Proplex
Italy
Table of Contents
Package leaflet: Information for the patient
PROPLEX
600 IU Powder and solvent for injectable solution
Active substance: human prothrombin complex
Please read this leaflet carefully before being given this medicine because it contains important information for you.
- Keep this leaflet. You may need to read it again.
- If you have any questions, consult your doctor.
- If you experience any side effects, including those not listed in this leaflet, contact your doctor or pharmacist. See section 4. Contents of this leaflet
- What PROPLEX is and what it is used for
- What you need to know before using PROPLEX
- How to use PROPLEX
- Possible side effects
- How to store PROPLEX
- Contents of the pack and other information
1. What PROPLEX is and what it is used for
PROPLEX is a preparation obtained from human plasma (the liquid portion of blood). It contains
blood coagulation factors II, VII, IX, and X (prothrombin complex coagulation factors)
as well as protein C. These vitamin K-dependent coagulation factors, similarly to vitamin K itself,
play an important role in blood coagulation. In case of deficiency of one of these factors,
blood does not clot as rapidly as it should, resulting in an increased tendency to
bleeding.
PROPLEX is used for:
- treatment of bleeding
- prevention of bleeding immediately before or after surgery
- acquired and congenital deficiencies of coagulation factors
Acquired deficiency:
You may develop a deficiency of vitamin K-dependent coagulation factors (acquired deficiency),
for example, as a result of treatment with medications that reduce the effect of vitamin K (so-called
vitamin K antagonists) or due to an overdose of such medications.
Congenital deficiency:
If you were born with a deficiency (congenital deficiency), this medicine may be administered to you immediately
before or after surgery when a specific single-factor concentrate is not available.
2. What you should know before using PROPLEX
Do not use PROPLEX
- if you are allergic to coagulation factors or to any of the other ingredients of this medicine (listed in section 6)
- if you have confirmed or suspected heparin-induced reduction in blood platelets (heparin-induced thrombocytopenia); platelets are important cells for blood clotting.
Warnings and precautions
Traceability
It is strongly recommended that, each time you receive a dose of PROPLEX, the product name and batch number are recorded, in order to maintain traceability of the batches used.
Talk to your doctor before using PROPLEX
- because there is a rare possibility that you may develop a severe, sudden allergic reaction (anaphylactic reaction) to PROPLEX, as such allergic reactions have been reported with PROPLEX. More detailed information on the initial symptoms of such an allergic reaction is provided in section 4 “Possible side effects”.
- if you have an acquired deficiency of vitamin K-dependent coagulation factors. This acquired deficiency may be caused by treatment with medicines that inhibit blood clotting by blocking vitamin K. In this case, PROPLEX should only be administered when rapid correction of the levels of vitamin K-dependent coagulation factors is required, such as in cases of severe bleeding or emergency surgery. In all other cases, reducing the dose of vitamin K antagonists or administering vitamin K is sufficient.
- if you are receiving medicines that inhibit blood clotting (vitamin K antagonists). You may have an increased tendency towards blood clotting, which may be enhanced by infusion of human prothrombin complex concentrate.
- if you have a congenital deficiency of a vitamin K-dependent coagulation factor, your doctor will administer a specific single-factor concentrate, if available.
- if you are being treated with a prothrombin complex concentrate, particularly with repeated administrations, because blood clots (thrombosis) may develop, which could enter the bloodstream (embolism).
- due to the risk of developing blood clots, if you belong to one of the following patient groups:
- patients with coronary artery disease or history of myocardial infarction
- patients with liver disease
- patients in pre- or post-operative phases
- newborns
- patients at risk of thromboembolic complications or disseminated intravascular coagulation (DIC)
In all these situations, your doctor will carefully evaluate the benefits of treatment with PROPLEX against the potential risk of these complications.
Viral safety
When medicines are manufactured from human blood or plasma, certain measures are taken to prevent transmission of infections to patients. These include
- careful selection of blood and plasma donors to exclude those at risk of transmitting infections,
- testing of each donation and plasma pool for signs of viruses/infections,
- inclusion of manufacturing steps that can inactivate or remove viruses. Despite these measures, when medicines derived from human blood or plasma are administered, the possibility of transmitting infection cannot be completely excluded. This also applies to unknown or emerging viruses or 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 against the non-enveloped hepatitis A virus. However, the measures may have limited effectiveness against non-enveloped viruses such as parvovirus B19. Parvovirus B19 infection may be severe in pregnant women (fetal infection) and in individuals with weakened immune systems or certain types of anemia (e.g. sickle cell anemia or hemolytic anemia). Your doctor may recommend considering vaccination against hepatitis A and B if you are receiving regular or repeated administration of plasma-derived prothrombin complex concentrates. It is strongly recommended that, each time you receive a dose of PROPLEX, the product name and batch number are recorded to maintain traceability of the batches used. Children and adolescents The safety and efficacy of PROPLEX in patients under 18 years of age have not been evaluated in clinical studies.
Other medicines and PROPLEX
Tell your doctor or pharmacist if you are taking, have recently taken, or might take any other medicines.
Inform your treating physician if you are receiving medicines that inhibit blood clotting (vitamin K antagonists). You may have an increased tendency towards blood clotting, which may be enhanced by infusion of human prothrombin complex concentrate.
Interference with laboratory tests:
When performing coagulation tests that are sensitive to heparin in patients treated with high doses of human prothrombin complex concentrate, the heparin content of the administered product should be taken into account.
