Beriplex P/N 500

Human prothrombin complex (PCC).

Beriplex is presented as powder and solvent for solution for injection containing human prothrombin complex. The product nominally contains the following IU of the human coagulation factors tabled as follows: (See Table 1.)

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The total protein content is 6-14 mg/ml of reconstituted solution.
The specific activity of factor IX is 2.5 IU per mg total protein.
The activities of all coagulation factors as well as Protein C and S (antigen) have been tested according to the current valid international WHO-Standards.
Presentation: Beriplex P/N 500: 1 vial with powder; 1 vial with 20 ml water for infections; 1 filter transfer device 20/20.
Excipients/Inactive Ingredients: Powder: Heparin, human albumin, human antithrombin III, sodium chloride, sodium citrate, HCl or NaOH (in small amounts for pH adjustment).
Solvent: Water for injections.
Excipients with known effect: Sodium up to 343 mg (approximately 15 mmol) per 100 ml solution.

Pharmacotherapeutic Group: Antihaemorrhagics/Blood coagulation factors II, VII, IX, and X in combination. ATC code: B02B D01.

Treatment and perioperative prophylaxis of bleedings in acquired deficiency of the prothrombin complex coagulation factors, such as deficiency caused by treatment with vitamin K antagonists, or in case of overdose of vitamin K antagonists, when rapid correction of the deficiency is required.
Treatment and perioperative prophylaxis of bleedings in congenital deficiency of any of the vitamin K dependent coagulation factors when purified specific coagulation factor products are not available.

Only general dosage guidelines are given as follows. Treatment should be initiated under the supervision of a physician experienced in the treatment of coagulation disorders. The dosage and duration of the substitution therapy depend on the indication for treatment, severity of the disorder, on the location and extent of bleeding and on the patient's clinical condition.
The amount and the frequency of administration should be calculated on an individual patient basis. Dosage intervals must be adapted to the different circulating half-lives of the respective coagulation factors in the prothrombin complex. Individual dosage requirements can only be identified on the basis of regular determinations of the individual plasma levels of the coagulation factors of interest, or on global tests of the prothrombin complex levels (INR, Quick's test), and a continuous monitoring of the clinical condition of the patient.
In case of major surgical interventions, precise monitoring of the substitution therapy by means of coagulation assays is essential (specific coagulation factor assays and/or global tests for prothrombin complex levels).
Bleeding and perioperative prophylaxis of bleedings during vitamin K antagonist treatment. The dose will depend on the INR before treatment and the targeted INR. The pre-treatment INR should be measured as close as possible to the time of dosing in order to calculate the appropriate dose of Beriplex. In table 2, the approximate doses (ml/kg body weight of the reconstituted product and IU Factor IX/kg b.w.) required for normalisation of INR (e.g. ≤1.3) at different initial INR levels are given.

