Beriata

APPROVED by the Order of the Ministry of Health of Ukraine _______ No ____ Registration Certificate No UA/17404/01/01, UA/17404/01/02, UA/17404/01/03 INSTRUCTION for medical use of the medicinal product Beryate® Beriate®

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 respectively, 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 Beryate® 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 characteristics: white or almost white powder;

Reconstituted solution: colorless 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 provided in the kit, these particles are removed, and the resulting solution should range from clear to slightly opalescent.

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

ATC code B02B D02.

Pharmacological Properties

Pharmacodynamics

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

When infused into a patient with hemophilia, coagulation factor VIII binds to von Willebrand factor in the patient's circulatory system.

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 into 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 severe bleeding into joints, muscles, or internal organs, either spontaneously or following trauma or surgical procedures. Replacement therapy increases the levels of coagulation factor VIII in plasma, thereby enabling temporary correction of the factor deficiency and the associated tendency to bleed.

In addition to its role as a protective 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 of using the drug 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%). Mean residence time (MRT) was 17 hours (standard deviation – 5.5 hours), mean extrapolated area under the concentration-time curve (AUC) was equivalent to 0.4 hour × kg/mL (standard deviation – 0.2), and mean clearance was 3 mL/hour/kg (standard deviation – 1.5 mL/hour/kg).

Pediatric population

Pharmacokinetic data in children are limited.

Preclinical safety data

General toxicity

Repeat-dose toxicity studies were not conducted due to the formation 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 changes in immunological responses compared to untreated protein.

Mutagenicity

As there are no clinical data suggesting possible tumorigenic or mutagenic effects of human coagulation factor VIII, conducting 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 medicinal product.

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.

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 should be advised to seek immediate medical attention and discontinue the use of the product. Patients should be informed about early symptoms of hypersensitivity reactions, such as rash, generalized urticaria, chest tightness, difficulty breathing, hypotension, and anaphylaxis. In the event of shock, standard shock treatment procedures should be applied.

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, with their concentration 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 inhibitor development depends 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 testing. 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. Treatment of such patients should be managed by a physician experienced in treating patients with hemophilia A and patients with factor VIII inhibitors (see also section "Adverse Reactions").

Cardiovascular disorders. 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, including local infections, bacteremia, and catheter site thrombosis, should be considered.

Viral safety. Standard measures to prevent transmission of infections from medicinal products derived from human blood or plasma include donor selection, screening of donor material and plasma pools for specific infection markers, and implementation of virus inactivation/removal procedures during manufacturing. Nevertheless, the possibility of transmitting infectious agents cannot be completely excluded when using products derived from human blood or plasma. 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 or repeatedly receive factor VIII products derived from human plasma, appropriate vaccination (against hepatitis A and hepatitis B) should be considered.

Children. The special precautions listed above 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 sodium intake of 2 g for adults.

Use during pregnancy or breastfeeding.

Reproductive toxicity 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, data on the use of factor VIII during pregnancy and breastfeeding are lacking. Therefore, administration of the product is possible only when clearly indicated and when benefit outweighs risk.

Fertility.

There are no data on the effect on fertility.

Ability to affect reaction speed when driving or operating machinery.

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

Administration and Dosage

The drug is administered intravenously.

Instructions for preparing the medicinal product prior to 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, the 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.

Patients should be monitored for the development of Factor VIII inhibitors (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 Factor VIII concentrates. Plasma Factor VIII activity is measured either in percentage (relative to normal human plasma) or in International Units (relative to the International Standard for plasma Factor VIII content).

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 kg of body weight raises plasma Factor VIII activity by approximately 2% (2 IU/dL) of normal activity. The required dose can be 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 should always be adjusted according to the clinical response in each individual case.

In the event of the hemorrhagic conditions listed below, Factor VIII activity should not fall below the recommended plasma levels (expressed as % of normal or IU/dL) during 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 during 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 product according to the "Instructions for Preparation of the Product Prior to Administration" provided below.

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

Patients should be monitored for immediate-type allergic reactions. If any reaction possibly related to the use 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 Product Prior to Administration

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 Mix2Vial transfer device provided, which contains an integrated filter. Filtration does not affect the dose calculation. After filtration and prior to administration, visually inspect the reconstituted product for particles and discoloration. Do not use cloudy solutions or solutions containing a precipitate (fine particles).

Once the product has been transferred 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 product and diluent. Disinfect the stoppers with an antiseptic solution and allow them to dry before opening the Mix2Vial transfer device with integrated filter.

Collection and disposal of the medicinal product

For injections, Berate® recommends using disposable plastic syringes, as the solution of this type of preparation may adhere to the walls of all-glass syringes.

Slowly administer the solution intravenously (see section "Instructions for use and dosage"), taking care to ensure that blood does not enter the syringe with the drug. 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 medicine or waste material must be disposed of in accordance with local requirements.

Children.

The drug is administered to children according to the instructions provided in the section "Instructions for use and dosage".

Overdose.

To date, there have been no reported cases of overdose with human coagulation factor VIII.

Adverse reactions.

Summary of safety profile

Allergic or hypersensitivity reactions (which may include angioneurotic edema, sensation of tingling and burning at the infusion site, chills, facial flushing, generalized urticaria, headache, rash, hypotension, somnolence, nausea, restlessness, tachycardia, dyspnea, paresthesia, vomiting, and stridor) 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 to the medicinal product Beriate®, may very rarely develop. Should such inhibitors occur, this condition may manifest as a lack of 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 organ system classification:

Very common ≥ 1/10

Common ≥ 1/100 – < 1/10

Uncommon ≥ 1/1000 – < 1/100

Rare ≥ 1/10000 – < 1/1000

Very rare < 1/10000

Not known – cannot be estimated from available data

* Frequency is based on studies with all Factor VIII products that included patients with severe Hemophilia 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 a medicinal product is authorized is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals, pharmacists, patients, and 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 in-use stability has been demonstrated for the reconstituted product for up to 8 hours at 25 °C. From a microbiological standpoint, the product 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 cardboard box 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 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 the Water for Injections supplied in the pack.

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»), all 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 an intravenous administration set (one single-use syringe, one butterfly needle, two disinfecting wipes in individual sealed packages, and one non-sterile plaster), all in a cardboard box with a first-opening control.

Prescription status.

Prescription only.

Manufacturer.

CSL Behring GmbH.

Manufacturer's address.

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

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

Date of last review.