Pregnancy, breast-feeding and fertility
If you are pregnant, suspect you may be pregnant, plan to become pregnant, or are breast-feeding, consult your doctor or pharmacist before using this medicine.
PROPLEX should be used during pregnancy and breast-feeding only if clearly indicated.
There is no information available on the effects of PROPLEX on fertility.
Driving and using machines
No studies have been performed regarding the effects on the ability to drive vehicles or use machines.
Proplex contains sodium and heparin
This medicine contains 81.7 mg of sodium per vial or 0.14 mg of sodium (main component of table salt) per International Unit. This corresponds to 4.1% of the maximum daily recommended dietary intake for an adult.
Heparin may cause allergic reactions and a reduction in red blood cells that may impair blood clotting. If you have previously experienced allergic reactions caused by heparin, do not take medicines containing heparin.
3. How to use PROPLEX
Treatment must be initiated, administered, and monitored by a physician experienced in the treatment of
coagulation disorders.
The required amount of PROPLEX and the duration of treatment depend on several factors, including body
weight, severity of the disorder, location and extent of bleeding, or the need to prevent bleeding during surgical procedures.
Your physician will determine the appropriate dosage for you and will regularly monitor your coagulation parameters and clinical condition (see section “ The following information is intended exclusively for healthcare professionals”).
Method of administration
For intravenous use.
Administration of PROPLEX must be supervised by a physician.
After reconstitution with sterile water for injections supplied in the package, PROPLEX must be administered slowly into a vein (intravenously). The rate of administration depends on your clinical condition and must not exceed 2 ml per minute (60 IU/min).
Use in children and adolescents:
Available data are insufficient to recommend administration of PROPLEX in patients under 18 years of age.
If you use more PROPLEX than you should
In case of overdose, there is a risk of developing thromboembolic complications or consumptive coagulopathy.
When high doses of human prothrombin complex concentrates are administered, myocardial infarction, increased consumption of blood platelets and coagulation factors, marked formation of clots in blood vessels (DIC, disseminated intravascular coagulation, consumptive coagulopathy), venous thrombosis, and pulmonary embolism have been observed.
If you forget to take PROPLEX
Not applicable
If you stop taking PROPLEX
Not applicable
If you have any doubts about the use of this medicine, consult your doctor.
4. Possible side effects
Like all medicines, this medicine can cause side effects, although not everybody gets them.
As with all therapies containing plasma derivatives, there is a possibility that you may develop an immediate allergic reaction (anaphylactic reaction). In individual cases, a severe hypersensitivity reaction, including shock, may occur.
Therefore, please pay attention to the possible early symptoms of an allergic reaction, such as:
- erythema (reddening of the skin)
- skin rash
- appearance of hives on the skin
- itching in any part of the body
- swelling of the lips and tongue
- difficulty breathing/dyspnoea
- chest tightness
- general malaise
- dizziness
- drop in blood pressure
If you notice one or more of these symptoms, stop the infusion immediately. Call your doctor immediately. Severe symptoms require immediate emergency treatment.
During treatment with prothrombin complex concentrates (including PROPLEX), patients may develop resistance (inhibitors) to one or more of the coagulation factors, resulting in inactivation of blood coagulation factors. The development of such inhibitors may manifest as an inadequate response to treatment.
During treatment with prothrombin complex concentrates, blood clots (thrombosis) may develop which can enter the bloodstream (embolism). This may cause complications such as heart attack, increased consumption of platelets and blood coagulation factors with marked formation of blood clots in blood vessels (consumption coagulopathy), blockage of veins by blood clots (venous thrombosis), and blockage of a blood vessel in the lungs by a blood clot (pulmonary embolism).
The following side effects may affect up to 1 in 10 people during treatment with PROPLEX:
- formation of blood clots throughout the body (disseminated intravascular coagulation), resistance (inhibitors) to one or more of the prothrombin complex factors (factors II, VII, IX, X)
- severe immediate allergic reaction (anaphylactic shock), anaphylactic reaction, hypersensitivity, stroke, headache
- heart attack (acute myocardial infarction), rapid heartbeat (tachycardia)
- arterial thrombosis, venous thrombosis, drop in blood pressure (hypotension), reddening of the skin (flushing)
- blockage of a blood vessel in the lungs by a blood clot (pulmonary embolism), difficulty breathing, shortness of breath (dyspnoea), wheezing
- vomiting, feeling of illness (nausea)
- hives over the entire body, skin rash (erythematous rash), itching
- a specific kidney disorder with symptoms such as swelling of the eyelids, face and lower limbs, weight gain and loss of protein in the urine (nephrotic syndrome)
- fever (pyrexia)
The following side effects have been observed with other prothrombin complex concentrates:
- swelling of the face, tongue and lips (angioedema), burning sensation, itching or tingling of the skin (paraesthesia)
- infusion site reaction
- lethargy
- restlessness
Reporting of side effects
If you experience any side effect, including those not listed in this leaflet, talk to your doctor. You can also report side effects directly via the national adverse reactions reporting system.
By reporting side effects, you can help provide more information on the safety of this medicine.
5. How to store PROPLEX
Store in a refrigerator (2°C - 8°C). Do not freeze.
Keep in the original packaging to protect the medicine from light.
Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date stated on the label and carton after "Exp.".
The expiry date refers to the last day of that month.
During the shelf life, the product may be stored at room temperature (up to 25°C) for a single period not exceeding six months.
