Beriate

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT B eriate® B eriate®

Composition:

Active substance: human blood coagulation factor VIII;

1 vial of powder contains:

Active substance: human blood coagulation factor VIII – 250 IU, 500 IU or 1000 IU;

Excipients: glycine, calcium chloride, D(+) sucrose, sodium chloride.

Solvent (water for injections) – 2.5 ml, 5 ml or 10 ml.

The reconstituted preparation, obtained by adding 2.5 ml, 5 ml or 10 ml of water for injections, contains 100 IU/ml of human blood coagulation factor VIII.

Activity (IU) is determined by chromogenic assay according to the European Pharmacopoeia. The average specific activity of Beriate® is approximately 400 IU/mg protein.

The product is manufactured from human donor plasma.

Pharmaceutical form. Powder and solvent for solution for injection or infusion.

Main physicochemical properties: white or almost white powder;

reconstituted solution: colourless clear or slightly opalescent liquid.

After reconstitution according to the instructions, a few small characteristic flaky particles may be observed in the solution. After filtration using the solvent addition device with an integrated filter supplied in the pack, these particles are removed, and the resulting solution should be from clear to slightly opalescent.

Pharmacotherapeutic group. Haemostatics. Coagulation factors. Coagulation factor VIII.

ATC code B02BD02.

Pharmacological properties.

Pharmacodynamics.

The coagulation factor VIII/von Willebrand factor complex consists of two molecules with different physiological functions.

Upon infusion into a patient with hemophilia, coagulation factor VIII binds to von Willebrand factor in the patient's circulation.

Activated coagulation factor VIII acts as a cofactor for activated factor IX, accelerating the conversion of factor X to activated factor X. Activated factor X then converts prothrombin to thrombin. Thrombin subsequently converts fibrinogen into fibrin, allowing the formation of a blood clot.

Hemophilia A is an X-linked inherited coagulation disorder caused by reduced levels of factor VIII:C, leading to prolonged bleeding into joints, muscles, or internal organs, either spontaneously or following trauma, accidental or surgical. Replacement therapy increases plasma levels of coagulation factor VIII, thereby enabling temporary correction of the factor deficiency and bleeding tendency.

In addition to its role as a stabilizing protein for factor VIII, von Willebrand factor mediates platelet adhesion to sites of vascular injury and plays a role in platelet aggregation.

Clinical efficacy and safety results based on available data from treatment of 16 children under 6 years of age are consistent with the experience observed in adult patients.

It should be noted that annual bleeding rates (ABR) are not comparable between different factor concentrates or across different clinical studies.

Pharmacokinetics.

After intravenous administration, factor VIII activity decreases in a mono- or biphasic manner. The terminal half-life ranges from 5 to 22 hours, averaging approximately 12 hours. The increase in factor VIII activity following administration of 1 IU/kg body weight (incremental recovery) was approximately 2%, with variability between individual patients (ranging from 1.5 to 3%). The mean residence time (MRT) is 17 hours (standard deviation – 5.5 hours). The mean area under the concentration-time curve extrapolated to infinity (AUC) was equivalent to 0.4 hr × kg/mL (standard deviation – 0.2). The mean clearance was 3 mL/hour/kg (standard deviation – 1.5 mL/hour/kg).

Children

Pharmacokinetic data in children are limited.

Preclinical safety data

General toxicity

Repeated-dose toxicity studies were not performed due to the development of neutralizing antibodies (inhibitors) against factor VIII.

Even doses several times higher than the recommended human dose per kilogram of body weight showed no toxic effects in laboratory animals.

Tests of heat-treated factor VIII product with polyclonal precipitating antibodies in the Ouchterlony analysis and in the passive cutaneous anaphylaxis test in guinea pigs showed no differences in immunological reactions compared to the untreated protein.

Mutagenicity

Given the lack of clinical evidence regarding potential tumorigenic and mutagenic effects of human coagulation factor VIII, performing experimental studies, particularly in heterologous species, is not considered necessary.

Clinical characteristics.

