Beriplex 500 IU powder and solvent for solution for injection
Spain
Table of Contents
Package leaflet: Information for the user
Introduction
Package leaflet: Information for the user
Beriplex 500 IU
Powder and solvent for injectable solution
Human prothrombin complex
Read the entire leaflet carefully before you start using this medicine, because it contains important information for you.
- Keep this leaflet as you may need to read it again.
- If you have any questions, consult your doctor or pharmacist.
- This medicine has been prescribed for you and should not be given to other people, even if they have the same symptoms, as it may harm them.
- If you experience any adverse effects, inform your doctor or pharmacist, including any adverse effects not listed in this leaflet.
Leaflet contents
- What Beriplex is and what it is used for
- What you need to know before using Beriplex
- How to use Beriplex
- Possible side effects
- How to store Beriplex
- Contents of the pack and other information
1. What BERIPLEX is and what it is used for
What Beriplex is
Beriplex is supplied as a powder and solvent. It is a white or slightly coloured powder or friable solid. The prepared solution must be administered by intravenous injection.
Beriplex is prepared from human plasma (the liquid part of blood) and contains human coagulation factors II, VII, IX, and X. Concentrates containing these coagulation factors are known as prothrombin complex products. Coagulation factors II, VII, IX, and X are vitamin K-dependent and are important for blood clotting. A deficiency in any of these factors means that blood does not clot as quickly as it should, resulting in an increased tendency to bleed. Replacement of factors II, VII, IX, and X with Beriplex restores normal blood coagulation mechanisms.
What Beriplex is used for
Beriplex is used for prophylaxis (during surgery) and treatment of bleeding caused by acquired or congenital deficiency of vitamin K-dependent coagulation factors, i.e. factors II, VII, IX, and X in the blood, when purified specific coagulation factor products are not available.
2. What you need to know before using Beriplex
The following sections contain information your doctor should consider before administering Beriplex to you.
Do not use Beriplex
- If you are allergic to the active substances or to any of the other components of this medicine (listed in section 6).
Inform your doctor if you are allergic to any medicines or foods.
- If you are more prone than usual to developing blood clots (patients at risk of disseminated intravascular coagulation).
- If you have an allergic reaction to heparin that causes a drop in blood platelet count (heparin-induced thrombocytopenia type II, HIT type II).
Inform your doctor or pharmacist if you have any of these conditions.
Warnings and precautions
Talk to your doctor or pharmacist before starting to use Beriplex if:
- You have acquired deficiency of vitamin K-dependent coagulation factors: this may be caused by medications that inhibit the effect of vitamin K. Beriplex should only be used when rapid correction of prothrombin complex levels is required, e.g., in cases of severe bleeding or emergency surgery.
- Congenital deficiency of any of the vitamin K-dependent factors: in such cases, specific coagulation factor products should be used if available.
- Allergic-type or anaphylactic reactions (a severe allergic reaction causing significant breathing difficulty or dizziness): administration of Beriplex must be stopped immediately (e.g., by stopping the injection).
- Increased risk of blood clot formation in a blood vessel (thrombosis), especially:
- If you have had a heart attack (history of coronary heart disease or myocardial infarction).
- If you have liver disease.
- If you have recently undergone surgery (pre- or postoperative patients).
- In newborns (neonates).
- If you are more prone than normal to blood clot formation (patients at risk of thromboembolic episodes or disseminated intravascular coagulation or concurrent deficiency of coagulation inhibitors).
- Increased risk of coagulation due to increased consumption of platelets or blood coagulation factors. Treatment with Beriplex should only be initiated once the underlying cause has been treated.
- Reduced platelet production due to heparin (heparin-induced thrombocytopenia, HIT type II). Heparin, a protein with clot-dissolving effects, is a component of Beriplex. The severe form of platelet reduction may be associated with:
- Blood clots in a vein or leg,
- Increased tendency to form blood clots,
- In some cases, skin rash at the injection site,
- Petechiae (pinpoint hemorrhages), and
- Black (tarry) stools.
In such cases, the effect of heparin may be reduced (heparin tolerance). If these symptoms occur, you must stop using the product immediately and inform your doctor. In the future, you should not use products containing heparin.
- A specific form of kidney inflammation has been reported after treatment in patients with hemophilia B who have inhibitors to factor IX. These patients were known to have a history of allergic reactions.
Your doctor will carefully weigh the benefits of treatment with Beriplex against the risk of these complications.
Viral safety
When medicines are prepared from human blood or plasma, certain measures are taken to prevent transmission of infections to patients. These measures include:
- Careful selection of blood and plasma donors to ensure that those at risk of carrying infections are excluded,
- Testing of each donation and pooled plasma samples for signs of viruses or infections,
- Inclusion of steps during blood or plasma processing that can inactivate or eliminate viruses.
