Afstyla^® (Lyophilisate) Instructions for Use

Marketing Authorization Holder

CSL Behring, GmbH (Germany)

ATC Code

B02BD02 (Blood coagulation factor VIII)

Active Substance

Lonoctocog alfa (Rec.INN registered by WHO)

Dosage Forms

	Afstyla®	Lyophilisate for preparation of solution for intravenous administration 250 IU: vial 1 pc.
		Lyophilisate for preparation of solution for intravenous administration 500 IU: vial 1 pc.
		Lyophilisate for preparation of solution for intravenous administration 1000 IU: vial 1 pc.
		Lyophilisate for preparation of solution for intravenous administration 1500 IU: vial 1 pc.
		Lyophilisate for preparation of solution for intravenous administration 2000 IU: vial 1 pc.
		Lyophilisate for preparation of solution for intravenous administration 2500 IU: vial 1 pc.
		Lyophilisate for preparation of solution for intravenous administration 3000 IU: vial 1 pc.

Dosage Form, Packaging, and Composition

Lyophilisate for preparation of solution for intravenous administration as a powder or friable mass from white to slightly yellowish; reconstituted solution is an almost colorless liquid, from clear to slightly opalescent; solvent is a colorless clear liquid.

* lonoctocog alfa (single-chain human blood coagulation factor VIII)
** after reconstitution with 2.5 ml of water for injections the solution contains 100 IU/ml of single-chain human blood coagulation factor VIII

Excipients: L-histidine – 7.8 mg, sucrose – 15 mg, polysorbate 80 – 0.5 mg, calcium chloride – 0.9 mg, sodium chloride – 41 mg, hydrochloric acid – q.s. to adjust pH.

Solvent water for injections 2.5 ml.

250 IU – vials of colorless glass with a capacity of 6 ml (1) in a kit with solvent (vial 1 pc.), solvent transfer device with built-in 15 µm filter (1 pc.) and a cardboard pack with an intravenous administration kit (disposable syringe (1 pc.), butterfly needle (1 pc.), disinfectant wipes (2 pcs.), non-sterile plaster (1 pc.)) – cardboard packs.

Lyophilisate for preparation of solution for intravenous administration as a powder or friable mass from white to slightly yellowish; reconstituted solution is an almost colorless liquid, from clear to slightly opalescent; solvent is a colorless clear liquid.

* lonoctocog alfa (single-chain human blood coagulation factor VIII)
** after reconstitution with 2.5 ml of water for injections the solution contains 200 IU/ml of single-chain human blood coagulation factor VIII

Excipients: L-histidine – 7.8 mg, sucrose – 15 mg, polysorbate 80 – 0.5 mg, calcium chloride – 0.9 mg, sodium chloride – 41 mg, hydrochloric acid – q.s. to adjust pH.

Solvent water for injections 2.5 ml.

250 IU – vials of colorless glass with a capacity of 6 ml (1) in a kit with solvent (vial 1 pc.), solvent transfer device with built-in 15 µm filter (1 pc.) and a cardboard pack with an intravenous administration kit (disposable syringe (1 pc.), butterfly needle (1 pc.), disinfectant wipes (2 pcs.), non-sterile plaster (1 pc.)) – cardboard packs.

Lyophilisate for preparation of solution for intravenous administration as a powder or friable mass from white to slightly yellowish; reconstituted solution is an almost colorless liquid, from clear to slightly opalescent; solvent is a colorless clear liquid.

* lonoctocog alfa (single-chain human blood coagulation factor VIII)
** after reconstitution with 2.5 ml of water for injections the solution contains 400 IU/ml of single-chain human blood coagulation factor VIII

Excipients: L-histidine – 7.8 mg, sucrose – 15 mg, polysorbate 80 – 0.5 mg, calcium chloride – 0.9 mg, sodium chloride – 41 mg, hydrochloric acid – q.s. to adjust pH.

Solvent water for injections 2.5 ml.

250 IU – vials of colorless glass with a capacity of 6 ml (1) in a kit with solvent (vial 1 pc.), solvent transfer device with built-in 15 µm filter (1 pc.) and a cardboard pack with an intravenous administration kit (disposable syringe (1 pc.), butterfly needle (1 pc.), disinfectant wipes (2 pcs.), non-sterile plaster (1 pc.)) – cardboard packs.

Lyophilisate for preparation of solution for intravenous administration as a powder or friable mass from white to slightly yellowish; reconstituted solution is an almost colorless liquid, from clear to slightly opalescent; solvent is a colorless clear liquid.

