Prothromplex total nf

Package leaflet: information for the patient

Prothromplex Total NF, 600 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 you.

• Keep this leaflet so that you can read it again if necessary.
• If you have any further questions, please consult your doctor.
• If you experience any adverse reactions, including any not listed in this leaflet, inform your doctor or pharmacist immediately. See section 4.

Leaflet contents

1. What Prothromplex Total NF is and what it is used for
2. Important information before administration of 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 made from human plasma (the fluid part of blood). It contains blood clotting factors II, VII, IX, and X (vitamin K-dependent coagulation 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 usual, leading to an increased tendency to bleed.

Prothromplex Total NF is used:

• to treat bleeding episodes,
• to prevent bleeding before and after surgery,
• in acquired or congenital deficiencies of clotting factors.

Acquired deficiency:
A deficiency of vitamin K-dependent clotting factors (acquired deficiency) may develop in patients, for example, due to treatment with drugs that reduce the action of vitamin K (so-called vitamin K antagonists) or overdose of such drugs.
Congenital deficiency:
If a patient was born with a deficiency (congenital deficiency), this medicine may be administered immediately before or after surgery 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 a reduced number of platelets (cells important for blood clotting) related to heparin administration (heparin-induced thrombocytopenia).

Warnings and precautions
Traceability
It is strongly recommended that each time Prothromplex Total NF is administered, the name and batch number of the product should be recorded, in order to maintain information about the batches used.
Before starting treatment with Prothromplex Total NF, 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 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 be used only in emergency situations requiring rapid replacement 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 drugs (medicines 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 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 (embolism).
• 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 the above cases, the doctor will carefully assess the benefits of using Prothromplex Total NF against the potential risks of the complications listed above.
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 medicines derived from human blood or plasma are administered, it cannot be completely ruled out that transmission of infection may occur. This includes unknown or newly emerging viruses and other types of infections.
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. Parvovirus B19 infection may be dangerous

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

For patients receiving regular or repeated infusions of 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 any other medicines you are currently taking, have recently taken, or plan to take.
Inform your treating physician if the patient is taking anticoagulant drugs (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 or 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 when 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 on the effect on the ability to drive and operate machinery.
Prothromplex Total NF contains sodium and heparin
The medicine contains 81.7 mg of sodium per vial or 0.14 mg of sodium (main component of table salt) per 1 international unit (IU). This corresponds to 4.1% of the maximum recommended daily dietary sodium intake for adults.
Heparin may cause allergic reactions and reduction in blood cell counts, which may affect the blood clotting 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 and administered by a physician experienced in
the treatment 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 condition (see section "Information intended exclusively for medical professionals").
Method of administration
Intravenous administration.
Administration of Prothromplex Total NF must be performed under medical supervision.
After reconstitution with the sterile water for injection provided, Prothromplex Total NF is administered slowly into a vein (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 the use of Prothromplex Total NF in children.
If more Prothromplex Total NF has been administered than recommended
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 administering high doses of human prothrombin complex concentrates, cases of myocardial infarction, increased consumption of platelets and coagulation factors with enhanced intravascular clot formation (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.
If you have any further questions regarding the use of this medicine, please consult your physician.

4. Possible adverse reactions

Like all medicines, 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 immediate allergic reaction (anaphylactic reaction). In individual cases, this may lead to a severe hypersensitivity reaction, including shock.
Therefore, attention should be paid to potential early signs of an allergic reaction, such as:

• erythema (redness 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, administration of the medicine must be stopped immediately. Contact a doctor 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 coagulation factors, resulting in inactivation of blood coagulation 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 coagulation 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 using the medicine
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)
• 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), redness of the skin (hot flushes)
• blockage of a pulmonary vessel by a blood clot (pulmonary artery 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 swelling of eyelids, face and lower limbs, 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 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 any adverse reactions not listed in this leaflet, inform a 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
Tel.: +48 22 49 21 301
Fax: +48 22 49 21 309
Website: https://smz.ezdrowie.gov.pl
Adverse reactions can also be reported to the marketing authorization holder.
Reporting adverse reactions helps to provide 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 stated month.
During the stated shelf life, this medicine may be stored once at room temperature (up to 25°C) for a single period of up to six months. The start and end dates of room temperature storage must 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. Do not return Prothromplex Total NF to the refrigerator.
The reconstituted solution should be used immediately after preparation.
Medicines must not be disposed of via the sewage system or in household waste. Ask a pharmacist how to dispose of medicines no longer in use. This will help protect the environment.

6. Contents of the packaging 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, as well as protein C.

One vial contains at least 400 IU of Protein C, co-purified with coagulation factors.
Other ingredients are: sodium chloride, dibasic sodium 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 contents of the pack
Powder and solvent for solution for injection.
Prothromplex Total NF is a white to slightly yellow lyophilized, brittle or solidified dry substance.
The pH value of the solution after reconstitution 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 (hydrolytic class I and correspondingly class II). The vials are closed with butyl rubber stoppers.

