Beriplex P/N 250 & 500 IU, powder and solvent for solution for injection

Beriplex P/N 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 below:

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.

For a full list of excipients, see section 6.1.

Powder and solvent for solution for injection.

- 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.

Posology

Only general dosage guidelines are given below. 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 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 (see section 5.2). 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).

The posology and method of administration in elderly people (> 65 years) is equivalent to the general recommendations.

There is no experience in children (see section 4.4 and 5.2).

Treatment and perioperative prophylaxis of bleedings during vitamin K antagonist treatment.

The dose will depend on the INR before treatment and the targeted INR. In the following table approximate doses (ml/kg body weight of the reconstituted product and IU FIX/kg b.w.) required for normalisation of INR (e.g. < 1.3) at different initial INR levels are given.

It is recommended that the maximum single dose should not exceed 5000 IU FIX.

The correction of the vitamin K antagonist-induced impairment of haemostasis is reached at the latest 30 minutes after the injection and will persist for approximately 6 –8 hours. However, the effect of vitamin K, if administered simultaneously, is usually achieved within 4 – 6 hours. Thus, repeated treatment with human prothrombin complex is not usually required when vitamin K has been administered.

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 1.8 % (0.018 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 0.018 IU/ml.

The required dosage is determined using the following formula:

Required units = body weight [kg] x desired factor X rise [IU/ml] x 56

where 56 (ml/kg) is the reciprocal of the estimated recovery.

If the individual recovery is known, that value should be used for calculation.

Method of administration

Beriplex P/N should be reconstituted according to section 6.6. The reconstituted solution should be administered intravenously (not more than 3 IU/kg/min, max. 210 IU/min, approximately 8 ml/min).

Known hypersensitivity to any of the components of the product.

Risk of thrombosis, angina pectoris, recent myocardial infarction (exception: life-threatening haemorrhages following overdosage of oral anticoagulants, and before induction of a fibrinolytic therapy).

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 P/N 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 P/N 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 prothombin 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 P/N to patients with a history of coronary heart disease or myocardial infarction, to patients with liver disease, to patients postoperatively, 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 P/N should be weighed against the potential risk of such complications. In patients with DIC and sepsis antithrombin III substitution should be considered prior to treatment with Beriplex P/N.

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).

When Beriplex P/N is used to normalize impaired coagulation, prophylactic administration of heparin should be considered.

No data are available regarding the use of Beriplex P/N in case of perinatal bleeding due to vitamin K deficiency in neonates.

Beriplex P/N contains up to 343 mg sodium (approximately 15 mmol) per 100 ml. To be taken into consideration by patients on a controlled sodium diet.

Virus safety

Standard measures to prevent infections resulting from the use of medicinal products prepared from human blood or plasma include selection of donors, screening 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 this, 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 unknown or emerging viruses and other pathogens.

The measures taken are considered effective for enveloped viruses such as HIV, HBV, HCV and for the non-enveloped virus HAV.

The measures taken may be of limited value against non-enveloped viruses such as parvovirus B19.

Parvovirus B19 infection may be serious for pregnant women (foetal infection) and for individuals with immunodeficiency or increased erythropoiesis (e.g. haemolytic anaemia).

Appropriate vaccination (hepatits A and B) should be generally considered for patients in regular/repeated receipt of human plasma-derived products.

It is strongly recommended that every time that Beriplex P/N is administered to a patient, the name and batch number of the product are recorded in order to maintain a link between the patient and the batch of the product.

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.

The safety of Beriplex P/N 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, Beriplex P/N should be used during pregnancy and lactation only if clearly indicated.

No studies on the effects on the ability to drive and use machines have been performed.

The following adverse reactions are based on post marketing experience as well as scientific literature. The following standard categories of frequency are used:

Very common: > 1/10

Common: > 1/100 and <1/10

Uncommon: > 1/1,000 and <1/100

Rare: > 1/10,000 and <1/1,000

Very rare: <1/10,000 (including reported single cases)

Renal and urinary disorders:

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.

Vascular disorders:

There is a risk of thromboembolic episodes following the administration of human prothrombin complex (see section 4.4).

General disorders and administration site conditions:

Increase in body temperature is observed in very rare cases.

Immune system disorders:

Hypersensitivity or allergic reactions (which may include angioedema, burning and stinging at the injection site, chills, flushing, generalized urticaria, headache, hives, hypotension, lethargy, nausea, restlessness, tachycardia, angina pectoris, tingling, vomiting or wheezing) have been observed very rarely in patients treated with factor IX containing products. In some cases, these reactions have progressed to severe anaphylaxis, and they have occurred in close temporal association with development of factor IX inhibitors (see section 4.4).

If allergic-anaphylactic reactions occur, the administration of Beriplex P/N has to be discontinued immediately (e.g. discontinue injection) and an appropriate treatment has to be initiated (see section 4.4).

Development of antibodies to one or several factors of the prothrombin complex may occur in very rare cases. 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 centre.

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 per cent 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).

For safety with respect to transmissible agents, see section 4.4.

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.

Pharmacotherapeutic group: antihaemorrhagics, blood coagulation factors II, VII, IX and X in combination

ATC code: B02B D01

The coagulation factors II, VII, IX and X, which are synthesised in the liver with the help of vitamin K, are commonly called the prothrombin complex. In addition to the coagulation factors Beriplex P/N contains the vitamin K dependent coagulation inhibitors Protein C and Protein S.