Indications.

Treatment and prevention of bleeding in patients with hemophilia A (hereditary deficiency of blood coagulation factor VIII). The drug can be used for treatment of acquired factor VIII deficiency.

Contraindications.

Hypersensitivity to the active substance or to any of the other components of the drug.

Interaction with other medicinal products and other forms of interaction.

There are no reports of interactions between human blood coagulation factor VIII products and other medicinal products.

Special precautions for use.

Traceability. In order to improve traceability of biological medicinal products, the name and batch number of the administered product should be clearly recorded.

Hypersensitivity. Hypersensitivity reactions of an allergic type may occur. If such reactions occur, patients are advised to seek immediate medical attention and discontinue use of the product. Patients should be informed about early signs of hypersensitivity reactions, such as rash, generalized urticaria, tightness of the chest, difficulty breathing, hypotension, and anaphylaxis. In the event of shock, standard shock treatment procedures should be followed.

Inhibitors. The development of neutralizing antibodies (inhibitors) to factor VIII is a known complication in the treatment of patients with hemophilia A. These inhibitors are usually immunoglobulins of the IgG class directed against the procoagulant activity of factor VIII. Their concentration is measured in Bethesda units (BU) per 1 ml of plasma by a modified assay. The risk of inhibitor development is related to the degree of exposure to factor VIII; this risk is highest during the first 50 exposure days, but persists throughout life, although it is rare.

The clinical significance of an inhibitor will depend on its titer, with a low titer posing a lower risk of inadequate clinical response than a high titer.

All patients receiving factor VIII-containing products should be carefully monitored for the development of inhibitors through appropriate clinical observations and laboratory tests. If the expected plasma factor VIII activity level is not achieved or bleeding is not controlled with an appropriate dose, the presence of a factor VIII inhibitor should be determined. The product may be ineffective in patients with high levels of factor VIII inhibitors; therefore, alternative treatment options should be considered. The management of such patients should be performed by a physician experienced in treating patients with hemophilia A and patients with factor VIII inhibitors (see also section "Side effects").

Cardiovascular diseases. In patients with existing cardiovascular risk factors, replacement therapy with FVIII may increase cardiovascular risk.

Complications associated with catheter use

If a central venous access device (CVAD) is required, the risk of complications associated with CVAD use should be considered, including local infections, bacteremia, and catheter site thrombosis.

Viral safety. Standard measures to prevent transmission of infection from medicinal products made from human blood or plasma include donor selection, screening of donor material and plasma pools for specific markers of infection, and implementation of virus inactivation/removal procedures during manufacturing steps. Nevertheless, when using products made from human blood or plasma, the possibility of transmitting infectious agents cannot be completely excluded. This also applies to unknown or emerging viruses and other pathogens.

These measures are considered effective against enveloped viruses such as HIV, hepatitis B and C viruses, as well as against non-enveloped viruses such as hepatitis A virus and parvovirus B19.

As a general preventive measure for patients who regularly/repeatedly use factor VIII products derived from human plasma, appropriate vaccination (against hepatitis A and hepatitis B) should be considered.

Children. The above-mentioned special precautions for use also apply to children.

Sodium content

Beriate® 250 IU and 500 IU contain less than 1 mmol of sodium (23 mg) per vial and can therefore be considered essentially "sodium-free".

Beriate® 1000 IU contains 27.55 mg of sodium per vial, equivalent to 1.4% of the WHO recommended maximum daily intake of sodium – 2 g for an adult.

Use during pregnancy or breastfeeding.

Reproductive studies with factor VIII in animals have not been conducted.

Pregnancy or breastfeeding.

Due to the low number of cases of hemophilia A in women, there are no data on the use of factor VIII during pregnancy and breastfeeding. Therefore, the use of the product is possible only when clearly indicated and only if the benefit outweighs the risk.

Fertility.

There are no data on the effect on fertility.

Ability to affect reaction speed when driving vehicles or operating machinery.

The product does not affect the ability to drive vehicles or operate machinery.

