Prothrombin Complex Concentrate (Beriplex®)

ADMINISTRATION ROUTES:

IV

ALTERNATIVE NAMES:

Beriplex® NZ

ICU INDICATIONS:

1. Rapid reversal of warfarin in the setting of bleeding
2. Reversal of direct/novel oral anticoagulants (DOAC/NOACs)
3. Post cardiac surgical bleeding

For detailed guidance on warfarin reversal in non-bleeding patients (such as before surgery), see Appendix 2.

PRESENTATION AND ADMINISTRATION:

IV:

White or slightly coloured powder. Contains human prothrombin complex as 500 IU per vial. Requires reconstitution with supplied vials of diluent (20 mL Water for Injections). Store at 2-8 degrees C. Do not freeze. Allow vials to come to room temperature before use. Protect from light - only remove vials from sealed box when ready to reconstitute.

Follow CSL Behring Mix2Vial instructions, using needle-free transfer technique to reconstitute with supplied diluent. The instructions are available here. The vial must be reconstituted on a flat surface. Do not tilt or shake the vial. Gently swirl contents until dissolved.

Do not dilute in saline or other fluids. Do not co-administer with any other drugs, diluents, solutions or blood products. Use immediately. Flush line pre & post administration with 10 mL saline. Do not pull back to check for blood as fibrin clot may form.

Administer by IV injection at rate of 3 units (IU) per kg body weight per minute (see table below). Do not exceed 210 IU per minute (8 mL/min). For larger volumes use syringe driver.

See Table 1 for dose calculation, preparation, and administration.

DOSAGE:

IV:

Single dose 50 IU/kg to maximum 5000 IU

For patients weighing >100 kg, use 5000 IU (10 vials)

Do not repeat dose within 14 days unless otherwise directed

DOSAGE IN RENAL FAILURE AND RENAL REPLACEMENT THERAPY:

Dose as in normal renal function

DOSAGE IN PAEDIATRICS:

IV:

Single dose 25 IU/kg to maximum 2000 IU

CLINICAL PHARMACOLOGY:

Beriplex is a 4-factor Prothrombin Complex Concentrate (PCC). A 500 IU vial contains the following:

• Factor II (400 IU)
• Factor VII (200 IU)
• Factor IX (400 IU)
• Factor X (440 IU)
• Protein C (300 IU)
• Protein S (240 IU)

Beriplex differs from Prothrombinex-VF which is a 3-factor PCC (containing only factors II, IX & X). For urgent warfarin reversal, only Beriplex and IV vitamin K are required. Unlike Prothombinex-VF, the addition of Fresh Frozen Plasma (FFP) is not required as Beriplex contains all 4 vitamin K-dependent clotting factors. FFP may however still be required for associated major haemorrhage as directed by a massive transfusion protocol.

PCC infusion causes a rapid and sustained increase in the plasma levels of the administered factors & proteins with distribution similar to that of the endogenous proteins in healthy individuals. After a single intravenous infusion, factor II has the longest serum half-life of all active components (around 60 hours).

In addition to warfarin reversal, Beriplex can be used to reverse the anticoagulant effects of DOAC/NOACs such as apixaban, rivaroxaban, and edoxaban. It can also be used to reverse the effects of dabigatran if its specific reversal agent (idarucizumab/praxbind) is unavailable.

Beriplex works within 5 minutes of administration. It should be co-administered with IV vitamin K (phytomenadione) for more sustained reversal (which may take 4-6 hours to have effect if given in isolation).

Beriplex contains up to 343 mg (approx 15 mmol) sodium and up to 200 IU heparin per 100 mL reconstituted solution. It must be ordered from Blood Bank on the NZBS Blood Bank Request Form (under the category 'Other'). The active ingredients in Beriplex are manufactured from human plasma pools obtained by blood donation which has undergone viral deactivation.

Compared to FFP alone, PCCs contain significantly higher amounts of clotting factors (1 dose of PCC is comparable to 8-16 units of FFP), are more rapidly available as don't require thawing time, require much smaller volumes to administer so are safer in cardiac or renal impairment, and are leukocyte-free so reducing the incidence of transfusion reactions.

CONTRAINDICATIONS:

1. Known hypersensitivity to Beriplex or any excipient
2. Heparin-induced thrombocytopenia (HIT)
3. Beriplex administered in previous 14 days
4. Use with caution in patients with thromboembolic events in the last 3 months
5. Patient refusal of human blood-derived products

WARNINGS:

Allergic or anaphylactic-type reactions may occur; if suspected, injection must be terminated immediately and appropriate treatment provided.

Thromboembolic risk: disseminated intravascular coagulation (DIC) or thrombosis may occur in patient with congenital or acquired deficiency. This risk may be higher in treatment of isolated Factor VII deficiency and other vitamin K dependent coagulation factors with longer half-lives may accumulate to levels considerably higher than normal. Patients given PCCs should be observed for signs or symptoms of DIC or thrombosis.

Nephrotic syndrome has been reported in patients with haemophilia B undergoing attempted immune tolerance induction with factor IX inhibitors.

As Beriplex contains heparin, it may contribute to the development of HIT (type II). Signs include a platelet count decrement >50% and/or occurrence of new thromboembolic events during heparin therapy. Onset is typically 4-14 days after dosing but may occur within 10 hours of exposure.

Different PCC products must not be combined - do not give Beriplex with Prothrombinex-VF

PRECAUTIONS:

General:

Reversing vitamin K antagonists exposes patients to risk of the underlying disease for which they were being treated. Resumption of anticoagulation should be carefully considered as soon as possible.

Laboratory Tests:

Beriplex will affect measurement of PT/INR (factors I, II, V, VII & X) & APTT (factors I, II, V, VIII, IX, XI, XII)

Drug/Laboratory Test Interactions:

None known

Pregnancy & fertility: The effects of Beriplex on fertility are unknown. Safety during pregnancy has not been established but there is no evidence that clotting factors cross the placental barrier.

Nursing Mothers: The safety of Beriplex during lactation has not been established.

IMPORTANT DRUG INTERACTIONS IN ICU:

None known outside of expected therapeutic effect

ADVERSE REACTIONS:

Nervous system:

Headache, insomnia

Respiratory:

Pleural effusion, dyspnoea, hypoxia, pulmonary oedema

Cardiovascular:

Thromboembolism (arterial and venous), tachycardia, hypotension, atrial fibrillation

Haematological:

DIC, anaemia

Gastrointestinal:

Nausea, vomiting, diarrhoea

Skin:

Rash with hypersensitivity or anaphylaxis

Other:

Increase in body temperature has been commonly observed