Factor VII is the zymogen of the active serine protease factor VIIa by which the extrinsic pathway of blood coagulation is initiated. The tissue thromboplastin factor-factor VIIa complex activates coagulation factors IX and X, whereby factor IXa and Xa are formed. With further activation of the coagulation cascade, prothrombin (factor II) is activated and transformed to thrombin. By the action of thrombin, fibrinogen is converted to fibrin, which results in clot formation. The normal generation of thrombin is also of vital importance for platelet function as a part of the primary haemostasis.

Isolated severe deficiency of factor VII leads to reduced thrombin formation and a bleeding tendency due to impaired fibrin formation and impaired primary haemostasis. Isolated deficiency of factor IX is one of the classical haemophilias (haemophilia B). Isolated deficiency of factor II or factor X is very rare but in severe form they cause a bleeding tendency similar to that seen in classical haemophilia.

The further ingredients, the coagulation inhibitors Protein C and Protein S, are also synthesized in the liver. The biological activity of Protein C is enforced by the cofactor Protein S.

Activated Protein C inhibits the coagulation by inactivating the coagulation factors Va and VIIIa. Protein S as cofactor of Protein C supports the inactivation of the coagulation. Protein C deficiency is associated with an increased risk of thrombosis.

Acquired deficiency of the vitamin K-dependent coagulation factors occurs during treatment with vitamin K antagonists. If the deficiency becomes severe, a severe bleeding tendency results, characterised by retroperitoneal or cerebral bleeds rather than muscle and joint haemorrhage. Severe hepatic insufficiency also results in markedly reduced levels of the vitamin K-dependent coagulation factors and a clinical relevant bleeding tendency. However this is often complex due to a simultaneously ongoing low-grade intravascular coagulation, low platelet levels, deficiency of coagulation inhibitors and disturbed fibrinolysis.

The administration of human prothrombin complex provides an increase in plasma levels of the vitamin K-dependent coagulation factors, and can temporarily correct the coagulation defect of patients with deficiency of one or several of these factors.

Plasma half-life is indicated as follows (data derived from a clinical study including 15 healthy volunteers; median values, range):

*terminal half-life; two-compartment-model

Beriplex P/N is distributed and metabolized in the organism in the same way as the endogenous coagulation factors II, VII, IX and X.

Intravenous administration means that the preparation is available immediately; bioavailability is proportional to the dose administered.

Beriplex P/N contains as active ingredients the factors of the prothrombin complex (factors II, VII, IX and X). They are derived from human plasma and act like endogenous constituents of plasma.

Single dose toxicity studies with the predecessing pasteurized but not nanofiltrated product showed moderate toxicity in mice after the administration of 200 IU/kg, the highest dose tested. Preclinical studies with repeated dose applications (chronic toxicity, cancerogenicity and reproductive toxicity) cannot be reasonably performed in conventional animal models due to the development of antibodies following the application of heterologous human proteins.

The local tolerance after intravenous administration of Beriplex P/N was shown in rabbits. A neoantigenicity study with rabbits has shown no indication of generation of a neoepitop due to the pasteurization process.

Powder:

Heparin

Human albumin

Human antithrombin III

Sodium chloride

Sodium citrate

HCl or NaOH (in small amounts for pH adjustment)

Solvent:

Water for injections

Beriplex P/N must not be mixed with other medicinal products, diluents or solvents.

3 years

After reconstitution, from a microbiological point of view and as Beriplex P/N contains no preservative, the reconstituted product should be used immediately. The physicochemical stability has been demonstrated for 24 hours at room temperature (max. 25°C). However, if it is not administered immediately, storage shall not exceed 8 hours at room temperature.

Do not store above 25°C. Do not freeze.

Keep the vial in the outer carton, in order to protect from light.

Beriplex P/N 250 IU:

Powder: Injection vial of colourless glass (Type I), sealed with rubber infusion stopper, aluminium seal and plastic flip-off cap.

Solvent: 10 ml Water for injections in an injection vial of colourless glass (Type I), sealed with rubber infusion stopper, aluminium seal and plastic flip-off cap.

Injection device: 1 filter transfer device 20/20

Beriplex P/N 500 IU:

Powder: Injection vial of colourless glass (Type II), sealed with rubber infusion stopper, aluminium seal and plastic flip-off cap.

Solvent: 20 ml Water for injections in an injection vial of colourless glass (Type I), sealed with rubber infusion stopper, aluminium seal and plastic flip-off cap.

Injection device: 1 filter transfer device 20/20

Not all pack sizes may be marketed.

Any unused product or waste material should be disposed of in accordance with local requirements.

Method of administration

General instructions

- The solution should be clear or slightly opalescent. After filtering/withdrawal (see below) 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 that product and diluent vial flip caps are removed and the stoppers are treated with an aseptic solution and allowed to dry prior to opening the Mix2Vial package.

Withdrawal and application

It has to be taken care 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 would therefore be administered to the patient.

The reconstituted solution should be administered by a separate infusion line.

CSL Behring GmbH

Emil-von-Behring-Strasse 76

35041 Marburg

Germany

Beriplex P/N 250 IU: PL 15036/0028

Beriplex P/N 500 IU: PL 15036/0029

11 January 2008

28 July 2011