The start and end dates of the room temperature storage period must be recorded on the packaging. After storage at room temperature,
PROPLEX must not be returned to the refrigerator (2°C - 8°C), but must be used within 6 months or disposed of.
The ready-to-use solution should be used immediately.
Do not dispose of any medicine via wastewater or household waste. Ask your pharmacist how to dispose of medicines you no longer use.
This will help protect the environment.
6. Contents of the pack and other information
What PROPLEX contains
Powder:
- The active substance is Human Prothrombin Complex, composed of human coagulation Factors II, VII, IX, and X and protein C.
| Per vial UI | After reconstitution in 20 ml of sterile water for injectable preparations UI/ml | |
| Human coagulation Factor II | 450 - 850 | 22.5 – 42.5 |
| Human coagulation Factor VII | 500 | 25 |
| Human coagulation Factor IX | 600 | 30 |
| Human coagulation Factor X | 600 | 30 |
One vial contains at least 400 IU of protein C, co-purified with blood coagulation factors.
The other components are:
sodium chloride, disodium citrate dihydrate, sodium heparin (0.2 – 0.5 IU/IU Factor IX), and antithrombin III 15 – 30 IU per vial (0.75 – 1.5 IU/ml).
Solvent:
Sterile water for injections.
Description of the appearance of PROPLEX and contents of the pack
Powder and solvent for solution for injection.
PROPLEX is a lyophilized powder or compact dry substance, white to pale yellow in colour.
After reconstitution, the pH of the solution ranges between 6.5 and 7.5 and osmolality must not be less than 240 mOsm/kg. The solution is clear or slightly opalescent.
The powder and solvent are supplied in single-dose glass vials (hydrolytic class I and II, respectively).
The vials are closed with butyl rubber stoppers.
Pack contents:
- 1 vial of PROPLEX powder for solution for injection
- 1 vial of 20 ml sterile water for injections
- 1 venting needle, 1 butterfly needle, 1 disposable needle, 1 filter needle, 1 transfer needle
Pack size: 1 x 600 IU
Marketing Authorization Holder and Manufacturer
Marketing Authorization Holder
Baxalta Innovations GmbH
Industriestrasse 67
A-1221 Vienna
Austria
Local representative in Italy: Takeda Italia S.p.A.
Tel. +39 06 502601
Manufacturer
Takeda Manufacturing Austria AG
Industriestrasse 67
1221 Vienna, Austria
This medicinal product is authorized in the European Economic Area Member States under the following
names:
| Austria: | Prothromplex TOTAL 600 I.E. Powder and solvent for solution for injection |
| Belgium, Luxembourg: | Prothromplex 600 UI, powder and solvent for injectable solution |
| Bulgaria: | Prothromplex Total NF 600 IU |
| Czech Republic, Poland: | Prothromplex Total NF |
| Denmark, Norway, Portugal: | Prothromplex |
| Estonia, Greece: | Prothromplex TOTAL |
| Germany: | Prothromplex NF 600 |
| Hungary: | Prothromplex TOTAL 600 NE |
| Ireland, Malta, United Kingdom: | Prothromplex TOTAL 600 IU |
| Italy: | PROPLEX |
| Lithuania: | Prothromplex 600 TV powder and solvent for injection solution |
| Latvia: | Prothromplex 600 SV powder and solvent for preparation of injection solution |
| Netherlands: | Prothromplex 600 IE powder and solvent for solution for injection |
| Romania: | Prothromplex TOTAL 600 IU powder and solvent for injectable solution |
| Slovakia: | Prothromplex NF 600 IU |
| Slovenia: | PROPLEX 600 i.e. powder and vehicle for solution for injection |
| Spain: | Prothromplex Total 600 UI |
The following information is intended for healthcare professionals only:
Dosage and method of administration
Dosage
The following are general guidelines for administration, except for the treatment of
bleeding and perioperative bleeding prophylaxis during treatment with vitamin K antagonists.
Treatment must 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 site and extent of bleeding, and the patient's clinical condition.
The dosage and frequency of administration must be individually calculated for each patient. The dosing intervals should be adjusted according to the different circulating half-lives of the various coagulation factors contained in the prothrombin complex.
The required dosage for each individual patient can only be determined based on regular measurements of individual plasma levels of the relevant coagulation factors or through global tests of prothrombin complex levels (e.g., Quick time value, INR, prothrombin time), along with continuous monitoring of the patient's clinical condition.
In the case of major surgical procedures, careful monitoring of replacement therapy using coagulation tests (specific factor assays and/or global tests of prothrombin complex levels) is essential.
Bleeding and perioperative bleeding prophylaxis during treatment with vitamin K antagonists:
In cases of severe hemorrhage or prior to surgical procedures with a high risk of bleeding, the aim should be to achieve normal values (Quick time value of 100%, INR 1.0). The following general rule applies: 1 IU of factor IX per kg of body weight increases the Quick time value by approximately 1%.
If PROPLEX administration is based on INR value, the dose will depend on the INR value before treatment and the target INR value.
The dosage reported in the following table should be followed according to the recommendation in the publication by Makris et al., 2001.
| PROPLEX dosing according to initial INR value | |
| INR | Dose, IU/kg (IU refers to factor IX) |
| 2.0–3.9 | 25 |
| 4.0–6.0 | 35 |
| >6.0 | 50 |
The correction of vitamin K antagonist-induced coagulation impairment lasts approximately 6–8 hours. However, the effects due to vitamin K, when administered simultaneously, are generally achieved within 4–6 hours. Therefore, repeated treatment with human prothrombin complex concentrate is generally not required when vitamin K has been administered.
