Pharmacotherapeutic group: antihemorrhagics, blood coagulation factors II, VII, IX and X in combination
ATC code: B02BD01.
Coagulation factors II, VII, IX and X, which are synthesized in the liver with the aid of vitamin K, are commonly referred to as the prothrombin complex. In addition to coagulation factors, Beriplex contains the vitamin K-dependent coagulation inhibitors protein C and protein S.
Factor VII is the zymogen of the active serine protease factor VIIa, which initiates blood coagulation via the extrinsic pathway. The tissue factor–factor VIIa complex activates coagulation factors IX and X, thereby generating factors IXa and Xa. With further activation of the coagulation cascade, prothrombin (factor II) is activated and converted to thrombin. Through the action of thrombin, fibrinogen is converted to fibrin, resulting in clot formation. Normal thrombin generation is also vitally important for platelet function as part of primary haemostasis.
In isolated cases, severe factor VII deficiency leads to decreased thrombin generation and a bleeding tendency due to impaired fibrin formation and impaired primary haemostasis. Isolated factor IX deficiency is one of the classical forms of haemophilia (haemophilia B). Isolated factor II or factor X deficiency is very rare but, in severe forms, may cause a bleeding tendency similar to that seen in classical haemophilia.
Additional components include the coagulation inhibitors protein C and protein S, which are also synthesized in the liver. The biological activity of protein C is potentiated by the cofactor protein S.
Activated protein C inhibits coagulation by inactivating coagulation factors Va and VIIIa. Protein S, as a cofactor of protein C, promotes the inactivation of coagulation. Protein C deficiency is associated with an increased risk of thrombosis.
Acquired deficiency of vitamin K-dependent coagulation factors occurs during treatment with vitamin K antagonists. When the deficiency becomes severe, it may result in a serious bleeding tendency characterised by retroperitoneal or cerebrovascular haemorrhage rather than haemorrhage into muscles or joints. Severe hepatic insufficiency also causes a marked reduction in vitamin K-dependent coagulation factor levels with a tendency to clinical bleeding, which is, however, more often complex due to simultaneously ongoing low-grade intravascular coagulation, low platelet counts, deficiency of coagulation inhibitors, and impaired fibrinolysis.
Administration of human prothrombin complex results in an increase in plasma levels of vitamin K-dependent coagulation factors, thereby temporarily correcting the coagulation defect in patients deficient in one or more of these factors.
⚠️ Warnings
Seek advice from a specialist experienced in the treatment of coagulation disorders.
In patients with acquired deficiency of vitamin K-dependent coagulation factors (e.g. deficiency induced by treatment with vitamin K antagonists), Beriplex should only be used when rapid correction of prothrombin complex levels is required, such as in major bleeding or emergency surgery. In other cases, reduction of the vitamin K antagonist dose and/or administration of vitamin K is usually sufficient.
Patients receiving vitamin K antagonists have an underlying hypercoagulable state, which may be exacerbated following infusion of human prothrombin complex.
In congenital deficiency of any vitamin K-dependent factor, a specific coagulation factor product should be used when available.
If an allergic or anaphylactic reaction occurs, administration of Beriplex must be stopped immediately (e.g. stop the injection) and appropriate treatment must be initiated. Treatment depends on the nature and severity of the adverse reaction. In the event of shock, standard anti-shock therapy must be initiated without delay.
There is a risk of thrombosis or disseminated intravascular coagulation when patients with congenital or acquired deficiency are treated with human prothrombin complex, particularly with repeated dosing. The risk may be higher in the treatment of isolated factor VII deficiency, because the other vitamin K-dependent coagulation factors with longer half-lives may accumulate to levels substantially above normal. Patients receiving human prothrombin complex concentrates should be closely monitored for signs of intravascular coagulation or thrombosis.
Due to the risk of thromboembolic complications, close monitoring is recommended when administering Beriplex to patients with a history of coronary heart disease, patients with liver disease, peri- and postoperative patients, neonates, or other patients at risk of thromboembolic events or disseminated intravascular coagulation, or with concomitant inhibitor deficiency.
In each of these situations, the potential benefit of treatment with Beriplex should be weighed against the risk of these complications.
In patients with disseminated intravascular coagulation, replacement of prothrombin complex coagulation factors may be necessary under certain circumstances. However, such replacement should only be carried out after the consumptive state has been resolved (e.g. treatment of the underlying cause, sustained normalisation of antithrombin III levels).
Reversal of vitamin K antagonist effect exposes patients to the thromboembolic risk of the underlying disease. Resumption of anticoagulation should be carefully considered as soon as possible.
Adverse reactions may include the development of heparin-induced thrombocytopenia type II (HIT type II). Characteristic features of HIT include a decrease in platelet count >50 percent and/or the occurrence of new or unexplained thromboembolic complications during heparin therapy. Onset is usually 4 to 14 days after initiation of heparin therapy but may occur within 10 hours in patients who have recently received heparin (within the last 100 days).
Nephrotic syndrome has been reported in isolated cases following attempted immune tolerance induction in patients with haemophilia B with factor IX inhibitors and a history of allergic reactions.
No data are available on the use of Beriplex in the case of perinatal bleeding due to vitamin K deficiency in neonates.
Beriplex contains up to 343 mg sodium (approximately 15 mmol) per 100 ml. This should be taken into consideration by patients on a controlled sodium diet.
Viral safety
Standard measures to prevent infections resulting from the use of medicinal products prepared from human blood or plasma include selection of donors, testing of individual donations and plasma pools for specific markers of infection, and the inclusion of effective manufacturing steps for the inactivation/removal of viruses. Despite these measures, when medicinal products prepared from human blood or plasma are administered, the possibility of transmitting infective agents cannot be totally excluded. This also applies to any unknown or emerging viruses or other pathogens.
The measures taken are considered effective for enveloped viruses such as human immunodeficiency virus (HIV), hepatitis B virus (HBV) and hepatitis C virus (HCV), and for the non-enveloped hepatitis A virus (HAV) and parvovirus B19.
Appropriate vaccination (hepatitis A and B) should be considered for patients receiving regular or repeated administration of prothrombin complex products derived from human plasma.
It is strongly recommended that, each time Beriplex is administered to a patient, the name and batch number of the product be recorded in order to maintain a link between the patient and the batch of the product.
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