Emoclot

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT EMOCLAT

Composition:

Active substance: human blood coagulation factor VIII;

1 vial of powder contains 500 IU or 1000 IU of human blood coagulation factor VIII;

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

the solvent vial contains 10 ml of water for injections.

The reconstituted solution contains human blood coagulation factor VIII at 50 IU/ml (500 IU/10 ml) or 100 IU/ml (1000 IU/10 ml).

The specific activity of EMOCLAT is approximately 80 IU/mg protein. Activity (IU) is determined by chromogenic assay according to the European Pharmacopoeia.

The product is manufactured from human plasma.

The product contains human von Willebrand factor.

Excipients with known effect: the medicinal product contains up to 41 mg of sodium per vial (10 ml).

Pharmaceutical form. Powder and solvent for solution for infusion.

Main physicochemical properties:
Powder: white or pale yellow hygroscopic powder or brittle mass;
Solvent: clear, colorless liquid.

Pharmacotherapeutic group. Haemostatics. Coagulation factors VIII. 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 different physiological functions.

When administered to a patient with hemophilia, Factor VIII binds to the Von Willebrand factor circulating in the patient's blood.

Activated Factor VIII acts as a cofactor for activated Factor IX, accelerating the conversion of Factor X into its active form. Activated Factor X converts prothrombin into thrombin, which in turn converts fibrinogen into fibrin, allowing clot formation.

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, occurring spontaneously or following trauma or surgical procedures. Replacement therapy increases plasma levels of Factor VIII and thus temporarily corrects the deficiency, 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 trials.

Von Willebrand factor plays a role as a stabilizer of Factor VIII, mediates platelet adhesion to sites of vascular injury, and participates in platelet aggregation.

Ten patients with severe hemophilia A (median age 15 years, range 5–51) with high-titer inhibitors, enrolled in the PROFIT registry managed by the Italian Association of Hemophilia Centers, received EMOCLOT for inhibitor eradication through immune tolerance induction (ITI) therapy. Eight of these 10 patients received first-line ITI, while 2 patients underwent emergency ITI therapy after a previous failed attempt using another Factor VIII concentrate. Five patients received daily treatment with medium/high doses (100/200 IU/kg/day), and 5 patients received various doses administered every other day or three times per week (50–150 IU/kg). Complete or partial sustained response after a median follow-up of 9 years was achieved in 50% of cases. Among the 4 patients who achieved complete success, the median time to inhibitor eradication was 26 months.

Additionally, the literature describes experience with 11 patients (median age 17 years) with high-titer inhibitors treated with EMOCLOT via ITI therapy; overall, ITI was successful in 9 out of 11 patients (82%), with complete inhibitor eradication in 4 (36%) and partial success in 5 (45%) patients.

Children

125 children under 6 years of age without inhibitors, who had either never been previously treated or had received minimal treatment with human coagulation Factor VIII, received EMOCLOT in a controlled randomized study (SIPPET), designed to evaluate the incidence of inhibitor development in patients treated with plasma-derived or recombinant human coagulation Factor VIII. Of the 125 patients, 61 received EMOCLOT at doses established for on-demand or prophylactic treatment. Of these 61 patients, 34 received on-demand treatment, 5 received standard prophylaxis (3 infusions/week), 15 received modified prophylaxis (2 infusions/week), and 7 received various combinations of treatment regimens.

According to post-hoc analysis evaluating the annualized bleeding rate (ABR) in patients treated with EMOCLOT, ABR values were 4.2 (342 episodes) in patients receiving on-demand treatment, 7.5 (25 episodes) in patients receiving standard prophylaxis (of the total 25 bleeding episodes recorded in this group, 24 occurred in one patient; excluding this patient reduced the ABR to 0.24), 5.8 (92 episodes) in patients receiving modified prophylaxis, and 5.9 (60 episodes) in patients receiving various combinations of treatment regimens.

Pharmacokinetics.

After administration, approximately 2/3–3/4 of Factor VIII remains in the circulating blood.