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Dose is based on body weight up to but not exceeding 100 kg. For patients weighing more than 100 kg the maximum single dose (IU of Factor IX) should therefore not exceed 2500 IU for an INR of 2.0-3.9, 3500 IU for an INR of 4.0-6.0 and 5000 IU for an INR of >6.0.
The correction of the vitamin K antagonist-induced impairment of haemostasis is commonly reached approximately 30 minutes after the injection. The simultaneous administration of vitamin K should be considered in patients receiving Beriplex for urgent reversal of vitamin K antagonists since vitamin K usually takes effect within 4-6 hours. Repeated dosing with Beriplex for patients requiring urgent reversal of vitamin K antagonist treatment is not supported by clinical data and therefore not recommended.
These recommendations are based on data from clinical studies with a limited number of subjects. Recovery and the duration of effect may vary, therefore monitoring of INR during treatment is mandatory.
Bleedings and perioperative prophylaxis in congenital deficiency of any of the vitamin K dependent coagulation factors when specific coagulation factor products are not available. The calculation of the required dosage of prothrombin complex concentrate is based on data from clinical studies: 1 IU of factor IX per kg body weight can be expected to raise the plasma factor IX activity by 1.3% (0.013 IU/ml) of normal.
1 IU of factor VII per kg body weight raises the plasma factor VII activity by 1.7% (0.017 IU/ml) of normal.
1 IU of factor II per kg body weight raises the plasma factor II activity by 1.9% (0.019 IU/ml) of normal.
1 IU of factor X per kg body weight raises the plasma factor X activity by 1.9% (0.019 IU/ml) of normal.
The dose of a specific factor administered is expressed in International Units (IU), which are related to the current WHO standard for each factor. The activity in the plasma 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 a coagulation factor activity is equivalent to the quantity in one ml of the normal human plasma.
For example, the calculation of the required dosage of factor X is based on the finding that 1 International Unit (IU) of factor X per kg body weight raises the plasma factor X activity by 0.019 IU/ml.
The required dosage is determined using the following formula: Required units = body weight [kg] x desired factor X rise [IU/ml] x 53 where 53 (ml/kg) is the reciprocal of the estimated recovery.
Note that the calculation is based upon data from patients receiving vitamin K antagonists. A calculation based upon data from healthy subjects would provide a lower estimate of the required dose.
If the individual recovery is known, that value should be used for calculation.
Product specific information is available from clinical studies in healthy volunteers (N=15), in reversal of vitamin K antagonist treatment for acute major bleeding or perioperative prophylaxis of bleeding (N=98, N=43).
Paediatric population: The safety and efficacy of Beriplex in children and adolescents has not yet been established in controlled clinical studies (see Precautions).
Older population: The posology and method of administration in older people (>65 years) is equivalent to the general recommendations.
Method of Administration: General instructions: The solution should be clear or slightly opalescent. After filtering/withdrawal reconstituted product should be inspected visually for particulate matter and discoloration prior to administration.
Do not use solutions that are cloudy or have deposits.
Reconstitution and withdrawal must be carried out under aseptic conditions.
Reconstitution: Bring the solvent to room temperature. Ensure product and solvent vial flip caps are removed and the stoppers are treated with an antiseptic solution and allowed to dry prior to opening the Mix2Vial package.
1. Open the Mix2Vial package by peeling off the lid. Do not remove the Mix2Vial from the blister package.
2. Place the solvent vial on an even, clean surface and hold the vial tight. Take the Mix2Vial together with the blister package and push the spike of the blue adapter end straight down through the solvent vial stopper.
3.Carefully remove the blister package from the Mix2Vial set by holding at the rim, and pulling vertically upwards. Make sure to only pull away the blister package and not the Mix2Vial set.
4. Place the product vial on an even and firm surface. Invert the solvent vial with the Mix2Vial set attached and push the spike of the transparent adapter end straight down through the product vial stopper. The solvent will automatically flow into the product vial.
5. With one hand grasp the product-side of the Mix2Vial set and with the other hand grasp the solvent-side and unscrew counterclockwise the set carefully into two pieces.
Discard the solvent vial with the blue Mix2Vial adapter attached.
6. Gently swirl the product vial with the transparent adapter attached until the substance is fully dissolved. Do not shake.
7. Draw air into an empty, sterile syringe. While the product vial is upright, connect the syringe to the Mix2Vial's Luer Lock fitting by screwing clockwise. Inject air into the product vial.
Withdrawal and application: 8. While keeping the syringe plunger pressed, turn the system upside down and draw the solution into the syringe by pulling the plunger back slowly.
9. Now that the solution has been transferred into the syringe, firmly hold on to the barrel of the syringe (keeping the syringe plunger facing down) and disconnect the transparent Mix2Vial adapter from the syringe by unscrewing counterclockwise.
Care should be taken that no blood enters the syringe filled with product, as there is a risk that the blood could coagulate in the syringe and fibrin clots could therefore be administered to the patient.
In case more than one vial of Beriplex is required, it is possible to pool several vials of Beriplex for a single infusion via a commercially available infusion device.
The Beriplex solution must not be diluted.
The reconstituted solution should be administered intravenously by a separate injection/infusion line by slow intravenous injection, at a rate not exceeding 3 IU/kg/minute, max. 210 IU/minute, approximately 8 ml/minute.