Administration and Dosage

The drug is administered intravenously.

Instructions for preparing the medicinal product before administration are provided below.

Treatment should be carried out under the supervision of a physician experienced in managing patients with hemophilia.

Monitoring of Treatment:

During the course of treatment, dosage and frequency of repeat infusions should be determined based on appropriate measurement of factor VIII levels. Careful monitoring of replacement therapy using coagulation assays (factor VIII activity) is mandatory during major surgical procedures. Individual patients may exhibit varying responses to factor VIII therapy, demonstrating different in vivo recovery rates and half-life periods.

Monitoring for the development of factor VIII inhibitors in patients is required (see also section "Special Warnings and Precautions for Use").

Dosage: The required dose and duration of replacement therapy depend on the severity of factor VIII deficiency, the location and intensity of bleeding, and the patient's clinical condition.

The quantity of factor VIII units is expressed in International Units (IU) according to the current World Health Organization standard for blood coagulation factor VIII concentrates. Factor VIII plasma activity is measured either in percentages (relative to normal human plasma) or in International Units (relative to the International Standard for factor VIII content in plasma).

1 IU of factor VIII activity is equivalent to the amount of factor VIII present in 1 ml of normal human plasma.

On-demand treatment: The required dose of factor VIII is calculated based on empirical data indicating that 1 IU of factor VIII per 1 kg body weight raises plasma factor VIII activity by approximately 2% (2 IU/dL) of normal activity. The required dose is calculated using the following formula:

Required number of units = body weight (kg) × desired increase in factor VIII level (% or IU/dL) × 0.5.

The dose and frequency of administration must always be adjusted according to the clinical response in each individual case.

In the event of the hemorrhagic manifestations listed below, factor VIII activity should not fall below the recommended plasma activity level (expressed as % of normal or IU/dL) for the appropriate period.

Dosing recommendations for bleeding episodes and surgical procedures are provided in Table 1.

Table 1

Prophylaxis. For long-term prevention of bleeding episodes in patients with severe hemophilia A, the usual doses are 20–40 IU of factor VIII per kg of body weight, administered every 2–3 days. In some cases, particularly in the treatment of young patients, it may be necessary to shorten the dosing intervals or increase the dose.

Children. Dosage for pediatric patients is calculated based on body weight, following the same principles as for adults. The frequency of administration should be determined according to clinical efficacy in each individual case. There is some experience with treatment of children under 6 years of age (see section "Pharmacological properties").

Reconstitute the preparation according to the "Instructions for preparation of the medicinal product prior to use" provided below.

Prior to administration, warm the preparation to room temperature or body temperature. Administer the preparation by intravenous injection or slow infusion at a rate comfortable for the patient. The infusion rate should not exceed 2 mL per minute.

The patient should be monitored for signs of immediate-type allergic reactions. If any reaction possibly related to the administration of Beriate® occurs, the infusion rate should be reduced or the infusion stopped altogether, depending on the patient's clinical condition (see also section "Special precautions for use").

Instructions for preparation of the medicinal product prior to use

General instructions:

The reconstituted solution should be clear or slightly opalescent. After reconstitution, a few small characteristic flaky particles may be observed in the solution. These particles are removed by filtration using the solvent addition device with an integrated filter (Mix2Vial) supplied in the kit. Filtration does not affect the dose calculation. After filtration and prior to administration, the reconstituted preparation should be inspected visually for particles and discoloration. Do not use cloudy solutions or solutions containing a precipitate (fine particles).

After transferring the product into a syringe, it should be used immediately. Do not store the product in the syringe.

Reconstitution and withdrawal of the solution must be performed under aseptic conditions.

Reconstitution of the solution

Allow the diluent to reach room temperature. Remove the caps from the vials containing the medicinal product and diluent. Disinfect the stoppers with an antiseptic solution and allow them to dry before opening the solvent addition device with integrated filter (Mix2Vial).

Collection and disposal of the medicinal product

For injections, it is recommended to use disposable plastic syringes, since the solution of this type of preparation may adhere to the walls of all-glass syringes.