Contents of the pack:

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

One of the following sets is included in the product package:
1 needle with vent, 1 filter needle, 1 double-ended needle
1 single-use syringe, 1 triple set (needle with vent, butterfly needle and single-use needle), 1 filter needle, 1 double-ended needle
1 single-use syringe, 1 needle with vent, 1 butterfly needle, 1 single-use needle, 1 filter needle, 1 double-ended needle
1 triple set (needle with vent, butterfly needle and single-use needle), 1 filter needle, 1 double-ended needle
1 double-ended needle, 1 filter needle, 1 needle with vent, 1 butterfly needle and 1 single-use needle
1 double-ended needle, 1 filter needle, 1 single-use syringe, 1 needle with vent, 1 double set (butterfly needle and single-use needle)

Pack size
1 x 600 IU

Marketing Authorisation Holder and Manufacturer
Marketing Authorisation Holder
Takeda Pharma Sp. z o.o.
Prosta 68 Street
00-838 Warsaw
Poland

Manufacturer
Takeda Manufacturing Austria AG
Industriestrasse 67
1221 Vienna
Austria

This medicinal product is authorised for sale in the European Economic Area countries under the following names:

Information intended exclusively for medical professionals:
Dosage and method of administration
Dosage
Except for the treatment of bleeding and perioperative prophylaxis of bleeding during therapy with vitamin K antagonists, the following are only general dosage recommendations.
Treatment should be initiated under the supervision of a physician experienced in the management of 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.
The intervals between doses must be determined considering the different half-lives of the individual prothrombin complex factors.
Individual dosage adjustment according to the patient's requirements is only possible through regular monitoring of the plasma levels of the relevant clotting factors, regular measurement of specific clotting factor levels, or tests assessing overall levels of all prothrombin complex factors (e.g., Quick's percentage, prothrombin time, INR), along with continuous monitoring of the patient's clinical status.
For major surgical procedures, precise monitoring of replacement therapy using coagulation tests (measurement of clotting factors and/or tests assessing overall levels of all prothrombin complex factors) is essential.
Bleeding or perioperative prophylaxis of bleeding during treatment with vitamin K antagonists:
In severe hemorrhage or prior to surgical procedures with a high risk of bleeding, normalization of coagulation parameters should be achieved (Quick's percentage 100%, INR 1.0).
A practical rule applies that 1 IU of factor IX per kg of body weight increases the Quick's percentage by approximately 1%.
If Prothromplex Total NF administration is based on INR measurement, the dose will depend on the pre-treatment INR value and the target INR.
According to the recommendation provided by Makris et al. 2001, the dosing recommendations given 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 simultaneously administered vitamin K is usually achieved within 4-6 hours. Therefore, when vitamin K is given, repeated administration of human prothrombin complex concentrate is usually not necessary.

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 coagulation 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 body weight increases plasma factor IX activity by about 0.015 IU/mL; and 1 IU of factor VII per kg body weight increases plasma factor VII activity by about 0.024 IU/mL. One IU of factor II or X per kg body weight increases plasma factor II or X activity by approximately 0.021 IU/mL.

The administered dose of the given factor is expressed in international units (IU), which refer to the current WHO standard for each coagulation factor. The activity of a given coagulation factor in plasma 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 (IU) of coagulation factor activity corresponds to the content in 1 mL of normal human plasma. For example, calculation of the required treatment dose of factor X is based on the empirical observation that 1 international unit (IU) of factor X per kg body weight increases plasma factor X activity by approximately 0.017 IU/mL. The required dose is determined 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 in children and adolescents have not been established in clinical trials conducted by Baxter.

Interactions with other medicinal products and other forms of interaction:

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

Pharmaceutical incompatibilities

This medicinal product must not be mixed with other medicinal products except the provided solvent.

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

Special precautions for storage and preparation for use

Only the provided reconstitution kit should be used.

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, always check whether the solution contains insoluble particles or has changed color. If the solution is cloudy or contains a precipitate, it must be discarded.

Reconstitution of the powder for injection solution:

Use aseptic technique.

1. Warm the vial containing the solvent (sterile water for injection) to room temperature or body temperature (max. 37°C).
2. Remove the protective caps from both vials (concentrate and solvent) (Fig. A) and clean the rubber stoppers of both vials.
3. Twist and remove the protective cover from the shorter end of the double-ended needle and insert the needle into the rubber stopper of the solvent vial (Fig. B and Fig. C).
4. Remove the cover 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 powder vial and pierce the rubber stopper of the powder vial with the needle end (Fig. D). The vacuum will draw the solvent into the powder vial.
6. Disconnect the two vials by pulling the double-ended needle with the solvent vial out of the powder vial (Fig. E). Gently rotate the powder vial to accelerate dissolution.
7. After complete dissolution of the powder, insert the venting needle (Fig. F); any foam formed will dissipate. Then remove the venting needle.

Administration of the solution by injection/infusion:

Before administration, always check whether the solution contains insoluble particles or has changed color.

Use aseptic technique.

1. Twist and remove the protective cover from one end of the provided filter needle and attach the needle to a sterile single-use syringe. Draw the solution from the vial into the syringe (Fig. G).
2. Disconnect the filter needle from the syringe and slowly administer the solution intravenously (maximum infusion/injection rate should not exceed 2 mL/min).

After administration, all unpacked needles, together with syringes and (or) infusion sets, should be discarded in the medicine carton to avoid endangering others.

Any unused portions of the medicinal product or waste material must be disposed of in accordance with local regulations.

Each administration of Prothromplex Total NF to a patient must be documented in the patient's medical records using the attached self-adhesive label.