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).
The safety and efficacy of Beriplex in children and adolescents has not yet been established in controlled clinical studies (see Precautions).
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.
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.