The plasma Factor VIII activity level achieved is 80–120% of the calculated Factor VIII activity in plasma.

Factor VIII activity in plasma decreases according to a biphasic exponential curve.

In the initial phase, distribution between intravascular and other body fluids occurs with a plasma half-life of 3–6 hours.

In the subsequent, slower phase (likely reflecting Factor VIII uptake), the half-life ranges from 8 to 20 hours, averaging 12 hours, reflecting the true biological half-life.

The pharmacokinetic properties of EMOCLOT were studied in the clinical trial "Study of Pharmacokinetics and Clinical Efficacy of Factor VIII Concentrate EMOCLOT in Patients with Hemophilia A" (study code KV030), conducted in 15 patients with severe hemophilia A (with Factor VIII levels < 1). Pharmacokinetic parameters were determined after two separate infusions (dose 25 IU/kg) administered 3–6 months apart. Between the two infusions, patients received EMOCLOT according to their usual therapeutic regimen (for treatment or prophylaxis).

Mean pharmacokinetic parameters of EMOCLOT determined during the study are presented in Table 1.

Table 1

Parameter	First infusion		Second infusion
	Without subtraction of baseline values	With subtraction of baseline values	Without subtraction of baseline values	With subtraction of baseline values
AUC0-t (MO·ml-1·h)	10.94	9.96	10.75	8.95
AUC0-∞ (MO·ml-1·h)	13.08	11.22	12.07	9.89
Cltot (ml·h-1·kg-1)	2.63	2.89	2.51	2.99
Gradual recovery (%)	2.688		2.671
t1/2α (h)	0.543		0.768
t1/2β (h)	12.05		15.16

Paediatric population

Although specific paediatric data are lacking, limited published pharmacokinetic studies have not demonstrated significant differences between adults and children with the same condition.

Preclinical safety data.

Human coagulation factor VIII concentrate is a natural component of human plasma and acts similarly to endogenous factor VIII.

Single-dose toxicity studies are not relevant, as high doses cause hypervolaemia.

Repeated-dose (multiple-dose) toxicity studies in animals are not feasible due to interference from antibodies formed against the heterologous protein.

Even doses substantially exceeding the recommended human dose per kg of body weight have not shown any toxic effects in test animals.

Since clinical experience with human coagulation factor VIII has not confirmed any carcinogenic or mutagenic effects, experimental studies, particularly those involving heterologous species, are not considered necessary.

Clinical characteristics.

Indications.

Treatment and prevention of bleeding in patients with hemophilia A (congenital deficiency of blood coagulation factor VIII).

Treatment of acquired deficiency of blood coagulation factor VIII.

Treatment of patients with hemophilia who have developed antibodies to blood coagulation factor VIII (inhibitors: see also "Special precautions").

Contraindications.

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

Interaction with other medicinal products and other forms of interaction.

There have been no reports of interactions between blood coagulation factor VIII preparations and other medicinal products.

Children

Specific data in children are lacking.

Special precautions for use.

Traceability

To improve the traceability of biological medicinal products, it is recommended to record the name and batch number of the EMOCLT product each time it is administered to a patient.

Hypersensitivity

Hypersensitivity reactions may occur during treatment with EMOCLT.

The product contains traces of human proteins other than factor VIII. If symptoms of hypersensitivity occur, patients should be advised to immediately discontinue use of the product and consult a physician. Patients should be informed about early signs of hypersensitivity reactions, including rash, generalized urticaria, chest tightness, wheezing, hypotension, and anaphylaxis.

In the event of shock, current medical standards for shock management should be followed.

Important information on excipients of the medicinal product EMOCLT

This medicinal product contains up to 41 mg of sodium per vial (10 mL), which corresponds to 2.05% of the WHO recommended maximum daily intake of sodium for adults (2 g).

Inhibitors

The development of neutralizing antibodies (inhibitors) to human blood coagulation factor VIII is a known complication in the treatment of patients with hemophilia A. These inhibitors are usually immunoglobulins IgG directed against the procoagulant activity of factor VIII, and their concentration is measured in Bethesda units (BU) per 1 mL of plasma using a modified assay. 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 formation depends on their titer. The risk of inadequate clinical response is lower with low inhibitor titers compared to high inhibitor titers.

