Advait

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT ADYVATE (ADVATE)

Composition:

Active substance: coagulation factor VIII (octocog alfa);

1 vial contains:

250 IU* of recombinant human blood coagulation factor VIII (rDNA)**, octocog alfa, which after reconstitution yields approximately 50 IU/mL of recombinant human blood coagulation factor VIII, octocog alfa;

500 IU* of recombinant human blood coagulation factor VIII (rDNA)**, octocog alfa, which after reconstitution yields approximately 100 IU/mL of recombinant human blood coagulation factor VIII, octocog alfa;

1000 IU* of recombinant human blood coagulation factor VIII (rDNA)**, octocog alfa, which after reconstitution yields approximately 200 IU/mL of recombinant human blood coagulation factor VIII, octocog alfa;

1500 IU* of recombinant human blood coagulation factor VIII (rDNA)**, octocog alfa, which after reconstitution yields approximately 300 IU/mL of recombinant human blood coagulation factor VIII, octocog alfa;

2000 IU* of recombinant human blood coagulation factor VIII (rDNA)**, octocog alfa, which after reconstitution yields approximately 400 IU/mL of recombinant human blood coagulation factor VIII, octocog alfa;

3000 IU* of recombinant human blood coagulation factor VIII (rDNA)**, octocog alfa, which after reconstitution yields approximately 600 IU/mL of recombinant human blood coagulation factor VIII, octocog alfa;

Excipients: trehalose, histidine, tris(hydroxymethyl)aminomethane, sodium chloride, calcium chloride, glutathione (reduced), polysorbate 80, mannitol.

* Activity (in international units) is determined using a chromogenic quantitative assay relative to an internal standard calibrated against the WHO standard. Specific activity is approximately 4000 – 10000 IU/mg protein.

** Recombinant human coagulation factor VIII is produced using recombinant DNA technology in Chinese hamster ovary (CHO) cells. No (exogenous) human or animal proteins are added during cell culture inoculation, purification, or final formulation steps.

Pharmaceutical form. Powder and solvent for solution for injection.

Main physicochemical properties: friable, white or almost white powder; after reconstitution – clear, colorless solution, free from foreign particles.

Pharmacotherapeutic group. Blood and blood forming organs. Antihemorrhagics. Vitamin K and other hemostatic agents. Coagulation factors. Coagulation factor VIII.

ATC code B02BD02.

Pharmacological properties.

Pharmacodynamics.

The factor VIII/von Willebrand factor complex consists of two molecules (factor VIII and von Willebrand factor) with distinct physiological functions. ADVATE contains recombinant human coagulation factor VIII (octocog alfa), a glycoprotein that is biologically equivalent to the factor VIII glycoprotein in human plasma.

Octocog alfa is a glycoprotein composed of 2332 amino acids with an approximate molecular weight of 280 kDa. When administered intravenously to patients with haemophilia, octocog alfa binds to endogenous von Willebrand factor in the patient's circulatory system. Activated 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, leading to the formation of a fibrin clot. Haemophilia A is an X-linked inherited coagulation disorder caused by reduced levels of factor VIII activity, resulting in prolonged bleeding into joints, muscles, or internal organs, occurring spontaneously or following trauma or surgery. Replacement therapy increases plasma factor VIII levels, allowing temporary correction of factor VIII deficiency and reducing bleeding frequency and tendency.

Data on immune tolerance induction (ITI) in patients with inhibitors to factor VIII have been collected. In sub-study 060103 involving previously untreated children, ITI procedures were documented in 11 such patients. A retrospective analysis was performed on 30 paediatric patients undergoing ITI (in study 060703). Immune tolerance induction was documented in 44 paediatric and adult patients in a prospective non-interventional registry (PASS-INT-004), of whom 36 completed ITI therapy. The data indicate that immune tolerance can be achieved.

