Transfusion medicine handbook

5. Fractionated Products

5.1.3 BERIPLEX® NZ (Factors II, VII, IX, X and Protein C & S)

Beriplex NZ 500 IU is a sterile, freeze-dried powder for injection, containing human prothrombin complex. Each pack contains one vial of Beriplex NZ for reconstitution, a vial of diluent (Water for Injections 20 mL) and a Mix2Vial™ filter transfer set. [1]. It is made from plasma donated by New Zealand voluntary and non-remunerated blood donors.

Each vial of Beriplex NZ 500 IU has the following  active ingredients [1]:

• Factor II, 400 – 960 IU
• Factor VII, 200 – 500 IU
• Factor IX, 400 – 620 IU
• Factor X, 440 – 1200 IU
• Protein C, 300 – 900 IU
• Protein S, 240 – 760

The total protein content is 6-14 mg/mL. The specific activity of factor IX is 2.5 IU per mg total protein.

Beriplex NZ contains up to 343 mg (approximately 15 mmol) sodium and up to 200 IU heparin per 100 mL reconstituted solution.

Beriplex NZ is a four-factor prothrombin complex concentrate (4FPCC). It is not interchangeable with Prothrombinex-VF, a three-factor prothrombin complex concentrate (3FPCC).

Indications for Use

• Beriplex NZ is indicated for the treatment and perioperative prophylaxis of bleeding 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.

Acquired Deficiency

Section 6.10 Oral Anticoagulant Induced Bleeding Or Overdose of this handbook and the NZBS Warfarin Reversal using Beriplex NZ leaflet summarise the updated Thrombosis & Haemostasis society of Australia and New Zealand (THANZ) Updated recommendations for warfarin reversal in the setting of four-factor prothrombin complex concentrate published in the Medical Journal of Australia, 222: 49-51, 2024. The recommendations also inform the NZBS Anticoagulant Reversal webpage which will replace the Reversing Warfarin (with Prothrombinex VF) app. Consultation with a specialist haematologist or a NZBS Transfusion Medicine Specialist / Medical Officer is recommended.

Patients receiving a vitamin K antagonist may have an underlying hypercoagulable state and the administration of a PCC may exacerbate this. Beriplex NZ should only be used when rapid correction of prothrombin complex levels is required during a major bleed or prior to emergency surgery. Correction is commonly achieved approximately 30 minutes after the injection. 

In patients > 100kg, the dose of Beriplex NZ should be calculated based on a capped 100kg body weight and maximum dose of 50 IU/kg (i.e., the maximum absolute dose is 5000 IU). Repeat dosing is not supported by clinical data and the product information documents the risk of thrombosis with repeat dosing . If repeat dosing is required within 14 days* discuss this requirement with a NZBS Transfusion Medicine Specialist (TMS).

*The interval for repeat dosage requiring consultation has been estimated based on >95% elimination of Factor II, which at 60 hours has the longest serum half-life of all the active ingredients.

Co-administration of vitamin K should be considered in patients receiving Beriplex NZ for urgent reversal of vitamin K antagonists to achieve a more sustained reversal. Vitamin K usually takes effect within 4–6 hours.

The addition of factor VII in the 4FPCC, Beriplex NZ removes the need to co-administer fresh frozen plasma (FFP).

Congenital Deficiency

To correct specific vitamin K dependent factor deficiency, specific coagulation factor products should be used when available.

Treatment should be initiated under the supervision of a doctor experienced in the treatment of coagulation disorders. The dosage and duration of the substitution therapy depend on the severity of the disorder, on the location and extent of bleeding and on the patient’s clinical condition [1].

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 (e.g. International Normalised Ratio (INR)), and a continuous monitoring of the clinical condition of the patient [1].

Administration

The reconstituted solution should be administered by slow intravenous injection at a rate not exceeding 3 IU/kg body weight/minute (0.12mL/kg/minute) up to a maximum of 210 IU/minute (8mL/minute).

It must not be diluted in saline or co-mixed with any other intravenous fluid or medication.

Precautions [1]

• Hypersensitivity reactions

If allergic or anaphylactic-type reactions occur, the administration of Beriplex NZ should be stopped immediately.

• Thromboembolic risk

There is a risk of thrombosis or disseminated intravascular coagulation when patients, with either congenital or acquired deficiency, are treated with human prothrombin complex. 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.

Close monitoring should be undertaken in patients with a history of coronary heart disease or myocardial infarction, liver disease, in the peri- or postoperative periods, neonates, and patients at risk of thromboembolic phenomena or disseminated intravascular coagulation or simultaneous inhibitor deficiency.

• Disseminated Intravascular Coagulation (DIC)

In patients with DIC, the use of prothrombin complex can only be considered after termination of the consumptive state.

• Resumption of anticoagulation

Reversing vitamin K antagonists exposes patients to the risk of the underlying disease. Resumption of anticoagulation should be carefully considered as soon as possible.

• Heparin-Induced Thrombocytopenia (HIT) type II

Characteristic signs of HIT are a platelet count drop >50% 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).