Overall, all patients receiving treatment with factor VIII coagulation products should be carefully monitored for inhibitor development through appropriate clinical observation and laboratory testing. If the expected plasma factor VIII activity level is not achieved with the appropriate dose, or if bleeding is not controlled by the administered dose, testing for the presence of factor VIII inhibitors should be performed. In patients with high inhibitor levels, factor VIII therapy may be ineffective, and alternative treatment options should be considered. The treatment of such patients should be managed by a physician experienced in treating patients with hemophilia and factor VIII inhibitors.

Cardiovascular complications

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

Catheter-related complications

If central venous access is required, the risk of device-related complications, including local infections, bacteremia, and catheter site thrombosis, should be considered.

Viral safety

Standard measures to prevent infections from medicinal products derived from human blood or plasma include donor selection, testing of individual plasma units and plasma pools for specific infection markers, and implementation of effective manufacturing steps for virus inactivation/removal.

Nevertheless, when administering medicinal products made from human blood or plasma, the possibility of transmitting infectious agents, including unknown or currently emerging viruses and other pathogens, cannot be entirely excluded.

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

Consideration should be given to administering appropriate vaccinations (e.g., against hepatitis A and B) to patients who are regularly or repeatedly treated with factor VIII coagulation products derived from human plasma.

To maintain the link between the patient and the product batch, it is strongly recommended to record the name and batch number of EMOCLT each time the product is administered.

Children

Specific data in pediatric patients are lacking.

Use during pregnancy or breastfeeding

Studies on the effects of factor VIII on reproductive function in animals have not been conducted. Since the incidence of hemophilia A in women is low, experience with the use of factor VIII during pregnancy and breastfeeding is limited. Therefore, factor VIII should be used during pregnancy and breastfeeding only if clearly indicated.

Ability to affect reaction speed when driving or operating machinery

EMOCLT does not affect the ability to drive or operate machinery.

Dosage and Administration

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 determination and the frequency of repeat administrations. Individual patients may respond differently to factor VIII, demonstrating variable half-lives and recovery times. Dose adjustments based on body weight may be necessary for patients with significantly low or high body weight.

In the case of major surgical procedures, it is essential to ensure precise monitoring of replacement therapy by performing coagulation tests (factor VIII activity in blood plasma).

When using a one-stage in vitro coagulation assay based on activated partial thromboplastin time (aPTT) to determine factor VIII activity in patient plasma samples, the results may significantly depend on both the type of aPTT reagent and the reference standard used. Furthermore, considerable discrepancies may occur between results obtained using the one-stage aPTT-based coagulation assay and the chromogenic assay according to the European Pharmacopoeia. This is particularly important when changing laboratories and/or reagents used for testing.

Dosage

The dosage 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 administered quantity of factor VIII is expressed in International Units (IU), corresponding to the current WHO standard for factor VIII preparations. Factor VIII activity in plasma is expressed 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 corresponds 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. 1 International Unit (IU) of factor VIII per 1 kg of body weight increases factor VIII activity in plasma by 1.5–2% 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 activity (%) (IU/dL) × 0.4

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 situations listed below, factor VIII activity should not fall below the specified plasma activity level (% of normal) during the indicated period. Table 2 can be used as a guideline for dosing in bleeding episodes and surgical procedures.

Table 2

Degree of bleeding / type of surgical procedure	Required Factor VIII level (%) (IU/dl)	Frequency of administration (hours) / duration of treatment (days)
Bleeding
Early haemarthrosis, muscle bleeding, or oral cavity bleeding	20–40	Repeat every 12–24 hours for at least 1 day until bleeding stops, as indicated by resolution of pain or healing.
More pronounced haemarthrosis, muscle bleeding, or hematoma	30–60	Repeat administration every 12–24 hours for 3–4 days or longer, until pain and acute disability have resolved.
Life-threatening bleeding	60–100	Repeat administration every 8–24 hours until the life-threatening situation is resolved.
Surgical procedures
Minor surgical procedures, including tooth extraction	30–60	Every 24 hours for at least 1 day until healing is achieved.
Major surgical procedures	80–100 (before and after surgery)	Repeat administration every 8–24 hours until adequate wound healing; then continue therapy for at least 7 days, maintaining Factor VIII activity at 30–60% (30–60 IU/dl).