Slowly administer the solution intravenously (see section "Administration and Dosage"), taking care to ensure that blood does not enter the syringe containing the preparation. Use the venipuncture set supplied with the product; insert the needle into the vein. Allow blood to flow back to the end of the tubing. Attach the syringe to the threaded end of the venipuncture set.

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

Children.

The medicinal product is administered to children according to the instructions provided in the section "Administration and Dosage".

Overdose.

There have been no reported cases of overdose with human coagulation factor VIII to date.

Adverse reactions

Safety profile summary

Allergic or hypersensitivity reactions (which may include angioneurotic edema, sensation of pricking and burning at the infusion site, chills, facial flushing, generalized urticaria, headache, rash, hypotension, somnolence, nausea, agitation, tachycardia, dyspnea, paresthesia, vomiting, and stridorous respiration) have been observed very rarely; in some cases, these may progress to severe anaphylaxis (including shock).

In patients with hemophilia A, neutralizing antibodies (inhibitors) to factor VIII, including against the medicinal product Beriate®, may very rarely develop. If such inhibitors occur, this condition may manifest as a suboptimal clinical response. In such cases, consultation with a specialized hemophilia treatment center is recommended.

Adverse reactions are presented in Table 2.

Information on the adverse reactions listed below is based on post-marketing surveillance data and scientific publications.

The following standard frequency categories are used according to MedDRA system organ class:

Very common: ≥ 1/10
Common: ≥ 1/100 to < 1/10
Uncommon: ≥ 1/1,000 to < 1/100
Rare: ≥ 1/10,000 to < 1/1,000
Very rare: < 1/10,000
Not known: cannot be estimated from available data

* Frequency is based on studies with all Factor VIII products that included patients with severe haemophilia A.

Information on viral safety is provided in the section "Special precautions for use".

Children

The frequency, type and severity of adverse reactions in children are expected to be the same as in adults.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after marketing authorization is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Medical and pharmaceutical professionals, as well as patients or their legal representatives, should report any suspected adverse reactions and lack of efficacy through the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua.

Shelf life. 3 years.

Chemical and physical stability of the reconstituted preparation has been demonstrated for 8 hours at 25 °C. From a microbiological standpoint, the preparation should be used immediately. If not used immediately, storage time should not exceed 8 hours at room temperature.

Do not use after the expiry date stated on the packaging.

Storage conditions.

Store in a refrigerator at 2–8 °C. Do not freeze. Keep the vial in the outer carton to protect from light.

During the shelf life, Beriate® may be stored at temperatures up to 25 °C, but the total storage time at this temperature must not exceed 1 month. Each period of storage of Beriate® at room temperature must be documented to ensure that the cumulative period does not exceed 1 month.

Do not expose vials to direct heat. Vials must not be heated above body temperature (37 °C). Keep out of the reach of children.

Incompatibilities

Do not mix Beriate® with other medicinal products, diluents or solvents except for water for injections supplied in the package.

Packaging.

One vial of powder with one vial of solvent (water for injections) of 2.5 mL (for 250 IU), 5 mL (for 500 IU), and 10 mL (for 1000 IU), and one solvent addition device with an integrated 15 µm filter («Mix-2Vial™ 20/20»), in a cardboard box.

Or

One vial of powder with one vial of solvent (water for injections) of 2.5 mL (for 250 IU), 5 mL (for 500 IU), and 10 mL (for 1000 IU), one solvent addition device with an integrated 15 µm filter («Mix-2Vial™ 20/20»), and
one cardboard box containing a set for intravenous administration of the medicinal product
(1 single-use syringe, 1 butterfly needle, 2 disinfectant wipes in individual sealed packages, and 1 non-sterile adhesive plaster), with a tamper-evident seal, all contained in a cardboard box with a tamper-evident seal.

Prescription category.

Prescription only.

Manufacturer.

CSL Behring GmbH.

Manufacturer's address.

Emil-von-Behring-Strasse 76, 35041 Marburg, Germany.