Since these are empirical recommendations and recovery and duration of effect may vary, monitoring of the INR value is mandatory during treatment.
Bleeding and perioperative prophylaxis in case of congenital deficiency of any vitamin K-dependent coagulation factor, when a specific factor concentrate is not available:
The calculation of the required treatment dose is based on the empirical observation 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 of body weight 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 0.021 IU/mL.
The dose of a specific factor administered is expressed in International Units (IU), relative to the current WHO standard for each factor. The plasma activity of a specific coagulation factor is expressed as a percentage (relative to normal human plasma) or in International Units (relative to the international standard for specific factor concentrates).
One International Unit (IU) of coagulation factor activity is equivalent to the amount present in 1 mL of normal human plasma.
The following formula may be used to estimate the required dosage:
For example, the calculation of the required dose of factor X is based on the empirical finding that 1 International Unit (IU) of factor X per kg of body weight increases plasma factor X activity by 0.017 IU/mL. The required dosage is determined using the following formula:
Units required = body weight (kg) × desired increase in factor IX (IU/mL) × 60
where 60 (mL/kg) is the reciprocal of the estimated recovery.
If the individual recovery value is known, this value should be used for the calculation.
Maximum single dose:
To correct the INR value, it is not necessary to exceed a dose of 50 IU/kg. If the severity of bleeding requires a higher dose, the risk/benefit ratio must be evaluated by the treating physician.
Paediatric population
The safety and efficacy of PROPLEX use in paediatric patients have not been established in Baxter clinical studies.
Interactions with other medicinal products and other forms of interaction
When high doses of PROPLEX are administered, the heparin content of the preparation must be taken into account when performing coagulation assays sensitive to heparin.
Incompatibilities
This medicinal product must not be mixed with other medicinal products except with the solvent supplied in the package.
As with all preparations containing coagulation factors, the efficacy and tolerability of this medicinal product may be compromised by mixing with other medicinal products. It is advisable to flush a common venous access with isotonic saline solution before and after administration of PROPLEX.
Special precautions for disposal and handling
Only the reconstitution set supplied in the package must be used for reconstitution.
Reconstitute PROPLEX only 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 inspect the reconstituted solution visually for the presence of suspended particles or discoloration. Solutions that are cloudy or contain precipitate must be discarded.
Reconstitution of the powder for injectable solution:
Use an aseptic technique!
- Warm the closed vial containing the solvent (sterile water for injections) to room or body temperature (maximum 37°C).
- Remove the protective caps from the powder vial and the solvent vial (Fig. A), and clean the rubber stoppers of both vials.
- Remove the protective cover from one end of the transfer needle supplied by rotating it, then insert the needle through the rubber stopper of the solvent vial (Fig. B and C).
- Remove the protective cover from the other end of the transfer needle, taking care not to touch the exposed end!
- Invert the solvent vial above the powder vial and insert the transfer needle’s end through the rubber stopper of the powder vial (Fig. D). The solvent will be drawn into the powder vial by vacuum.
- Disconnect the two vials by removing the transfer needle, together with the solvent vial, from the powder vial (Fig. E). Gently swirl the powder vial to accelerate dissolution.
- Once the powder is completely dissolved, insert the vent needle supplied (Fig. F); any foam formed will dissipate. Remove the vent needle.
Injection/Infusion: Before administration, the reconstituted solution must always be visually inspected for suspended particles or abnormal discoloration. Use an aseptic technique!
- Remove the protective cover from one end of the filter needle supplied by rotating it, then attach the filter needle to a sterile disposable syringe. Draw the solution into the syringe (Fig. G).
- Disconnect the filter needle from the syringe and administer the solution slowly by intravenous route (maximum infusion/injection rate: 2 mL per minute).
Fig.A Fig.B Fig.C Fig.D Fig.E Fig.F Fig.G
After administration, dispose of all open needles, together with the syringe and/or infusion set, into the product box to prevent endangering others.
Unused medicine and waste material derived from this medicine must be disposed of in accordance with local regulations.
Document each administration of PROPLEX in the patient’s medical record using the self-adhesive label supplied.
Package leaflet: Information for the user
PROPLEX
500 IU Powder and solvent for injectable solution
Human prothrombin complex
Read this leaflet carefully before being administered this medicine because
it contains important information for you.
- Keep this leaflet. You may need to read it again.
- If you have any questions, consult your doctor or pharmacist.
- If you experience any side effects, including those not listed in this leaflet, consult your doctor or pharmacist. See section 4. Contents of this leaflet:
- What PROPLEX is and what it is used for
- What you need to know before using PROPLEX
- How to use PROPLEX
- Possible side effects
- How to store PROPLEX
- Contents of the pack and other information
1. What PROPLEX is and what it is used for
PROPLEX is a preparation derived from human plasma (the liquid component of blood). It contains
blood coagulation factors II, VII, IX, and X (prothrombin complex coagulation factors) as well as
protein C.
These coagulation factors are vitamin K-dependent and, like vitamin K, play an important role in blood
coagulation. In case of deficiency of one of these factors, blood does not clot as quickly as it should,
leading to an increased tendency to bleed.