Prophylaxis

For long-term prevention of bleeding in patients with severe hemophilia A, doses of 20 to 40 IU of factor VIII per kg of body weight are usually administered at intervals of every 2 to 3 days. In individual cases, especially in younger patients, shorter intervals between doses or higher doses may be required.

Method of administration

The drug is administered intravenously by injection or slow infusion.

When administered by intravenous injection, the preparation should be injected over 3–5 minutes, with monitoring of the patient's pulse rate. Infusion should be interrupted or the rate reduced if an increase in pulse rate occurs.

The infusion rate should be individually determined for each patient.

Reconstitution of powder with solvent

1. Allow the vial of powder and the vial of solvent to reach room temperature.
2. Maintain room temperature throughout the entire reconstitution (dissolving) process (maximum 10 minutes).
3. Remove the protective caps from the vial of powder and the vial of solvent.
4. Disinfect the stopper surfaces of both vials with ethyl alcohol.
5. Open the device package as shown in Figure A, taking care not to touch the inner part of the packaging (Figure A).
6. Do not remove the device from the packaging.
7. Invert the package with the device and pierce the stopper of the solvent vial with the plastic spike of the device, so that the blue part of the device connects to the solvent vial (Figure B).
8. Remove the device packaging by holding its edge, taking care not to touch the device itself (Figure V).
9. Ensure that the powder vial is placed on a stable surface. Invert the solvent vial with the attached device so that the solvent vial is positioned above the device. Press the transparent adapter on the powder vial's stopper to pierce the powder vial's stopper with the plastic spike. The solvent will then automatically begin to transfer into the powder vial (Figure G).
10. After the transfer of solvent, unscrew the blue part of the system to which the solvent vial is attached, and remove it (Figure D).
11. Gently swirl the vial until the powder is completely dissolved (Figure E).
12. Do not shake the vial vigorously to avoid foaming.

Fig. A	Fig. B

Fig. B	Fig. C

Fig. D	Fig. E

Administration of the solution

After reconstitution, the solution may contain a small amount of fine filaments or particles.

The solution should be visually inspected for particulate matter or discoloration prior to administration. The solution should be clear or slightly opalescent. Do not use the solution if it is cloudy or contains precipitate.

1. Draw air into the syringe by pulling back the plunger; attach the syringe to the device and inject the air from the syringe into the vial containing the reconstituted solution (Fig. E).
2. While holding the plunger, invert the system so that the vial with the reconstituted solution is positioned above the device. Slowly pull back the plunger to draw the concentrate into the syringe (Fig. F).
3. Detach the syringe by turning it counterclockwise.
4. Visually inspect the solution in the syringe, which should be clear or slightly opalescent and free from particles.
5. Attach a butterfly needle to the syringe and administer the medication intravenously by infusion or slow injection.

Fig. E	Fig. F

After opening, the contents of the vial must be used immediately.

The reconstituted solution filled into a syringe must be used immediately.

The contents of the vial should be used for a single administration only.

Use of the medicinal product after the expiry date stated on the packaging is prohibited.

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

Children.

The safety and efficacy of EMOKLOT in children under 12 years of age have not been established. Available data are described in section “Pharmacodynamics”, but dosage recommendations cannot be provided.

Dosing in adolescents (12–18 years) for each indication is based on body weight.

Overdose.

There have been no reports of symptoms related to overdose with human blood coagulation factor VIII.

Adverse reactions.

Summary of safety profile

Hypersensitivity or allergic reactions (including angioedema, burning and sharp pain at the infusion site, chills, flushing, generalized urticaria, headache, rash, hypotension, lethargy, nausea, restlessness, tachycardia, chest tightness, tingling, vomiting, and wheezing) are rare and in some cases may progress to severe anaphylaxis (including shock).