In study 060201, 53 previously treated patients were enrolled to compare two long-term prophylactic treatment regimens: an individualised pharmacokinetic dosing regimen (20–80 IU factor VIII per kg body weight administered at intervals of 72 ± 6 hours, n = 23) versus a standard prophylactic dosing regimen (20–40 IU/kg every 48 ± 6 hours, n = 30). The pharmacokinetic-based dosing regimen was designed to maintain minimum factor VIII levels ≥ 1% throughout the 72-hour dosing interval. Data from this study indicate that both prophylactic regimens are comparable in reducing bleeding frequency.

The European Medicines Agency has waived the obligation to submit results of clinical trials with ADVATE in all paediatric subpopulations of patients with haemophilia A (congenital factor VIII deficiency) for the following indications: "Immune tolerance induction (ITI) in patients with haemophilia A (congenital factor VIII deficiency) who have developed inhibitors to factor VIII" and "Treatment and prevention of bleeding in patients with haemophilia A (congenital factor VIII deficiency)" (see section "Posology and method of administration" for information on use in paediatric patients).

Pharmacokinetics.

All pharmacokinetic studies of ADVATE were conducted in previously treated patients with severe and moderate haemophilia A (baseline factor VIII levels ≤ 2%). Plasma samples were analysed at a central laboratory using a one-stage assay.

Overall, 195 patients with severe haemophilia A (baseline factor VIII level < 1%) provided pharmacokinetic parameters included in the per-protocol pharmacokinetic analysis set. Categories for infants (aged ≥1 month to <2 years), young children (aged ≥2 to <5 years), older children (aged ≥5 to <12 years), adolescents (aged ≥12 to <18 years), and adults (aged ≥18 years) were used to summarise pharmacokinetic parameters, with age defined as the age at the time of the PK infusion.

Table 1

a Calculated as Cmax – baseline factor VIII level, divided by dose in IU/kg, where Cmax is the maximum post-infusion factor VIII value.

The safety and haemostatic efficacy of the medicinal product ADYNOVATE in the paediatric population are comparable to those in adult patients. Adjusted recovery and terminal half-life (t½) were approximately 20% lower in younger children (up to 6 years) than in adults, which may be partly explained by the known increase in plasma volume per kilogram of body weight in younger patients.

Currently, there are no data on the pharmacokinetics of ADYNOVATE in previously untreated patients.

Clinical characteristics.

Indications.

Treatment and prevention of bleeding episodes in patients with haemophilia A (congenital factor VIII deficiency). ADVATE is indicated for patients of all age groups.

Contraindications.

Hypersensitivity to the active substance or to any of the excipients listed in the section "Composition", or to mouse or hamster proteins.

Interaction with other medicinal products and other forms of interaction.

Interaction studies with the medicinal product ADVATE have not been conducted.

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 recorded.

Hypersensitivity

Hypersensitivity reactions, including anaphylaxis, have been reported with the use of ADVATE. The product contains trace amounts of mouse and hamster proteins. Patients should be advised to discontinue administration immediately and contact their physician if symptoms of hypersensitivity occur. Patients should be informed about early signs of hypersensitivity reactions such as urticaria, generalized urticaria, chest tightness, wheezing, hypotension, and anaphylaxis.

In the event of shock, standard anti-shock measures should be initiated.

Inhibitors

The development of neutralizing antibodies (inhibitors) against factor VIII is a known complication in the treatment of patients with haemophilia A. These inhibitors are usually immunoglobulins IgG directed against the procoagulant activity of factor VIII, measured in Bethesda Units (BU) per 1 mL of plasma using a modified assay. The risk of inhibitor formation depends on the severity of the disease and the extent of factor VIII exposure, and is highest during the first 20 exposure days. In rare cases, inhibitors may develop after more than 100 exposure days.

Cases of recurrent inhibitor development (with low titre) have been observed more than 100 days after switching from one recombinant factor VIII product to another in previously treated patients with a history of inhibitor development. Therefore, careful monitoring for inhibitor development is required after changing factor VIII products.