PROPLEX is used for:
- treatment of bleeding
- prevention of bleeding immediately before or after surgery
- acquired and congenital deficiencies of coagulation factors
Acquired deficiency:
You may develop a deficiency of vitamin K-dependent coagulation factors (acquired deficiency), for
example following treatment with medications that reduce the effect of vitamin K (so-called vitamin K
antagonists) or due to an overdose of such medications.
Congenital deficiency:
If you were born with a deficiency (congenital deficiency), this medicine may be administered
immediately before or after surgery when a specific single-factor concentrate is not available.
2. What you need to know before using PROPLEX
Do not use PROPLEX
- if you are allergic to coagulation factors or to any of the other ingredients of this medicine (listed in section 6)
- if you have confirmed or suspected heparin-induced reduction in blood platelets (heparin-induced thrombocytopenia); platelets are important cells for blood clotting.
Warnings and precautions
Talk to your doctor before using PROPLEX
- because there is a rare possibility that you may develop a severe, sudden allergic reaction (anaphylactic reaction) to PROPLEX, as such allergic reactions have been reported with PROPLEX. More detailed information on the initial symptoms of such an allergic reaction is provided in section 4 “Possible side effects”.
- if you have an acquired deficiency of vitamin K-dependent coagulation factors. This acquired deficiency may be caused by treatment with medicines that inhibit blood clotting by blocking vitamin K. In this case, PROPLEX should only be administered when rapid correction of vitamin K-dependent coagulation factor levels is required, for example in cases of severe bleeding or emergency surgery. In all other cases, reducing the dose of vitamin K antagonists or administering vitamin K is sufficient.
- if you are receiving medicines that inhibit blood clotting (vitamin K antagonists). You may have an increased tendency towards blood clotting, which may be enhanced by infusion of human prothrombin complex concentrate.
- if you have a congenital deficiency of a vitamin K-dependent coagulation factor, your doctor will administer a specific single-factor concentrate, if available.
- if you are being treated with a prothrombin complex concentrate, particularly with repeated administrations, because blood clots (thrombosis) may develop, which could enter the bloodstream (embolism).
- due to the risk of developing blood clots, if you belong to any of the following patient groups:
- patients with coronary artery disease or myocardial infarction
- patients with liver disease
- patients in pre- or post-operative phases
- newborns
- patients at risk of thromboembolic complications or disseminated intravascular coagulation (DIC)
In all these situations, your doctor will carefully weigh the benefits of treatment with PROPLEX against the potential risks of these complications.
Traceability
It is strongly recommended that, each time you receive a dose of PROPLEX, the product name and batch number are recorded, in order to maintain traceability of the batches used.
Viral safety
When medicines are manufactured from human blood or plasma, certain measures are taken to prevent transmission of infections to patients. These include:
- careful selection of blood and plasma donors to exclude those at risk of transmitting infections,
- testing of each donation and plasma pool for signs of viruses/infections,
- inclusion of manufacturing steps that can inactivate or remove viruses.
Despite these measures, when medicines derived from human blood or plasma are administered, the possibility of transmitting an infection cannot be completely ruled out. This also applies to unknown or emerging viruses or 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 against the non-enveloped hepatitis A virus. The measures may have limited effectiveness against non-enveloped viruses such as parvovirus B19. Parvovirus B19 infection can be serious for:- pregnant women (fetal infection)
- individuals with suppressed immune systems or suffering from certain types of anemia (e.g. sickle cell anemia or hemolytic anemia).
Your doctor may recommend considering vaccination against hepatitis A and B if you are receiving regular or repeated administrations of plasma-derived prothrombin complex concentrates.
Children and adolescents
The safety and efficacy of PROPLEX in patients under 18 years of age have not been established in clinical studies.
Other medicines and PROPLEX
Tell your doctor or pharmacist if you are taking, have recently taken, or might take any other medicines.
Inform your treating physician if you are receiving medicines that inhibit blood clotting (vitamin K antagonists). You may have an increased tendency towards blood clotting, which may be enhanced by infusion of human prothrombin complex concentrate.
Interference with biological tests
When performing coagulation tests that are sensitive to heparin in patients treated with high doses of human prothrombin complex, the heparin content of the administered product should be taken into account.
Pregnancy, breastfeeding and fertility
If you are pregnant, think you may be pregnant, are planning a pregnancy, or are breastfeeding, consult your doctor or pharmacist before using this medicine.
PROPLEX should only be used during pregnancy and breastfeeding if clearly indicated.
There is no information available on the effects of PROPLEX on fertility.
Driving and use of machines
No studies have been conducted regarding the effects on the ability to drive vehicles or use machinery.
Proplex 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 International Unit. This corresponds to 3.4% of the maximum daily recommended dietary intake for an adult.
Heparin may cause allergic reactions and a reduction in red blood cells, which may impair blood clotting. If you have previously experienced allergic reactions caused by heparin, do not take medicines containing heparin.
3. How to use PROPLEX
Treatment must be initiated, administered, and monitored by a physician experienced in the treatment of
coagulation disorders.
The required dose of PROPLEX and the duration of treatment depend on several factors, including body
weight, severity of the disorder, location and extent of bleeding, or the need to prevent bleeding during surgical procedures.
Your physician will determine the appropriate dosage for you and will regularly monitor your coagulation parameters and clinical condition (see section “ The following information is intended exclusively for healthcare professionals”).
Method of administration
For intravenous use.
Administration of PROPLEX must be supervised by a physician.