Elevated body temperature has also been observed.

Patients with hemophilia A receiving treatment with factor VIII products, including EMOKLOT, may develop neutralizing antibodies (inhibitors). The development of inhibitors in patients with hemophilia A may manifest as a lack of clinical response. In such cases, consultation with a specialized hemophilia center is recommended.

Information on safety regarding transmissible agents is provided in the section "Special precautions for use".

List of adverse reactions in tabular form

The adverse effects that may occur during administration of human blood coagulation factor VIII are presented in Table 3 according to MedDRA (Medical Dictionary for Regulatory Activities) system organ class and preferred terms.

Frequency was estimated using the following categories: 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), frequency not known (cannot be estimated from available data).

Confirmed data on the frequency of adverse reactions from clinical trials are lacking.

The information listed below is based on the safety profile of human blood coagulation factor VIII and has been partially observed during the post-marketing period (post-marketing experience); since post-marketing adverse reaction reports are voluntary and come from a population of unknown size, it is not possible to reliably estimate their frequency.

Table 3

MedDRA System Organ Class	Adverse Reaction	Frequency
Blood and lymphatic system disorders	Development of factor VIII inhibitors	Uncommon (PRL) ** Very common (PRN) **
Immune system disorders	Hypersensitivity	Not known
	Allergic reactions (hypersensitivity)*	Not known
	Anaphylactic reaction	Not known
	Anaphylactic shock	Not known
Psychiatric disorders	Restlessness	Not known
Nervous system disorders	Headache	Not known
	Lethargy	Not known
	Paraesthesia	Not known
Cardiac disorders	Tachycardia	Not known
Vascular disorders	Flushing	Not known
	Hypotension	Not known
Respiratory, thoracic and mediastinal disorders	Wheezing*	Not known
Gastrointestinal disorders	Nausea	Not known
	Vomiting	Not known
Skin and subcutaneous tissue disorders	Angioedema	Not known
	Generalized urticaria (urticaria)*	Not known
	Rash (urticaria)*	Not known
General disorders and administration site conditions	Burning sensation at infusion site (pain at infusion site)*	Not known
	Acute pain at infusion site (pain at infusion site)*	Not known
	Chills	Not known
	Chest tightness (chest discomfort)*	Not known
	Pyrexia	Not known

* MedDRA lower level terms more appropriate for describing these adverse reactions; the MedDRA preferred term is provided in parentheses.

** Frequency data are based on results from clinical studies of all Factor VIII products conducted in patients with severe haemophilia A. PEP – previously treated patients, PUNP – previously untreated patients.

Children

Specific data in children are lacking.

Reporting of suspected adverse reactions

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

Shelf life

3 years.

Solvent (water for injections) – 5 years.

The medicinal product should be used immediately after reconstitution.

Storage conditions

Store in a refrigerator (at 2 to 8 ℃). Do not freeze. Store in the original packaging to protect from light, and in a place inaccessible to children.

Prior to use and within its shelf life, the vial containing the powder may be stored at room temperature not exceeding 25 ℃ for up to 6 consecutive months. After this period, the vial with powder must be destroyed.

After storage of the powder vial at room temperature, further storage in the refrigerator is prohibited.

The date when storage at room temperature was initiated should be indicated on the original packaging of the medicinal product in the designated space provided for this purpose.

Incompatibilities

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

Only the provided injection/infusion set should be used, as treatment may be ineffective due to adsorption of human coagulation factor VIII onto the internal surfaces of other administration devices.

Packaging

One vial containing 500 IU or 1000 IU, supplied with one vial of 10 ml solvent (water for injections) and a reconstitution and administration set, packed in a cardboard box.

Prescription category: Prescription only.

Manufacturer

KEDRION S.P.A.

Manufacturer's location and address of its business site

VIA PROVINCIALE (loc. BOLOGNANA) - 55027 GALLICANO (LU), ITALY