Beriplex 1000 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 1000 IU
Powder and solvent for injectable solution
Human prothrombin complex
Read the entire leaflet carefully before starting to use this medicine, as 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 reactions, inform your doctor or pharmacist, even if they are adverse reactions 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 adverse 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, friable solid. The prepared solution must be administered by intravenous injection.
Beriplex is prepared from human plasma (the liquid portion 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 the blood coagulation mechanism.
What Beriplex is used for
Beriplex is used for the 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.
- You have congenital deficiency of any of the vitamin K-dependent factors: in this case, specific coagulation factor products should be used, if available.
- You experience 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).
- You are at increased risk of forming blood clots 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 post-operative 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 with concomitant 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 reduced platelets may be associated with:
- Blood clots in a vein or leg,
- Increased formation of blood clots,
- In some cases, skin rash at the injection site,
- Petechiae (pinpoint bleeding spots), 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 risks of these complications.
Viral safety
When medicines are prepared from human blood or plasma, certain measures are applied to prevent the 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 plasma pools for signs of viruses or infections,
- Inclusion of steps during processing of blood or plasma that can inactivate or remove viruses.
Despite these measures, when medicines prepared 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 applied are considered effective against enveloped viruses such as human immunodeficiency virus (HIV), hepatitis B virus, hepatitis C virus (liver inflammation), and against non-enveloped viruses such as hepatitis A and parvovirus B19.
Your doctor may recommend vaccination against hepatitis A and B if you are treated periodically/repeatedly with 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 batches used.
Use of Beriplex with other medicines
- Inform your doctor or pharmacist if you are taking, have recently taken, or might need to take 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 using 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 several 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 experiences them.
The following adverse effects have been frequently observed (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 less frequently (may affect up to 1 in 100 patients):
- Hypersensitivity or allergic reactions (see section 2).
The frequency of the following adverse effects is not known (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 available data 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 on the packaging after 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, so 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 medicines and packaging you no longer need, ask your pharmacist. This will help protect the environment.
6. Contents of the pack and other information
Composition of Beriplex
Beriplex 1000 IU contains 800 – 1240 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.
The 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 40 ml of water for injections.
The prepared solution should be clear or slightly opalescent; that is, it may show tiny bubbles when held up to the light, but must not contain visible particles.
Presentation
One pack with 1000 IU containing:
- 1 vial of powder
- 1 vial with 40 ml water for injections
- 1 transfer device with 20/20 filter
Marketing Authorization Holder and Manufacturer
CSL Behring GmbH
Emil-von-Behring-Strasse 76
35041 Marburg
Germany
Further information on this medicinal product is available by contacting the local representative of the Marketing Authorization Holder:
CSL Behring, S.A.
c/ Tarragona 157, 18th floor
08014 Barcelona
Spain
This medicinal product is authorized in the Member States of the European Economic Area under the following names:
Austria | Beriplex P/N 1000 I.E. Powder and solvent for solution for injection |
Belgium | Confidex 1000 I.E., powder and solvent for solution for injection |
Bulgaria | Beriplex P/N 1000, 1000 IU, Powder and solvent for solution for injection |
Croatia | Beriplex P/N 1000 IU powder and solvent for solution for injection |
Czech Republic | Beriplex 1000 IU |
Denmark | Confidex |
Finland | Confidex 1000 IU for injection, powder and solvent for solution |
France | Confidex 1000 UI, powder and solvent for injectable solution |
Germany, Poland | Beriplex P/N 1000 |
Greece | Beriplex P/N Powder and solvent for injectable solution 1000 IU/vial |
Hungary | Beriplex P/N 1000 powder and solvent for solution for injection |
Italy | Confidex 1000 |
Luxembourg | Confidex 1000 UI powder and solvent for injectable solution |
Malta Netherlands | Beriplex P/N 1000, powder and solvent for solution for injection Beriplex P/N 1000 IE, powder and solvent for solution for injection |
Norway | Confidex 1000 IU powder and solvent for injectable solution, solution |
Romania Spain | Beriplex P/N 1000 UI powder and solvent for injectable solution Beriplex 1000 UI powder and solvent for injectable solution |
Sweden | Confidex 1000 IE, powder and liquid for injectable solution, solution |
United Kingdom | Beriplex P/N 1000 IU, powder and solvent for solution for injection |
Date of last review of this summary: July 2017
The detailed and up-to-date information about this medicinal product is available on the website of the Spanish Agency of 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 1000 IU content per vial (IU) |
Active ingredients | ||
Coagulation Factor II, human | 20 – 48 | 800 – 1920 |
Coagulation Factor VII, human | 10 – 25 | 400 – 1000 |
Coagulation Factor IX, human | 20 – 31 | 800 – 1240 |
Coagulation Factor X, human | 22 – 60 | 880 – 2400 |
Other active ingredients | ||
Protein C | 15 – 45 | 600 – 1800 |
Protein S | 12 – 38 | 480 – 1520 |
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 dosage guidelines are 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 by global assessment of prothrombin complex levels (INR, Quick's test), along with continuous monitoring of the patient's clinical condition.
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 antagonist medications.
The dosage will depend on the INR value prior to treatment and the target INR to be achieved. The INR value before treatment 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) should 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 kg of body weight may 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 reversal of vitamin K antagonists in the treatment of serious 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 by 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/withdrawal (see below), and before administration, the reconstituted product should be visually inspected for the presence of foreign particles and discoloration.
- Do not use turbid solutions or those containing particulate matter.
- Reconstitution and withdrawal must be performed under aseptic conditions.
Reconstitution
Bring the solvent to room temperature. Ensure that the seals on the product and solvent vials have been removed 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 attached. |
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Care should be taken to ensure that blood does not enter the syringe loaded with the product, since there is a risk that blood may coagulate in 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 medication and of all materials that have come into contact with it must be carried out in accordance with local regulations.
Warnings and special precautions for use
There are no data available regarding the use of Beriplex in cases of perinatal haemorrhage due to vitamin K deficiency in neonates.
Guidelines for platelet count monitoring:
Monitor platelet count carefully.
Interaction with other medicinal products and other forms of interaction
When performing coagulation tests that are sensitive to heparin in patients treated with high doses of human prothrombin complex, 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