After reconstitution with sterile water for injection supplied in the package, PROPLEX must be administered slowly into a vein (intravenously). The rate of administration depends on your clinical condition and must not exceed 2 ml per minute (60 IU/min).
Use in children and adolescents:
Available data are insufficient to recommend administration of PROPLEX in patients under 18 years of age.
If you use more PROPLEX than you should
In case of overdose, there is a risk of developing thromboembolic complications or consumption coagulopathy.
When high doses of human prothrombin complex concentrates are administered, myocardial infarction, increased consumption of blood platelets and coagulation factors, marked clot formation in blood vessels (DIC, disseminated intravascular coagulation, consumption coagulopathy), venous thrombosis, and pulmonary embolism have been observed.
If you have any doubts about the use of this medicinal product, consult your doctor.
4. Possible side effects
Like all medicines, this medicine can cause side effects, although not everybody gets them.
As with all therapies containing plasma derivatives, there is a possibility that you may develop an immediate allergic reaction (anaphylactic reaction). In individual cases, a severe hypersensitivity reaction, including shock, may occur.
Therefore, please pay attention to the following possible early symptoms of an allergic reaction:
- erythema (redness of the skin)
- skin rash
- appearance of hives on the skin
- itching anywhere on the body
- swelling of the lips and tongue
- difficulty breathing/dyspnea
- chest tightness
- general malaise
- dizziness
- drop in blood pressure
If you notice one or more of these symptoms, inform your doctor immediately, who will stop the infusion at once. Severe symptoms require immediate emergency treatment.
During treatment with prothrombin complex concentrates (including PROPLEX), patients may develop resistance (inhibitors) to one or more of the blood clotting factors, resulting in inactivation of blood clotting factors. The development of such inhibitors may manifest as an inadequate response to treatment.
During treatment with prothrombin complex concentrates, blood clots (thrombosis) may develop which can enter the bloodstream (emboli). This may cause complications such as heart attack, increased consumption of platelets and blood clotting factors with marked formation of blood clots in blood vessels (consumption coagulopathy), blockage of veins by blood clots (venous thrombosis), and blockage of a blood vessel in the lungs by a blood clot (pulmonary infarction).
The following side effects may affect up to 1 in 10 people during treatment with PROPLEX:
- formation of blood clots throughout the body (disseminated intravascular coagulation), resistance (inhibitors) to one or more of the prothrombin complex factors (factors II, VII, IX, X)
- severe immediate allergic reaction (anaphylactic shock), anaphylactic reaction, hypersensitivity, stroke, headache
- heart attack (acute myocardial infarction), rapid heartbeat (tachycardia)
- arterial thrombosis, venous thrombosis, drop in blood pressure (hypotension), redness of the skin (flushing)
- blockage of a blood vessel in the lungs by a blood clot (pulmonary embolism), difficulty breathing, shortness of breath (dyspnea), wheezing
- vomiting, feeling of illness (nausea)
- hives over the entire body, skin rash (erythematous rash), itching
- a specific kidney disorder with symptoms such as swelling of the eyelids, face and lower legs, weight gain and loss of protein in the urine (nephrotic syndrome)
- fever (pyrexia)
The following side effects have been observed with other prothrombin complex concentrates:
- swelling of the face, tongue and lips (angioedema), sensation of burning, itching or tingling of the skin (paresthesia)
- infusion site reaction
- lethargy
- restlessness
Reporting of side effects
If you experience any side effects, including those not listed in this leaflet, please consult your doctor. You can also report side effects directly via the national reporting system for adverse reactions.
By reporting side effects, you can help provide more information on the safety of this medicine.
5. How to store PROPLEX
Store in a refrigerator (2°C - 8°C). Do not freeze.
Keep in the original packaging to protect the medicine from light.
Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date stated on the label and carton after "Exp.". The expiry date refers to the last day of that month.
During its shelf life, the product may be stored at room temperature (not above 25°C) for a single period not exceeding six months. The start and end dates of the room temperature storage period must be recorded on the packaging. After storage at room temperature, PROPLEX must not be returned to the refrigerator (2°C - 8°C), but must be used within 6 months or be disposed of.
The ready-to-use solution must be used immediately.
Do not dispose of any medicine via wastewater or household waste. Ask your pharmacist how to dispose of medicines no longer required. This will help protect the environment.
6. Contents of the pack and other information
What PROPLEX contains
Powder:
The active substance is Human Prothrombin Complex, which consists of coagulation factors
human II, VII, IX, and X and protein C.
| Per vial [IU] | After reconstitution in 17 ml of sterile water for injectable preparations [IU/ml] | |
| Human coagulation Factor II | 375 - 708 | 22.5 – 42.5 |
| Human coagulation Factor VII | 417 | 25 |
| Human coagulation Factor IX | 500 | 30 |
| Human coagulation Factor X | 500 | 30 |
One vial contains at least 333 IU of protein C, co-purified with blood coagulation factors.
The other components are:
sodium chloride, sodium citrate, sodium heparin (0.2 - 0.5 IU/IU Factor IX), and antithrombin III 12.5 - 25 IU per vial (0.75 - 1.5 IU/ml).
Solvent:
Sterile water for preparations for injection.
Description of the appearance of PROPLEX and contents of the pack
Powder and solvent for solution for injection.
PROPLEX is a lyophilized powder or compact dry substance, white to pale yellow in colour.
After reconstitution, the pH of the solution ranges between 6.5 and 7.5, and osmolality must not be less than 240 mOsm/kg. The solution is clear or slightly opalescent.