To avoid overdosage, regular monitoring of the coagulation status is indicated during the treatment as the use of high doses of prothrombin complex concentrate (overdosage) has been associated with instances of myocardial infarction, disseminated intravascular coagulation, venous thrombosis and pulmonary embolism. In case of overdosage the risk of thromboembolic complications or disseminated intravascular coagulation is enhanced in patients at risk of these complications.

Hypersensitivity to the active substance or to any of the excipients listed in Description.
In the case of disseminated intravascular coagulation, prothrombin complex-preparations may only be applied after termination of the consumptive state. Known history of heparin-induced thrombocytopenia.

The advice of a specialist experienced in the management of coagulation disorders should be sought.
In patients with acquired deficiency of the vitamin K-dependent coagulation factors (e.g. as induced by treatment of vitamin K antagonists), Beriplex should only be used when rapid correction of the prothrombin complex levels is necessary, such as major bleedings or emergency surgery. In other cases, reduction of the dose of the vitamin K antagonist and/or administration of vitamin K is usually sufficient.
Patients receiving a vitamin K antagonist may have an underlying hypercoaguable state and infusion of human prothrombin complex may exacerbate this.
In congenital deficiency of any of the vitamin K-dependent factors, specific coagulation factor products should be used when available.
If allergic or anaphylactic-type reactions occur, the administration of Beriplex has to be stopped immediately (e.g. discontinue injection) and an appropriate treatment has to be initiated. Therapeutic measures depend on the kind and severity of the undesirable effect. The current medical standards for shock treatment are to be observed.
There is a risk of thrombosis or disseminated intravascular coagulation when patients, with either congenital or acquired deficiency, are treated with human prothrombin complex particularly with repeated dosing. The risk may be higher in treatment of isolated factor VII deficiency, since the other vitamin K-dependent coagulation factors, with longer half-lives, may accumulate to levels considerably higher than normal. Patients given human prothrombin complex should be observed closely for signs or symptoms of disseminated intravascular coagulation or thrombosis.
Because of the risk of thromboembolic complications, close monitoring should be exercised when administering Beriplex to patients with a history of coronary heart disease or myocardial infarction, to patients with liver disease, to patients per- or post operatively, to neonates or to patients at risk of thromboembolic phenomena or disseminated intravascular coagulation or simultaneous inhibitor deficiency. In each of these situations, the potential benefit of treatment with Beriplex should be weighed against the potential risk of such complications.
In patients with disseminated intravascular coagulation, it may, under certain circumstances, be necessary to substitute the coagulation factors of the prothrombin complex. This substitution may, however, only be carried out after termination of the consumptive state (e.g. by treatment of the underlying cause, persistent normalization of the antithrombin III level).
Reversing vitamin K antagonists exposes patients to the thromboembolic risk of the underlying disease. Resumption of anticoagulation should be carefully considered as soon as possible.
Undesirable reactions may include the development of heparin-induced thrombocytopenia, type II (HIT, type II). Characteristic signs of HIT are a platelet count drop >50 percent and/or the occurrence of new or unexplained thromboembolic complications during heparin therapy. Onset is typically from 4 to 14 days after initiation of heparin therapy but may occur within 10 hours in patients recently exposed to heparin (within the previous 100 days).
Nephrotic syndrome has been reported in single cases following attempted immune tolerance induction in haemophilia B patients with factor IX inhibitors and a history of allergic reaction.
No data are available regarding the use of Beriplex in case of perinatal bleeding due to vitamin K deficiency in neonates.
Beriplex contains sodium: Beriplex contains up to 343 mg sodium (approximately 15 mmol) per 100 ml. To be taken into consideration by patients on a controlled sodium diet.
Use in pregnancy, lactation and fertility: The safety of human prothrombin complex for use in human pregnancy and during lactation has not been established. Animal studies are not suitable to assess the safety with respect to pregnancy, embryonal/foetal development, parturition or postnatal development.
Therefore, human prothrombin complex should be used during pregnancy and lactation only if clearly indicated.
No fertility data are available.
Driving and using machines: No effects on the ability to drive and use machines have been observed.
Virus safety: When medicines are made from human blood or plasma, certain measures are put in place to prevent infections being passed on to patients. These include: careful selection of blood and plasma donors to make sure those at risk of carrying infections are excluded, the testing of each donation and pools of plasma for signs of virus/infections, the inclusion of steps in the processing of the 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 passing on infection cannot be totally excluded. This also applies to any unknown or emerging viruses or other types of infections.
The measures taken are considered effective for enveloped viruses such as human immunodeficiency virus (HIV), hepatitis B virus and hepatitis C virus and for the non-enveloped hepatitis A and parvovirus B19 viruses.
The doctor may recommend to consider vaccination against hepatitis A and B if the patient regularly/repeatedly receives human plasma-derived prothrombin complex products.
It is strongly recommended that every time the patient receives a dose of Beriplex, the name and batch number of the medicine are recorded in order to maintain a record of the batches used.