Despite these measures, when medicines prepared from human blood or plasma are administered, the possibility of transmitting infection cannot be completely ruled out. This also applies to unknown or emerging viruses or other types of infections.
The measures applied are considered effective against enveloped viruses such as human immunodeficiency virus (HIV), hepatitis B virus, and hepatitis C virus (liver inflammation), and against the non-enveloped hepatitis A virus and parvovirus B19.
Your doctor may recommend vaccination against hepatitis A and B if you are treated periodically/repeatedly with human plasma-derived prothrombin complex products.
It is strongly recommended that each time a dose of Beriplex is administered, the name and batch number of the medicine be recorded, in order to maintain a history of the batches used.
Use of Beriplex with other medicines
- Inform your doctor or pharmacist if you are using, have recently used, or might need to use any other medicines.
- Beriplex may inhibit the effect of vitamin K antagonist treatment. No interactions with other medicines are known.
- This medicine must not be mixed with other medicines except those mentioned in section 6.
Pregnancy, breastfeeding, and fertility
- If you are pregnant or breastfeeding, think you may be pregnant, or plan to become pregnant, consult your doctor or pharmacist before using this medicine.
- During pregnancy and breastfeeding, Beriplex should only be used if clearly indicated.
- There are no data available on fertility.
Driving and use of machines
No studies on the ability to drive or operate machinery have been conducted.
Beriplex contains sodium
Patients on low-sodium diets should be aware that this medicine contains up to 343 mg of sodium (approximately 15 mmol) per 100 ml. This should be taken into account by patients on sodium-controlled diets.
3. How to Use Beriplex
Treatment must be initiated and supervised by a physician experienced in the treatment of this type of disorder.
Dosage
The amount of Factor II, VII, IX, and X you require and the duration of treatment will depend on various factors, such as your body weight, the severity and nature of your condition, the location and severity of bleeding, or the need to prevent bleeding during surgery or a procedure (see the section “This information is intended for healthcare professionals only”).
If you have any further questions about the use of this medicine, ask your doctor or pharmacist.
Overdose
Your doctor should periodically monitor your blood coagulation status during treatment. High doses of prothrombin complex concentrate have been associated with episodes of heart attack, disseminated intravascular coagulation, and increased formation of blood clots in blood vessels in patients at risk of such complications.
4. Possible adverse effects
Like all medicines, this medicine can cause adverse effects, although not everyone will experience them.
The following adverse effects have been observed frequently (may affect up to 1 in 10 patients):
- Risk of blood clot formation (see section 2).
- Headache.
- Increase in body temperature.
The following adverse effects occurred infrequently (may affect up to 1 in 100 patients):
- Hypersensitivity or allergic reactions (see section 2).
The frequency of the following adverse effects is unknown (cannot be estimated from the available data):
- Excessive coagulation leading to severe bleeding.
- Anaphylactic reactions including shock (see section 2).
- Development of circulating antibodies that inhibit one or more coagulation factors.
Paediatric population
There are no data available on the use of Beriplex in the paediatric population.
Reporting of adverse effects
If you experience any type of adverse effect, consult your doctor or pharmacist, even if it is a possible adverse effect not listed in this leaflet. You can also report them directly via the Spanish Pharmacovigilance System for Human Medicinal Products: www.notificaRAM.es. By reporting adverse effects, you can help provide more information on the safety of this medicine.
5. Storage of BERIPLEX
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Keep this medicine out of the sight and reach of children.
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Do not use this medicine after the expiry date stated on the label and packaging following EXP.
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Do not store above 25 °C.
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Do not freeze.
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Store the container in the outer packaging to protect it from light.
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Beriplex does not contain preservatives; therefore, the prepared solution should preferably be used immediately.
Medicines should not be disposed of via wastewater or household waste. If you are unsure how to dispose of unused medicines or their packaging, please consult your pharmacist. This will help protect the environment.
6. Contents of the pack and other information
Composition of Beriplex
Beriplex 500 IU contains 400 – 620 IU of human coagulation factor IX per vial.
The active substance is:
A concentrate of human coagulation factors II, VII, IX and X, and Proteins C and S.
Other components are:
Human antithrombin III, heparin, human albumin, sodium chloride, sodium citrate, HCl or NaOH (in small quantities to adjust pH).
Solvent: Water for injections.
Appearance of the product and contents of the container
Beriplex is presented as a white or slightly coloured powder and is supplied with water for injections as solvent. The powder must be dissolved in 20 ml of water for injections.
The reconstituted solution should be clear or slightly opalescent; that is, it may show tiny bubbles when held up to the light, but must not contain any visible particles.