The clinical significance of inhibitor formation depends on its titre. Low-titre inhibitors, which are transient or remain persistently low, pose a lower risk of inadequate clinical response compared to high-titre inhibitors.

All patients receiving factor VIII replacement therapy should be carefully monitored for the development of inhibitors through clinical observation and laboratory testing. If expected plasma factor VIII activity levels are not achieved or if bleeding is not controlled with an appropriate dose, testing for the presence of factor VIII inhibitors should be performed. In patients with high-titre inhibitors, factor VIII therapy may be ineffective, and alternative treatment options should be considered. The management of such patients should be performed by physicians experienced in the treatment of haemophilia and factor VIII inhibitor management.

Complications associated with catheterization

If a central venous access device (CVAD) is required, there is a risk of CVAD-related complications, including local infections, bacteraemia, and thrombosis at the catheter site.

Factors related to excipients

Sodium

This medicinal product contains 10 mg of sodium per vial, equivalent to 0.5% of the WHO recommended maximum daily intake of 2 g sodium for an adult.

It is strongly recommended that the name and batch number of the medicinal product be recorded each time ADVATE is administered to a patient, in order to establish a link between the patient and the product batch.

Children

Precautions and safety measures in children do not differ from those in adults.

Use during pregnancy and breastfeeding.

Reproductive toxicity studies of factor VIII in animals have not been conducted. Due to the low prevalence of haemophilia A in women, there is limited experience with the use of factor VIII during pregnancy and breastfeeding. Therefore, factor VIII should be used during pregnancy and breastfeeding only if clearly indicated.

Ability to affect reaction speed when driving or operating machinery.

ADVATE has no influence on the ability to drive or operate machinery.

Method of Administration and Dosage

Treatment should be initiated under the supervision of a physician experienced in the management of hemophilia; resuscitation equipment should also be readily available in case of anaphylaxis.

Dosage

The dosage and duration of replacement therapy depend on the severity of factor VIII deficiency, the location and extent of bleeding, and the patient's clinical condition.

The quantity of factor VIII units is expressed in International Units (IU), which are referenced to the WHO standard for factor VIII preparations. Factor VIII activity in plasma is expressed either as a percentage (relative to normal human plasma) or in IU (relative to the international standard for factor VIII in plasma).

1 International Unit (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 the empirically established relationship: 1 IU of factor VIII per kg of body weight raises factor VIII activity by 2 IU/dL in plasma. The required dose is determined by the following formula:

Required dose (IU) = body weight (kg) × desired increase in factor VIII activity (%) × 0.5

In the event of ongoing bleeding episodes, factor VIII activity should not fall below certain plasma activity levels (expressed as % of normal or IU/dL) during the appropriate period. The table below (Table 2) can be used as a guide for dose selection in bleeding episodes and surgical procedures.

Table 2

The dose and frequency of administration should be adjusted according to the clinical situation in each individual case. In certain circumstances (e.g., presence of an inhibitor with low titer), a higher dose than that calculated by the formula may be required.

During treatment, it is advisable to measure plasma factor VIII activity levels and use these values to determine the required dose and frequency of repeat injections. When performing major surgical procedures, precise monitoring of replacement therapy using a quantitative assay of factor VIII activity in plasma is necessary. Different patients may respond differently to factor VIII, achieving varying levels of in vivo recovery and demonstrating different elimination half-lives.

Prophylaxis

For long-term prevention of bleeding episodes in patients with severe hemophilia A, the usual dose is 20–40 IU of factor VIII per kg of body weight, administered at intervals of every 2 to 3 days.

Route of administration

ADYNOVATE should be administered intravenously. If administered by a non-medical person, appropriate training is required.

The infusion rate should be adjusted to a comfortable rate for the patient and should not exceed 10 ml/minute.

After reconstitution, the solution should be clear, colorless, free of foreign particles, and have a pH between 6.7 and 7.3.

Instructions for reconstitution of the medicinal product prior to administration

ADYNOVATE should be administered intravenously after reconstitution.