The powder and solvent are supplied in single-dose glass vials (hydrolytic class II and I, respectively). The vials are closed with butyl rubber stoppers.
Contents of the pack:
- 1 vial of PROPLEX powder for solution for injection 500 IU
- 1 vial of sterile water for preparations for injection 17 ml
- 1 Mix2Vial transfer device for reconstitution
Pack size: 1 x 500 IU
Marketing Authorization Holder and Manufacturer
Marketing Authorization Holder
Baxalta Innovations GmbH
Industriestrasse 67
A-1221 Vienna
Austria
Representative in Italy: Takeda Italia S.p.A.
Tel. +39 06 502601
Manufacturer
Takeda Manufacturing Austria AG
Industriestrasse 67
1221 Vienna
Austria
This medicinal product is authorized in the European Economic Area and in the United Kingdom (Northern Ireland) under the following names:
| Austria | Prothromplex TOTAL 500 I.E. Powder and solvent for the preparation of an injectable solution |
| Estonia, Greece, Hungary, Ireland, Latvia, Malta, Romania, United Kingdom (Northern Ireland) | Prothromplex Total |
| Bulgaria, Czech Republic, Poland | Prothromplex Total NF |
| Belgium, Denmark, Lithuania, Luxembourg, Netherlands, Norway, Portugal | Prothromplex |
| Germany, Slovakia | Prothromplex NF |
| Italy, Slovenia | Proplex |
| Spain | Prothromplex Total 500 IU powder and solvent for injectable solution |
The following information is intended exclusively for healthcare professionals:
Instructions for Preparation and Administration
General Instructions
- For reconstitution, use only the reconstitution set supplied in the package.
- Before preparation, check the expiration date and ensure that the PROPLEX powder and water for injection (solvent) are at room temperature. Do not use the product after the expiration date indicated on the labels and packaging.
- Use an aseptic technique (clean, low-germ conditions) and work on a flat surface during the reconstitution procedure. Wash hands and wear clean examination gloves (gloves are optional).
- Warm the unopened solvent vial (sterile water for injection) to room or body temperature (maximum 37°C).
- PROPLEX must be reconstituted only immediately before administration. The solution is clear or slightly opalescent. Discard cloudy solutions or those containing deposits.
Instructions for Reconstitution of the Powder for Injection Solution:
Steps Image
1 Remove the protective caps from the powder vial and the solvent vial.
Steps Image
2 Disinfect each stopper with a separate sterile alcohol swab (or other suitable sterile solution), rubbing for several seconds.
- Allow the rubber stopper to dry. Place the vials on a flat surface.
3 Completely remove the lid to open the Mix2Vial transfer device package, taking care not to touch the contents.
- Do not remove the Mix2Vial transfer device from its packaging.
4 Invert the package containing the Mix2Vial transfer device and place it onto the top of the solvent vial.
- Firmly insert the blue plastic spike of the device into the center of the solvent vial’s stopper by pushing downward. Grasp the package by the edge and lift it off the Mix2Vial transfer device.
- Take care not to touch the transparent plastic spike.
- At this point, the solvent vial is now equipped with the Mix2Vial device and is ready to be connected to the PROPLEX vial.
5 To connect the solvent vial to the PROPLEX vial, invert the solvent vial and place it on top of the vial containing PROPLEX powder.
- Fully insert the transparent plastic spike into the PROPLEX vial stopper by pressing firmly downward. To maintain sterility, perform this step as quickly as possible.
- The solvent will automatically transfer into the PROPLEX vial by vacuum. Ensure that all solvent has transferred.
- Do not use if, due to loss of vacuum, the solvent fails to transfer into the PROPLEX vial.
Steps Image
6 Gently and continuously rotate the connected vials until dissolution is complete, or let the reconstituted product stand for 5 minutes. Finally, gently rotate to ensure complete dissolution of the powder.
- Do not shake, as this may compromise the product. Do not refrigerate after reconstitution.
7 Disconnect the two sides of the Mix2Vial device by holding the transparent plastic side attached to the PROPLEX vial with one hand and the blue plastic side attached to the solvent vial with the other.
- Rotate the blue plastic side counterclockwise and gently separate the two vials.
- Do not touch the end of the plastic connector attached to the PROPLEX vial containing the dissolved product.
- Place the PROPLEX vial on a flat working surface. Discard the empty solvent vial.
8 Draw air into an empty sterile plastic single-use syringe by pulling back the plunger.
- The volume of air drawn should equal the volume of reconstituted PROPLEX to be withdrawn from the vial.
9 Leaving the PROPLEX vial (containing the reconstituted product) on the flat working surface, attach the syringe to the transparent plastic connector and rotate it clockwise.
10 Holding the vial with one hand, use the other hand to push the syringe plunger fully to inject all air into the vial.
Steps Image
11 Invert the syringe and PROPLEX vial together as a single unit so that the vial is above. Keep the plunger depressed. Slowly pull back the plunger to draw PROPLEX into the syringe.
- Avoid repeatedly transferring and aspirating the solution between the syringe and vial, as this may compromise the product.
12 When ready for infusion, disconnect the syringe by rotating it counterclockwise. Visually inspect the syringe to ensure it is free from particles. The solution should be clear and slightly opalescent.
- Do not use if the solution is cloudy or contains residues.
