Octanate

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT OKTANATE (OCTANATE®)

Composition:

International non-proprietary name: coagulation factor VIII;

Active substance: 1 vial of solution for injection contains 250 IU, 500 IU, or 1000 IU of human blood coagulation factor VIII;

total protein not more than 5.5 mg (for 250 IU/vial), not more than 11 mg (for 500 IU/vial), not more than 22 mg (for 1000 IU/vial);

Excipients: sodium citrate, sodium chloride, calcium chloride, glycine.

250 IU/vial, 500 IU/vial: the product contains not more than or equal to 30 IU/mL von Willebrand factor (VWF:RCo – ristocetin cofactor activity);

1000 IU/vial: the product contains not more than or equal to 60 IU/mL von Willebrand factor (VWF:RCo – ristocetin cofactor activity);

Solvent: water for injections.

Pharmaceutical form. Powder for solution for injection.

Main physicochemical properties: white or pale-yellow powder or fragile mass. Solvent: clear, colorless liquid, free from particles.

Pharmacotherapeutic group. Antihemorrhagics. Blood coagulation factor VIII.

ATC code B02B D02.

Pharmacological properties.

Pharmacodynamics.

Factor VIII/von Willebrand factor complex consists of two molecules (FVIII and VWF) with different physiological functions. When administered to a patient with hemophilia, factor VIII binds to von Willebrand factor in the patient's bloodstream.

Activated factor VIII, in combination with activated factor IX, activates factor X. Activated factor X converts prothrombin into thrombin. Thrombin then converts fibrinogen into fibrin, thus forming a blood clot.

Hemophilia A is a sex-linked inherited coagulation disorder caused by reduced levels of factor VIII:C, leading to prolonged bleeding into joints, muscles, and internal organs, either spontaneously or following accidental or surgical trauma. Replacement therapy increases factor VIII levels in plasma, temporarily correcting the deficiency and reducing the tendency to bleed.

It should be noted that the annualized bleeding rate (ABR) varies when different factor concentrates are used and across different clinical studies.

Patients previously untreated

Development of antibodies against FVIII occurs primarily in patients who have previously not been treated (PUPs). A prospective, open-label study evaluating the immunogenicity of Octanate in PUPs included 51 patients. Twenty patients were primarily treated on-demand, and 31 patients received prophylactic treatment. Forty-four patients met the criteria for immunogenicity assessment (i.e., >50 exposure days and FVIII:C <1%). Inhibitors disappeared during treatment with Octanate without changing dose or frequency in two out of five patients who developed inhibitors (one with high titer and one with low titer inhibitors). All inhibitors were detected in patients treated on-demand. The median time to development of high-titer inhibitors was 10 exposure days (range 3–19), and for low-titer inhibitors, 48 exposure days.

Octanate was evaluated for immune tolerance induction (ITI) in an ongoing non-interventional clinical study.

In an interim analysis of 69 patients receiving Octanate treatment for the purpose of immune tolerance induction, 49 patients completed the study. In patients who successfully eliminated inhibitors, the monthly bleeding rate significantly decreased.

Pharmacokinetics.

Human plasma coagulation factor VIII (from concentrate) is a component of human blood plasma and acts as endogenous factor VIII. After injection, approximately 2/3 to 3/4 of factor VIII remains in circulation; the achieved factor VIII activity in plasma should be within 80–120% of the predicted factor VIII activity. Factor VIII activity in plasma decreases in two phases following an exponential curve. During the initial phase, distribution occurs with a plasma half-life of 3–6 hours. During the subsequent slower phase (which likely reflects factor VIII consumption), the half-life is 8–20 hours, averaging 12 hours. This corresponds to the normal biological half-life.

The pharmacokinetic results for Octanate listed below were obtained from two studies involving 10 and 14 patients with hemophilia A, respectively.

Table 1

Study	Recovery (% × IU-1 × kg)	AUC*norm (% × h × IU-1 × kg)	Half-life (hours)	MRT* (hours)	Clearance (ml × h-1 × kg)
Study 1, n = 10, Mean ± SD*	2.4 + 0.36	45.5 + 17.2	14.3 + 4.01	19.6 + 6.05	2.6 + 1.21
Study 2, n = 14, Mean ± SD*	2.4 + 0.25	33.4 + 8.50	12.6 + 3.03	16.6 + 3.73	3.2 + 0.88

*AUC – area under the concentration-time curve,

*MRT – mean residence time,

*SD – standard deviation.

Clinical characteristics.

Indications.

For the treatment and prevention of bleeding episodes in patients with hemophilia A (congenital factor VIII deficiency).

Octanate can be used in patients of all age groups.