A visual inspection of the reconstituted solution should be performed to detect any particulate matter and/or discoloration.

After reconstitution, the solution should be clear, colorless, and free from foreign particles. Do not use solutions that are cloudy or contain particulates.

• A syringe with a Luer-lock fitting should be used for administration.
• Use within three hours after reconstitution.
• The reconstituted solution must not be refrigerated.

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

Reconstitution using the BAXJECT II device

• Only use sterile water for injection and the diluent device provided in the package for reconstitution.
• Do not use if the BAXJECT II device, its sterile barrier system, or the packaging is damaged or shows signs of deterioration.
• Aseptic techniques must be observed.
  1. If the product has been stored in the refrigerator, remove both vials — the ADYNOVATE powder vial and the diluent vial — from the refrigerator and allow them to warm to room temperature (approximately 15–25 °C).
  2. Wash hands thoroughly with warm water and soap.
  3. Remove the caps from the powder and diluent vials.
  4. Clean the stoppers with alcohol swabs. Place the vials on a clean, flat surface.
  5. Open the BAXJECT II device package by removing the paper lid without touching the device inside (Fig. a). Do not remove the device from the package. Do not use if the BAXJECT II device, its sterile barrier system, or the packaging is damaged or shows signs of deterioration.
  6. Turn the package over and insert the clear plastic spike into the diluent vial stopper. Hold the package by the edge and remove it from the BAXJECT II device (Fig. b). Do not remove the blue cap from the BAXJECT II device.
  7. For reconstitution, use only sterile water for injection and the diluent device provided in the package. Turn the system (with the BAXJECT II device attached to the diluent vial) upside down so that the diluent vial is above the device. Insert the white plastic spike into the stopper of the ADYNOVATE vial. The vacuum will draw the diluent into the ADYNOVATE vial (Fig. c).
  8. Gently swirl to ensure complete dissolution of the product. Ensure that ADYNOVATE is completely dissolved, otherwise not all of the reconstituted solution may pass through the device filter. The product dissolves rapidly (usually within less than 1 minute). After reconstitution, the solution should be clear, colorless, and free of particulates.

Fig. a Fig. b Fig. c

Administration

Follow aseptic techniques.

Parenteral medicinal products should be inspected visually for particulate matter immediately before use, whenever possible, depending on the solution and container. Only clear, colorless solutions should be used.

1. Remove the blue cap from the BAXJECT II device. Do not draw air into the syringe. Attach the syringe to the BAXJECT II device.
2. Invert the system (with the vial of reconstituted solution on top). Slowly draw the reconstituted solution into the syringe by pulling back the plunger.
3. Detach the syringe.
4. Attach a butterfly needle to the syringe. Administer intravenously. The solution should be infused slowly at a rate comfortable for the patient, not exceeding 10 ml per minute. Pulse rate should be monitored before and during administration of ADYNOVATE. If a significant increase in pulse rate occurs, reduce the infusion rate or temporarily interrupt the injection, which is usually sufficient for rapid resolution of symptoms (see sections “Special precautions” and “Adverse reactions”).

From a microbiological standpoint, the product should be used immediately after reconstitution. However, chemical and physical stability of the medicinal product after reconstitution has been demonstrated for up to 3 hours at 25 °C.

During its shelf life, the product may be stored at room temperature (not above 25 °C) for one period not exceeding 6 months. The expiration date after 6 months of room temperature storage must be indicated on the product packaging. The product must not be returned to refrigerated storage after room temperature storage.

Children

For on-demand treatment, dosing in pediatric patients (aged 0 to 18 years) does not differ from that in adults. For prophylactic therapy in patients under 6 years of age, 20–50 IU of factor VIII per kg body weight should be administered 3–4 times per week.

Overdose.

There have been no reports of symptoms related to overdose of this medicinal product.

Adverse Reactions

Clinical trials of the medicinal product ADYNOVATE included 418 studies involving single-dose administration of ADYNOVATE, with 93 reported adverse reactions. Common adverse reactions included development of neutralizing antibodies to factor VIII (inhibitors), headache, and fever.