Presentation
One pack containing 500 IU comprising:
- 1 vial of powder
- 1 vial with 20 ml water for injections
- 1 transfer device with 20/20 filter
Marketing Authorisation Holder and Manufacturer
CSL Behring GmbH
Emil-von-Behring-Strasse 76
35041 Marburg
Germany
Further information on this medicine is available from the local representative of the Marketing Authorisation Holder:
CSL Behring, S.A.
c/ Tarragona 157, planta 18
08014 Barcelona, Spain
This medicine is authorised in the Member States of the European Economic Area under the following names:
Austria | Beriplex P/N 500 I.E. Powder and solvent for solution for injection |
Belgium | Confidex 500 I.E., powder and solvent for solution for injection |
Bulgaria | Beriplex P/N 500, 500 IU, Powder and solvent for solution for injection |
Croatia | Beriplex P/N 500 IU powder and solvent for solution for injection |
Czech Republic Denmark | Beriplex 500 IU Confidex |
Finland | Confidex 500 IU, powder and solvent for solution for injection |
France | Confidex 500 UI, powder and solvent for solution for injection |
Germany | Beriplex P/N 500 |
Greece | Beriplex P/N Powder and solvent for solution for injection 500 IU/vial |
Hungary Ireland | Beriplex P/N 500 powder and solvent for solution for injection Beriplex P/N 500 IU, powder and solvent for solution for injection |
Italy | Confidex 500 |
Luxembourg | Confidex 500 UI, powder and solvent for solution for injection |
Malta Netherlands | Beriplex P/N 500, powder and solvent for solution for injection Beriplex P/N 500 IU, powder and solvent for solution for injection |
Norway | Confidex 500 IU, powder and solvent for solution for injection |
Poland Portugal | Beriplex P/N 500 Beriplex 500 IU, powder and solvent for solution for injection |
Romania Slovakia Slovenia Spain | Beriplex P/N 500 IU, powder and solvent for solution for injection Beriplex 500 IU Beriplex P/N 500 IU, powder and solvent for solution for injection Beriplex 500 UI, powder and solvent for solution for injection |
Sweden | Confidex 500 IU, powder and solvent for solution for injection |
United Kingdom | Beriplex P/N 500 IU, powder and solvent for solution for injection |
Date of the most recent review of this summary: July 2017
Detailed and up-to-date information on this medicine is available on the website of the Spanish Agency for Medicines and Health Products (AEMPS):
http://www.aemps.gob.es
This information is intended for healthcare professionals only:
Qualitative and quantitative composition
The nominal content of human coagulation factors is shown in the following table, expressed in IU:
Name of component | Content after reconstitution (IU/mL) | Beriplex 500 IU content per vial (IU) |
Active substances | ||
Coagulation Factor II, human | 20 – 48 | 400 – 960 |
Coagulation Factor VII, human | 10 – 25 | 200 – 500 |
Coagulation Factor IX, human | 20 – 31 | 400 – 620 |
Coagulation Factor X, human | 22 – 60 | 440 – 1200 |
Other active substances | ||
Protein C | 15 – 45 | 300 – 900 |
Protein S | 12 – 38 | 240 – 760 |
The total protein content is 6 – 14 mg/ml of reconstituted solution.
The specific activity expressed as factor IX is 2.5 IU/mg of total protein.
The activity of all coagulation factors, as well as proteins C and S (antigen), has been tested according to current international standards established by the World Health Organization (WHO).
Posology and method of administration
Posology
The following dosing guidelines are intended for general information only.
Dosage and frequency of administration must be individually determined for each patient. Dosing intervals should be adjusted according to the circulating half-lives of the respective coagulation factors in the prothrombin complex. Individual dosage requirements can only be determined based on periodic measurements of plasma levels of the relevant coagulation factors, or global assessment of prothrombin complex levels (INR, Quick test), along with continuous monitoring of the patient's clinical status.
In the case of major surgical procedures, precise monitoring of replacement therapy is essential, using coagulation analyses (specific coagulation factor assays and/or global tests to measure prothrombin complex levels).
- Bleeding and perioperative bleeding prophylaxis during treatment with vitamin K antagonists:
The dosage will depend on the INR value prior to treatment and the target INR to be achieved. The pre-treatment INR should be measured as close as possible to the time of administration in order to calculate the appropriate dose of Beriplex. The following table provides approximate doses (ml of reconstituted solution/kg body weight and IU of Factor IX/kg body weight) required to normalize the INR (e.g., < 1.3) at different initial INR levels.