This product does not contain von Willebrand factor in a pharmacologically effective amount and is therefore not indicated for use in von Willebrand disease.

Contraindications.

Hypersensitivity to the active substance or to any of the excipients.

Interaction with other medicinal products and other forms of interaction.

No interactions between human coagulation factor VIII products and other medicinal products have been reported.

Special precautions for use

Traceability

To improve traceability of biological medicinal products, it is essential to clearly record the name and batch number of the administered product.

Allergic reactions

Allergic reactions may occur during treatment with Octanate. This medicinal product contains traces of human proteins, unlike factor VIII. If symptoms of allergic reactions occur, patients are advised to immediately discontinue use of the medicinal product and consult a physician. Patients should be informed about early signs of allergic reactions such as: rash, generalized urticaria, dyspnea, wheezing/shortness of breath, hypotension, and anaphylaxis.

In case of shock, standard medical treatment for shock should be initiated.

Inhibitors

The development of neutralizing antibodies (inhibitors) against factor VIII is a known complication in the treatment of patients with hemophilia A. These inhibitors are typically immunoglobulins IgG directed against the procoagulant activity of factor VIII. Their concentration is measured in Bethesda Units (BU) per 1 ml of plasma using appropriate assays. The risk of inhibitor development correlates with disease severity and exposure to factor VIII, and is highest during the first 50 days of treatment. Although this risk is infrequent, it persists throughout life.

The clinical significance of inhibitor development depends on the inhibitor titer. Inhibitors with low titers pose a lower risk of inadequate clinical response compared to those with high titers.

In general, patients receiving treatment with factor VIII-containing products should be closely monitored by a physician for the development of inhibitors and undergo appropriate clinical and laboratory evaluations. 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 inhibitor levels, treatment with factor VIII-based products may be ineffective, and alternative treatment options should be considered. Management of such patients should be performed by a physician experienced in the treatment of hemophilia and factor VIII inhibitors.

Cardiovascular complications

In patients with pre-existing risk factors for cardiovascular disease, replacement therapy with factor VIII may increase this risk.

Central venous access device (CVAD) complications

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

Transmission of infectious agents

Standard precautions to prevent infections from medicinal products derived from human blood or plasma include donor selection, screening of individual donor blood and pooled donor plasma for specific infection markers, and inclusion of effective manufacturing steps for virus inactivation/removal. Nevertheless, when administering medicinal products derived 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 pathogenic organisms.

The measures taken are considered effective against enveloped viruses such as human immunodeficiency virus (HIV), hepatitis B virus (HBV), hepatitis C virus (HCV), and also against non-enveloped hepatitis A virus (HAV). However, these measures may have limited effectiveness against non-enveloped viruses such as parvovirus B19. Parvovirus B19 infection may be dangerous for pregnant women (fetal infection) and for individuals with immunodeficiency or increased erythropoiesis (e.g., hemolytic anemia).

Appropriate vaccination (hepatitis A and B) should be considered for patients who receive repeated or long-term treatment with factor VIII products derived from human plasma.

It is strongly recommended that the name and batch number of Octanate be recorded at each administration to allow traceability between the patient's condition and the administration of a specific batch.

This medicinal product contains less than 1 mmol (23 mg) of sodium per vial, i.e., practically sodium-free in a 250 IU Octanate vial, and contains up to 1.75 mmol (40 mg) of sodium per vial of Octanate 500 IU and 1000 IU, equivalent to 2% of the WHO recommended maximum daily intake of 2 g sodium for adults. Caution should be exercised when administering to patients on a sodium-restricted diet.

Pediatric population

The above-mentioned warnings and precautions apply to both adults and children.

Use during pregnancy or breastfeeding

There are no data on the use of factor VIII during pregnancy and breastfeeding. Therefore, factor VIII should be used during pregnancy and lactation only if clearly indicated, with careful consideration of the benefit/ risk balance for the mother and fetus/infant.

Ability to affect the speed of reaction while driving or operating machinery

No effect on the ability to drive or operate machinery has been observed.

Administration and Dosage

Treatment should be initiated under the supervision of a physician experienced in the management of hemophilia.

Monitoring of Treatment

During the course of treatment, appropriate monitoring of factor VIII levels is recommended to guide dose selection and frequency of repeat infusions. Individual patients may exhibit variable responses (i.e., pharmacological response) to factor VIII, demonstrating different half-lives and recovery rates. Doses calculated according to body weight may require adjustment in patients with underweight or overweight body mass. In the case of major surgical procedures, precise monitoring of replacement therapy using coagulation assays (factor VIII activity in plasma) is essential and mandatory.

