be taken.
The patient should inform their treating doctor if they are taking medications that inhibit blood clotting (vitamin K antagonists). In such cases, an increased tendency to form blood clots may occur, which may be exacerbated by the administration of human prothrombin complex concentrate.
Effect on laboratory tests
During the performance of coagulation tests sensitive to heparin, in patients receiving high doses of human prothrombin complex, the heparin content should be taken into account as a component of the administered product.

Pregnancy, breastfeeding, and fertility

If the patient is pregnant or breastfeeding, suspects 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 indicated.
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 on the ability to drive and use machines.

Prothromplex Total NF contains sodium and heparin

The medicine contains 81.7 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 4.1% of the maximum recommended daily sodium intake in the diet for adults.
Heparin may 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 medications.

3. How to use Prothromplex Total NF

Treatment should be initiated and administered 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 will regularly monitor blood clotting and the patient's clinical condition (see "Information intended exclusively for healthcare professionals").

Method of administration

Intravenous administration.
Administration of Prothromplex Total NF is performed under the supervision of a doctor.
After preparation of 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 administration of Prothromplex Total NF in children.

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 clotting factors (consumption coagulopathy).
During the administration of large doses of human prothrombin complex concentrates, cases of myocardial infarction, increased platelet consumption, and clotting factors, with enhanced thrombus formation in blood vessels (DIC, disseminated intravascular coagulation, consumption coagulopathy), venous thrombosis, and pulmonary embolism have been observed.

Missed dose of Prothromplex Total NF

Not applicable.

Discontinuation of Prothromplex Total NF

Not applicable.
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, this medicine 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 anaphylactic 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

In case of noticing one or more of the above symptoms, the administration of the medicine should be stopped immediately. The doctor should be contacted immediately. Severe symptoms require immediate emergency treatment.
In the case of the use of prothrombin complex concentrates (including Prothromplex Total NF), patients may develop resistance (inhibitors) to one or more clotting factors, which is associated with the inactivation of blood clotting factors. The appearance of such inhibitors may manifest as an inadequate response to treatment.
During treatment with prothrombin complex concentrates, blood clots may form in the bloodstream (thromboembolism). This can lead to complications such as myocardial infarction, increased platelet consumption, and clotting factors, with enhanced thrombus formation in blood vessels (coagulopathy with consumption), 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 (factor 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 limbs, with weight gain and loss of protein 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, stinging, itching, tingling (sensory disturbances)
• reaction at the injection site
• lethargy
• restlessness

Reporting side effects

If side effects occur, including any side effects not listed in the leaflet, the patient should inform their doctor. Side effects can be reported directly to the Department of Adverse Reaction Monitoring of Medicinal Products, Medical Devices, and Biocides
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 outer 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 stated.
During the stated shelf life, this medicine can be stored at room temperature (up to 25°C) for a single period of up to six months. The start and end of storage at room temperature should be recorded 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. Do not return Prothromplex Total NF to the refrigerator.
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 clotting factor II, VII, IX, and X, as well as protein C.

One vial contains at least 400 IU of protein C, copurified with clotting factors.
The other ingredients are: sodium chloride, disodium citrate dihydrate, sodium heparin (0.2–0.5 IU/IU of factor IX), antithrombin III 15–30 IU/vial (0.75–1.5 IU/ml).
Solvent:
Sterile water for injections

What Prothromplex Total NF looks like and what the packaging contains

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 (hydrolytic class I and corresponding class II). The vials are closed with butyl rubber stoppers.
Contents of the packaging

• 1 vial of Prothromplex Total NF powder for solution for injection
• 1 vial of 20 ml sterile water for injections

The product packaging includes one of the following sets:
1 needle with air filter, 1 needle with filter, 1 double-ended needle
1 single-use syringe, 1 triple set (needle with air filter, butterfly needle, and single-use needle), 1 needle with filter, 1 double-ended needle
1 single-use syringe, 1 needle with air filter, 1 butterfly needle, 1 single-use needle, 1 needle with filter, 1 double-ended needle
1 triple set (needle with air filter, butterfly needle, and single-use needle), 1 needle with filter, 1 double-ended needle
1 double-ended needle, 1 needle with filter, 1 needle with air filter, 1 butterfly needle, and 1 single-use needle
1 double-ended needle, 1 needle with filter, 1 single-use syringe, 1 needle with air filter, 1 double set (butterfly needle and single-use needle)
Package size
1 x 600 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 under the following names:

Date of last revision of the leaflet: 10/2024

Information intended exclusively for healthcare professionals:

Dosage and method of administration

Dosage

Except for the treatment of bleeding and the prevention of bleeding during surgery in patients treated with vitamin K antagonists, the following are only general dosage recommendations.
Treatment should be initiated under the supervision of a doctor with experience in treating coagulation disorders.
The dosage and duration of substitution therapy 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.
Determination of individual dosage, according to the patient's needs, is only possible during regular monitoring of the levels of the relevant clotting factors in the patient's plasma or regular determination of the levels of the relevant clotting 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 therapy is necessary using coagulation tests (determination of clotting 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 normalize coagulation parameters (Quick test 100%, INR 1.0).
A practical rule is 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 treatment and the target value.
According to the recommendation given in the publication by Makris et al. 2001, the following dosage recommendations should be followed.

Normalization of hemostasis disorder induced by vitamin K antagonists is maintained for about 6-8 hours. However, the effect of vitamin K administered simultaneously is usually achieved within 4-6 hours. Therefore, in the case of vitamin K administration, repeated administration of prothrombin complex is usually not necessary.
Since these recommendations are empirical, and recovery and duration of action may vary, monitoring of INR during treatment is mandatory.
Bleeding or prevention of bleeding during surgery in congenital deficiency of any of the vitamin K-dependent clotting factors, when a specific factor concentrate is not available:
The required dose for treatment is calculated based on empirical data indicating that approximately 1 IU of factor IX per kg of body weight increases the activity of factor IX in plasma by about 0.015 IU/ml; and 1 IU of factor VII per kg of body weight increases the activity of factor VII in plasma by about 0.024 IU/ml; and 1 IU of factor II or X per kg of body weight increases the activity of factor II or X in plasma by about 0.021 IU/ml.
The dose is determined using the following formula:

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

where 60 (ml/kg) is the inverse 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 conducted by Baxter.
Interactions with other medicines and other types of interactions
When performing coagulation tests sensitive to heparin, in patients receiving high doses of human prothrombin complex, the heparin content should be taken into account as a component of the administered product.

Incompatibilities

This medicine must not be mixed with other medicines except the supplied solvent.
As with other medicines containing clotting factors, the efficacy and tolerability of the medicinal product may be reduced if mixed with other medicines. Before and after administration of Prothromplex Total NF, it is recommended to flush the common venous access with isotonic saline solution.

Special precautions for storage and handling

Only the supplied set should be used for reconstitution.
Prothromplex Total NF should be reconstituted immediately before administration. The solution should then be used immediately (the solution does not contain preservatives).
Ostermann 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 solution is clear or slightly opalescent. Before administration, the solution should always be checked for the presence of insoluble particles and any change in color. If the solution is cloudy or contains sediment, it should be discarded.
Reconstitution of the powder for solution for intravenous injection:

• 1. Warm the closed vial of solvent (sterile water for injections) to room temperature or body temperature (max. 37°C).
• 2. Remove the protective caps from the vials of concentrate and solvent and clean the surfaces of the rubber stoppers of both vials.
• 3. Twist and remove the protective cap from the shorter end of the double-ended needle and insert the needle into the rubber stopper of the solvent vial (Fig. A and Fig. B).
• 4. Remove the protective cap from the other end of the needle, taking care not to touch the exposed end of the needle.
• 5. Invert the solvent vial over the vial of powder and puncture the rubber stopper of the powder vial with the other end of the needle (Fig. D). The vacuum will draw the solvent into the powder vial.
• 6. Separate the two vials by withdrawing the double-ended needle and the solvent vial from the powder vial (Fig. E). Gently rotate the vial of powder to facilitate dissolution.
• 7. After complete dissolution of the powder, insert the needle with air filter (Fig. F), and the foam will settle. Then remove the needle with air filter.

Administration of the solution by injection/infusion:
Before administration, the solution should always be checked for the presence of insoluble particles and any change in color.
Use aseptic technique.

• 1. Twist and remove the protective cap from one end of the supplied needle with filter and attach the needle to a single-use syringe. Draw the solution from the vial into the syringe (Fig. G)
• 2. Detach the needle with filter from the syringe and slowly administer the solution intravenously (the maximum rate of administration in infusion/injection should not exceed 2 ml/min).

After administration, all unpacked needles, together with syringes and/or infusion sets, should be discarded in the packaging of the medicine to avoid exposing others.
Any unused medicinal product or waste material should be disposed of in accordance with local regulations.
Each administration of Prothromplex Total NF to the patient should be recorded in the patient's medical record using the attached self-adhesive label.