INR before treatment | 2.0 – 3.9 | 4.0 – 6.0 | > 6.0 |
Approximate dose (ml/kg body weight) | 1 | 1.4 | 2 |
Approximate Factor IX dose (IU)/kg body weight | 25 | 35 | 50 |
The dose is based on body weight up to, but not exceeding, 100 kg. For patients whose body weight exceeds 100 kg, the maximum single dose (IU of Factor IX) must not exceed 2,500 IU for an INR of 2.0 – 3.9, 3,500 IU for an INR of 4.0 – 6.0, and 5,000 IU for an INR > 6.0.
Correction of vitamin K antagonist-induced coagulation disorder is generally achieved approximately 30 minutes after injection. Concomitant administration of vitamin K should be considered in patients treated with Beriplex for urgent reversal of vitamin K antagonists, since the effect of vitamin K is typically achieved 4 to 6 hours after administration. Repeated administration of Beriplex is not recommended in patients requiring urgent reversal of vitamin K antagonists, as it is not supported by clinical data.
These recommendations are based on clinical trial data from a limited number of individuals. Recovery and duration of effect may vary; therefore, monitoring of INR during treatment is mandatory.
- Bleeding and perioperative prophylaxis in congenital deficiency of certain vitamin K-dependent coagulation factors, when specific coagulation factor products are not available.
The calculation of the required dose of prothrombin complex concentrate is based on clinical trial data:
?1 IU of Factor IX per kilogram of body weight can increase plasma Factor IX activity by 1.3% (0.013 IU/mL) of normal activity.
?1 IU of Factor VII per kg of body weight increases plasma Factor VII activity by 1.7% (0.017 IU/mL) of normal activity.
?1 IU of Factor II per kg of body weight increases plasma Factor II activity by 1.9% (0.019 IU/mL) of normal activity.
?1 IU of Factor X per kg of body weight increases plasma Factor X activity by 1.9% (0.019 IU/mL) of normal activity.
The dosage of a specific administered factor is expressed in International Units (IU), which are related to the current WHO standard for each factor. Plasma activity of a specific coagulation factor 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 is equivalent to the amount contained in 1 mL of normal human plasma.
For example, the calculation of the required dose of Factor X is based on the finding that 1 International Unit (IU) of Factor X per kg of body weight increases plasma Factor X activity by 0.019 IU/mL.
The required dose is determined using the following formula:
Required units = body weight [kg] × desired increase in Factor X [IU/mL] × 53, where 53 (mL/kg) is the reciprocal value of the estimated recovery.
It should be noted that this calculation is based on data from patients who received vitamin K antagonists. A calculation based on data from healthy volunteers would yield a lower estimate of the required dose.
If individual recovery is known, this value should be used in the calculation.
Specific product information is available from clinical trials in healthy volunteers (N = 15), and from the reversal of vitamin K antagonists in the treatment of severe bleeding or perioperative bleeding prophylaxis (N = 98, N = 43).
Paediatric population
The safety and efficacy of Beriplex in children and adolescents have not yet been established in controlled clinical trials.
Elderly population
Dosage and route of administration in elderly patients (over 65 years of age) correspond to the general recommendations.
Method of administration
General instructions
- The solution should be clear or slightly opalescent. After filtration/extraction (see below), and before administration, the reconstituted product should be inspected visually for foreign particles and discoloration.
Do not use cloudy solutions or those containing residues.
- Reconstitution and extraction must be performed under aseptic conditions.
Reconstitution
Bring the solvent to room temperature. Check that the seals have been removed from the product and solvent vials and that the stoppers have been treated with an antiseptic solution, allowing them to dry before opening the Mix2Vial device package.
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Discard the solvent vial with the blue adapter of the Mix2Vial still attached. |
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7Extraction and administration
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Care must be taken to ensure that blood does not enter the syringe loaded with the product, since there is a risk that blood may coagulate within the syringe, potentially leading to the administration of fibrin clots to the patient.
If more than one vial of Beriplex is required, several vials of Beriplex may be combined into a single infusion using a commercially available infusion set.
Beriplex solution must not be diluted.
The reconstituted solution must be administered intravenously (at a maximum rate of 8 ml/minute*).
Disposal of unused medicine and of all materials that have been in contact with it must be carried out in accordance with local regulations.
Warnings and special precautions for use
There are no data available on the use of Beriplex in cases of perinatal hemorrhage due to vitamin K deficiency in neonates.
Guidelines for monitoring platelet count:
Monitor platelet count carefully.
Interaction with other medicinal products and other forms of interaction
When performing coagulation tests sensitive to heparin in patients treated with high doses of human prothrombin complex concentrate, the heparin contained in the administered product should be taken into consideration.
*In clinical trials with Beriplex, doses were administered at a maximum infusion rate of 0.12 ml/kg/min in patients weighing <70 kg.