Dosage

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

The amount of factor VIII administered is expressed in International Units (IU), corresponding to the World Health Organization (WHO) standard for factor VIII concentrates. Factor VIII activity in plasma is expressed either as a percentage (relative to normal human plasma) or in International Units (relative to the international standard for factor VIII in plasma).

One 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 calculation of the required factor VIII dose is based on empirical data indicating that 1 IU of factor VIII per kg of body weight raises plasma factor VIII activity by 1.5–2% above baseline.

The required dose is calculated using the following formula:

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

The amount of product to be administered and the frequency of administration should always be guided by the clinical response in each individual case.

In the case of the bleeding episodes listed below, factor VIII activity should not fall below the recommended plasma activity levels (expressed as % of normal) during the specified time periods. Table 2 below can be used to calculate the required dose in cases of bleeding and during surgical procedures.

Table 2

Severity of bleeding / type of surgical procedure	Required Factor VIII level (%) (IU/dl)	Dosing frequency (hours) / duration of treatment (days)
Bleeding
Early haemarthrosis, muscle bleeding or oral bleeding	20–40	Repeat every 12–24 hours for at least 1 day until bleeding stops or recovery occurs.
More extensive haemarthrosis, muscle bleeding or haematoma	30–60	Repeat every 12–24 hours for 3–4 days or more until pain symptoms resolve or acute disability subsides.
Life-threatening bleeding	60–100	Repeat every 8–24 hours until the life-threatening condition has resolved.
Surgery
Minor surgery, including tooth extraction	30–60	Every 24 hours for at least 1 day until full recovery.
Major surgery	80–100 (before and after surgery)	Repeat every 8–24 hours until adequate wound healing is achieved, then continue therapy for at least 7 days to maintain Factor VIII activity between 30 and 60 %.

During the course of treatment, Factor VIII levels should be monitored to determine the required dose and frequency of administration. In the case of major surgical interventions, particularly careful monitoring of replacement therapy is mandatory by performing coagulation analyses (measurement of plasma Factor VIII activity). Response to Factor VIII may vary among individual patients, resulting in different levels of in vivo recovery and different half-lives.

Prophylaxis

When used for long-term prevention of bleeding in patients with severe haemophilia A, the usual dose is 20–40 IU of Factor VIII per kg of body weight, administered every 2–3 days.

In some cases, particularly in younger patients, shorter intervals between doses or higher doses may be required.

Continuous infusion

Prior to surgery, a pharmacokinetic analysis should be performed to determine clearance.

The initial infusion rate can be calculated using the following formula:

Clearance × desired steady-state level of Factor VIII in plasma =

infusion rate (IU/kg/hour).

After the first 24 hours of continuous infusion, clearance should be recalculated and this should be done daily, by comparing the steady-state level of Factor VIII in plasma with the measured Factor VIII plasma level, taking into account the known infusion rate.

Children

In a clinical study involving 15 patients aged up to 6 years, no special dosage requirements for children were identified.

Doses are the same for adults and children, both for treatment and prophylaxis.

Method of administration

Prepare the solution as described below. The product should be administered intravenously. It is recommended to administer the product very slowly, at a rate not exceeding 2–3 ml per minute.

Carefully read all instructions given below and strictly follow them! The procedure described below should be carried out under sterile conditions!

Instructions for preparation of the solution

1. Allow the vials containing the solvent (water for injections) and the powder to reach room temperature. Room temperature should be maintained during the preparation of the solution. If a water bath is used for warming, care must be taken to ensure that water does not come into contact with the rubber stoppers or caps of the vials. The temperature of the water bath must not exceed 37 °C.
2. Remove the caps from the vials containing the powder and the water. Wipe the rubber stoppers with an alcohol-soaked swab.
3. Remove the protective cap from the short end of the double-ended needle without touching the tip. Insert the needle vertically through the center of the rubber stopper of the vial containing water. To ensure complete withdrawal of water from the vial, insert the needle through the stopper so that it just pierces it and is visible inside the vial.
4. Remove the protective cap from the other, longer end of the double-ended needle without touching the tip.

Holding the vial with water upside down above the vertically positioned vial with powder, quickly insert the needle through the center of the rubber stopper of the vial with powder. The vacuum inside the vial with powder will ensure the transfer of water from the solvent vial into the vial with powder.

1. Remove the double-ended needle from the empty solvent vial and from the vial with the product powder, then gently swirl the vial until the powder is completely dissolved.

At room temperature, Octanate dissolves rapidly, forming a clear solution. The dissolution time is less than 10 minutes at room temperature.