Instructions for Administration
Before administration, visually inspect the prepared solution in the syringe to ensure it is free from particles and discoloration. The solution should be clear, colorless, and particle-free. The filter included in the Mix2Vial device completely removes any particles. Filtration does not affect dosage calculations. The solution in the syringe must not be used if, after filtration, it appears cloudy or contains flakes or particles.
- Attach the infusion needle to a syringe containing the PROPLEX solution. For convenience, a butterfly infusion set is recommended. Point the needle upward and remove any air bubbles by gently tapping the syringe with a finger and slowly and carefully expelling air from the syringe and needle.
- Apply a tourniquet and prepare the infusion site by thoroughly cleaning the skin with a sterile alcohol swab (or other suitable sterile solution).
- Insert the needle into the vein and remove the tourniquet. Administer PROPLEX slowly by infusion. Do not administer at a rate exceeding 2 mL/min. Disconnect the empty syringe. Note: Do not remove the butterfly needle before completing the infusion of all syringes, and do not touch the Luer port that connects to the syringe.
- Remove the needle from the vein and, using a sterile gauze pad, apply pressure to the infusion site for several minutes. Do not recap the needle. Dispose of the needle, syringe, and empty PROPLEX and solvent vials in a rigid sharps container for proper disposal. Do not dispose of these materials in household waste.
Dosage and Method of Administration
Dosage
The following are general guidelines for administration, except for bleeding treatment and perioperative bleeding prophylaxis during treatment with vitamin K antagonists.
Treatment must 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.
Dosage and frequency of administration must be individually determined for each patient. Dosing intervals should be adjusted based on the differing plasma half-lives of the various coagulation factors contained in the prothrombin complex.
The required dosage for each individual patient can only be determined through regular monitoring of individual plasma levels of the relevant coagulation factors or through global tests of prothrombin complex levels (e.g., Quick time value, INR, prothrombin time) and continuous monitoring of the patient’s clinical condition.
In the case of major surgery, careful monitoring of replacement therapy using coagulation tests (specific coagulation factor assays and/or global prothrombin complex level tests) is essential.
Bleeding and Perioperative Bleeding Prophylaxis During Treatment with Vitamin K Antagonists:
In cases of severe hemorrhage or prior to high-bleeding-risk surgical procedures, the goal is to achieve normal values (Quick time value of 100%, INR 1.0).
The following general rule applies: 1 IU of factor IX per kg of body weight increases the Quick time value by approximately 1%.
If PROPLEX administration is based on INR, the dose will depend on the pre-treatment INR value and the target INR.
The dosage listed in the following table should be followed according to the recommendation in Makris et al., 2001.
| PROPLEX dosing based on initial INR value | |
| INR | Dose [IU/kg] (IU refers to factor IX) |
| 2.0 - 3.9 | 25 |
| 4.0 - 6.0 | 35 |
| > 6.0 | 50 |
The correction of vitamin K antagonist-induced coagulation impairment lasts approximately 6–8 hours. However, the effects of vitamin K, when administered simultaneously, are generally achieved within 4–6 hours. Therefore, repeated treatment with human prothrombin complex concentrate is generally not required when vitamin K has been administered.
Since these are empirical recommendations and recovery and duration of effect may vary, monitoring of the INR value during treatment is mandatory.
Bleeding and perioperative prophylaxis in cases of congenital deficiency of any vitamin K-dependent coagulation factor, when a specific factor concentrate is not available:
The dose calculation for treatment is based on the empirical finding 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 of body weight 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 0.021 IU/mL.
The dose of a specific factor administered is expressed in International Units (IU), relative to the current WHO standard for each factor. The activity of a specific coagulation factor in plasma is expressed as a percentage (relative to normal human plasma) or in International Units (relative to the international standard for specific factor concentrates).
One International Unit (IU) of coagulation factor activity is equivalent to the amount present in 1 mL of normal human plasma.
For example, the calculation of the required dose of factor X is based on the empirical finding that 1 International Unit (IU) of factor X per kg of body weight increases plasma factor X activity by 0.017 IU/mL. The required dosage is determined using the following formula:
Units required = body weight (kg) × desired increase in factor X (IU/mL) × 60
where 60 (mL/kg) is the reciprocal of the estimated recovery.
If the individual recovery value is known, this value should be used for the calculation.
Maximum single dose:
To correct the INR value, it is not necessary to exceed a dose of 50 IU/kg. If the severity of bleeding requires a higher dose, the risk/benefit ratio must be evaluated by the treating physician.
Paediatric population
The safety and efficacy of PROPLEX in paediatric patients have not been established in clinical studies.
Interactions with other medicinal products and other forms of interaction
When administering high doses of PROPLEX, the heparin content of the preparation must be taken into account when performing coagulation tests sensitive to heparin.
Incompatibilities
This medicinal product must not be mixed with other medicinal products except with the solvent supplied in the package.
As with all preparations containing coagulation factors, the efficacy and tolerability of this medicinal product may be compromised by mixing with other medicinal products. It is advisable to flush a common venous access with isotonic saline solution before and after administration of PROPLEX.
Special precautions for disposal and handling
Only the reconstitution set supplied in the package must be used for reconstitution.
Reconstitute PROPLEX only 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 inspect the reconstituted solution visually for the presence of particulate matter or discoloration. Turbid solutions or those containing precipitate must be discarded.
Name and batch number of the medicinal product
It is strongly recommended to record the name and batch number of the product each time PROPLEX is administered to a patient, in order to maintain a link between the patient and the product batch.