Pregnancy, lactation and fertility: The safety of human prothrombin complex for use in human pregnancy and during lactation has not been established. Animal studies are not suitable to assess the safety with respect to pregnancy, embryonal/foetal development, parturition or postnatal development.
Therefore, human prothrombin complex should be used during pregnancy and lactation only if clearly indicated.
No fertility data are available.

Summary of the Safety Profile: Allergic or anaphylactic-type reactions have been uncommonly observed, including severe anaphylactic reactions (see Precautions).
Replacement therapy may lead to the formation of circulating antibodies inhibiting one or more of the human prothrombin complex factors. If such inhibitors occur, the condition will manifest itself as a poor clinical response. In such cases, it is recommended to contact a specialised haemophilia center for guidance. Anaphylactic reactions have been observed in patients with antibodies to factors contained in Beriplex.
Increase in body temperature has been commonly observed.
There is a risk of thromboembolic episodes following the administration of human prothrombin complex (see Precautions).
Tabulated list of adverse drug reactions of Beriplex: The following adverse reactions are based on clinical trial data, post marketing experience as well as scientific literature.
The table presented as follows is according to the MedDRA system organ classification (SOC and Preferred Term Level). Frequencies have been based on clinical trial data, according to the following convention: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000) or not known (cannot be estimated from the available data). (See Table 3.)

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For safety with regard to transmissible agents, see Precautions.
Paediatric population: No data are available regarding the use of Beriplex in paediatric population.
Reporting of side effects: If the patient gets any side effects, talk to the doctor, nurse, or pharmacist. This includes any possible side effects not listed in this monograph. By reporting side effects, it can help provide more information on the safety of this medicine.

Human prothrombin complex products neutralise the effect of vitamin K antagonist treatment, but no interactions with other medicinal products are known.
When performing clotting tests which are sensitive to heparin in patients receiving high doses of human prothrombin complex, the heparin as a constituent of the administered product must be taken into account.

Incompatibilities: This medicinal product must not be mixed with other medicinal products except those mentioned in Presentation.
Stability: Chemical and physical in-use stability has been demonstrated for 24 hours at room temperature (max. 25°C). However, from a microbiological point of view, the product should be used immediately.
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

Do not store above 25°C. Do not freeze. Protect from light.
Keep this medicine out of the sight and reach of children.

Haemostatics

B02BD01 - coagulation factor IX, II, VII and X in combination ; Belongs to the class of blood coagulation factors. Used in the treatment of hemorrhage.

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