After reconstitution with the solvent, Octanate is administered intravenously. The solution should be clear or slightly opalescent. If the solution is cloudy or contains a precipitate, the product must not be used. Before administration, the prepared solution should be inspected visually for the presence of particulate matter or discoloration.

The prepared solution should be used immediately. The solution in the vial is intended for single use only.

Instructions for administration

Before and during administration of Factor VIII, the patient's pulse should be monitored as a precautionary measure. If the pulse rate increases, the rate of administration should be reduced or administration should be temporarily stopped.

1. After reconstitution of the powder, remove the protective cap from the filter needle and pierce the rubber stopper of the vial with powder.
2. Remove the cap from the filter needle, then attach and secure it to the syringe.
3. Invert the vial with the attached syringe upside down and draw the solution into the syringe.
4. Disinfect the injection site with an alcohol-soaked swab.
5. Remove the filter needle from the syringe and attach an injection needle instead.
6. Administer the solution intravenously very slowly, at a rate not exceeding 2–3 ml per minute.

Patients who use more than one vial of Octanate per treatment session may reuse the same injection needle and syringe; however, the filter needle is intended for single use only. A filter needle must always be used when drawing the product into the syringe.

Any unused product and waste material should be disposed of in accordance with local regulations.

Children

The product is used in pediatric practice.

Overdose

No symptoms of overdose have been reported.

Side effects

Summary of safety profile

Hypersensitivity or allergic reactions (which may include angioneurotic edema, burning and tingling sensations at the injection site, chills, flushing, generalized urticaria, headache, rash, hypotension, somnolence, nausea, restlessness, tachycardia, dyspnea, pruritus, vomiting, and wheezing) are rare and in some cases may progress to severe anaphylaxis (including shock).

Fever has been observed rarely.

In patients with hemophilia A receiving factor VIII, including Octanate, neutralizing antibodies (inhibitors) may develop. The appearance of such inhibitors is characterized by inadequate clinical response. In such cases, consultation with a specialized hemophilia treatment center is recommended.

For safety information regarding transmission of infectious agents, see section "Special precautions for use".

Tabulated list of adverse reactions

Table 3 is organized according to the MedDRA organ system classification.

Frequency of adverse reactions is categorized according to the following conventional terms: 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).

Table 3

MedDRA Standard Organ System Class

Adverse Reaction

Frequency

Immune system disorders	Hypersensitivity Anaphylactic shock	rare very rare
General disorders and administration site reactions	Fever	rare
Blood and lymphatic system disorders	FVIII inhibition	uncommon (PTPs)* very common (PUPs)*
Investigations	Positive antibodies to anti-factor VIII	rare

*The frequency is based on results from clinical trials of all FVIII products conducted in patients with severe hemophilia A.

PTPs – previously treated patients; PUPs – previously untreated patients.

Pediatric patients

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

Reporting of suspected adverse reactions

Reporting of suspected adverse reactions after marketing authorization is important. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are requested to report any suspected adverse reactions.

Shelf life.

2 years.

The reconstituted solution must be used immediately.

Incompatibilities.

Due to the lack of appropriate studies, this medicinal product must not be mixed with other medicinal products.

Only the provided infusion set should be used, as treatment failure may occur due to adsorption of human coagulation factor VIII onto the internal surface of certain types of infusion equipment.

Storage conditions.

Store at a temperature of 2 to 25 °C. Do not freeze.

Keep in the original packaging to protect from light.

Keep out of the reach of children.

Packaging.

Carton box No. 1: contains 1 type I glass vial with powder for solution for injection and package leaflet.

Carton box No. 2: contains 1 type I glass vial with solvent (water for injections, 5 or 10 ml) and a reconstitution and intravenous administration kit (1 single-use syringe, 1 double-ended needle, 1 filter needle, 1 injection needle, 2 alcohol swabs) in a bag or blister.

Box No. 1 and Box No. 2 are combined together with a plastic film.

Prescription category. Prescription only.

Manufacturers.

1. Octapharma Pharmazeutika Produktionsges m.b.H.
   Octapharma Pharmazeutica Produktionsges m.b.H.

2. Octapharma/Octapharma.

3. Octapharma AB/Octapharma AB.

Manufacturers' locations and addresses of sites of operation.

1. Oberlaaer Straße 235, 1100 Vienna, Austria
   Oberlaaerstrasse 235, 1100 Vienna, Austria.

2. 72 rue du Maréchal Foch, 67380 Lingolsheim, France
   72 rue du Maréchal Foch, 67380 Lingolsheim, France.

3. Lars Forssells gata 23, Stockholm, 11275, Sweden
   Lars Forssells gata 23, Stockholm, 11275, Sweden.