Hypersensitivity or allergic reactions (which may include angioedema, burning and stinging at the infusion site, chills, flushing, generalized urticaria, headache, urticaria, hypotension, lethargy, nausea, restlessness, tachycardia, chest tightness, pruritus, vomiting, wheezing) were observed rarely, and in some cases progressed to acute anaphylaxis (including shock).

Hypersensitivity reactions may occur in patients who develop antibodies to mouse and/or hamster proteins.

In patients with haemophilia A receiving factor VIII, including ADYNOVATE, neutralizing antibodies (inhibitors) may develop. If such inhibitors develop, clinical response may be insufficient. In such cases, it is recommended to consult a specialized haemophilia treatment centre.

List of adverse reactions in tabular form

Table 3 below lists adverse reactions reported during clinical trials and in spontaneous reports, categorized by frequency of occurrence. The table follows the MedDRA system organ classification (SOC) and preferred terms.

Frequency categories are defined as follows: 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), and not known (cannot be estimated from available data). Within each frequency category, adverse reactions are listed in order of decreasing severity.

Table 3

Frequency of adverse reactions reported in clinical trials and spontaneous reports

a Calculated based on the total number of patients who received ADYNOVATE (418).

b In one patient, an unexpected decrease in factor VIII coagulation levels occurred during continuous infusion of ADYNOVATE after surgery (10–14 days post-operatively). Hemostasis was maintained throughout this period, and factor VIII plasma levels and clearance rate returned to normal by day 15 post-operatively. Quantitative assays for factor VIII inhibitors performed after completion of the continuous infusion and after study completion were negative.

c Explanation regarding this adverse reaction is provided in the section below.

d Frequency is based on data from studies with all factor VIII coagulation products that included patients with severe haemophilia A. PTP – previously treated patients; PUP – previously untreated patients.

Description of selected adverse reactions

Adverse reactions related to process residuals

In 229 patients receiving treatment, antibodies to Chinese hamster ovary (CHO) cell proteins were investigated: 3 patients showed statistically significant trends in titers, 4 patients had sustained peaks or transient peak potentials, and 1 patient had both findings, but no clinical symptoms were observed. Among the 229 patients tested for antibodies to mouse IgG, 10 showed statistically significant increases, 2 demonstrated sustained peaks or transient peak potentials, and 1 patient had both findings. Four patients reported isolated incidents of urticaria, pruritus, rash, and slightly elevated eosinophil counts upon repeated administration of the medicinal product.

Hypersensitivity

Allergic-type reactions, including anaphylaxis, may present as dizziness, paresthesia, rash, flushing, facial swelling, urticaria, and pruritus.

Children

Apart from the development of neutralizing antibodies (inhibitors) in previously untreated children and complications related to catheterization, no differences in adverse reactions were observed in clinical studies.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after medicinal product authorization is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare and pharmaceutical professionals, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of efficacy through the automated pharmacovigilance information system at: https://aisf.dec.gov.ua.

Shelf life.

2 years.

Diluent (water for injections) – 5 years.

Storage conditions.

Store at 2 to 8 °C. Do not freeze! Store in the original packaging to protect from light.

Keep out of reach of children.

Incompatibilities

Since compatibility studies have not been conducted, this medicinal product must not be mixed with other medicinal products or diluents.

Packaging.

One vial of powder for solution for injection (250 IU, 500 IU, 1000 IU, 1500 IU, 2000 IU, or 3000 IU) with one vial of diluent (5 mL water for injections) and one reconstitution device BAXJECT II per carton.

Prescription category.

Prescription only.

Manufacturer.

Baxalta Belgium Manufacturing SA, Belgium / Baxalta Belgium Manufacturing SA, Belgium.

Manufacturer's location and address of place of business.

Boulevard Rene Branquart 80, Lessines, 7860, Belgium / Boulevard Rene Branquart 80, Lessines, 7860, Belgium.