* lonoctocog alfa (single-chain human blood coagulation factor VIII)
** after reconstitution with 5 ml of water for injections the solution contains 300 IU/ml of single-chain human blood coagulation factor VIII

Excipients: L-histidine – 15.5 mg, sucrose – 30 mg, polysorbate 80 – 1 mg, calcium chloride – 1.9 mg, sodium chloride – 82 mg, hydrochloric acid – q.s. to adjust pH.

Solvent water for injections 5 ml.

250 IU – vials of colorless glass with a capacity of 10 ml (1) in a kit with solvent (vial 1 pc.), solvent transfer device with built-in 15 µm filter (1 pc.) and a cardboard pack with an intravenous administration kit (disposable syringe (1 pc.), butterfly needle (1 pc.), disinfectant wipes (2 pcs.), non-sterile plaster (1 pc.)) – cardboard packs.

Lyophilisate for preparation of solution for intravenous administration as a powder or friable mass from white to slightly yellowish; reconstituted solution is an almost colorless liquid, from clear to slightly opalescent; solvent is a colorless clear liquid.

* lonoctocog alfa (single-chain human blood coagulation factor VIII)
** after reconstitution with 5 ml of water for injections the solution contains 400 IU/ml of single-chain human blood coagulation factor VIII

Excipients: L-histidine – 15.5 mg, sucrose – 30 mg, polysorbate 80 – 1 mg, calcium chloride – 1.9 mg, sodium chloride – 82 mg, hydrochloric acid – q.s. to adjust pH.

Solvent water for injections 5 ml.

250 IU – vials of colorless glass with a capacity of 10 ml (1) in a kit with solvent (vial 1 pc.), solvent transfer device with built-in 15 µm filter (1 pc.) and a cardboard pack with an intravenous administration kit (disposable syringe (1 pc.), butterfly needle (1 pc.), disinfectant wipes (2 pcs.), non-sterile plaster (1 pc.)) – cardboard packs.

Lyophilisate for preparation of solution for intravenous administration as a powder or friable mass from white to slightly yellowish; reconstituted solution is an almost colorless liquid, from clear to slightly opalescent; solvent is a colorless clear liquid.

* lonoctocog alfa (single-chain human blood coagulation factor VIII)
** after reconstitution with 5 ml of water for injections the solution contains 500 IU/ml of single-chain human blood coagulation factor VIII

Excipients: L-histidine – 15.5 mg, sucrose – 30 mg, polysorbate 80 – 1 mg, calcium chloride – 1.9 mg, sodium chloride – 82 mg, hydrochloric acid – q.s. to adjust pH.

Solvent water for injections 5 ml.

250 IU – vials of colorless glass with a capacity of 10 ml (1) in a kit with solvent (vial 1 pc.), solvent transfer device with built-in 15 µm filter (1 pc.) and a cardboard pack with an intravenous administration kit (disposable syringe (1 pc.), butterfly needle (1 pc.), disinfectant wipes (2 pcs.), non-sterile plaster (1 pc.)) – cardboard packs.

Lyophilisate for preparation of solution for intravenous administration as a powder or friable mass from white to slightly yellowish; reconstituted solution is an almost colorless liquid, from clear to slightly opalescent; solvent is a colorless clear liquid.

* lonoctocog alfa (single-chain human blood coagulation factor VIII)
** after reconstitution with 5 ml of water for injections the solution contains 600 IU/ml of single-chain human blood coagulation factor VIII

Excipients: L-histidine – 15.5 mg, sucrose – 30 mg, polysorbate 80 – 1 mg, calcium chloride – 1.9 mg, sodium chloride – 82 mg, hydrochloric acid – q.s. to adjust pH.

Solvent water for injections 5 ml.

250 IU – vials of colorless glass with a capacity of 10 ml (1) in a kit with solvent (vial 1 pc.), solvent transfer device with built-in 15 µm filter (1 pc.) and a cardboard pack with an intravenous administration kit (disposable syringe (1 pc.), butterfly needle (1 pc.), disinfectant wipes (2 pcs.), non-sterile plaster (1 pc.)) – cardboard packs.

Clinical-Pharmacological Group

Hemostatic agent. Blood clotting factors (VIII and von Willebrand) preparation

Pharmacotherapeutic Group

Hemostatic agent

Pharmacological Action

Hemostatic agent. Lonoctocog alfa is a single-chain human blood coagulation factor VIII, obtained by genetic engineering in CHO cells, necessary for effective hemostasis in hemophilia A.

Lonoctocog alfa is a polypeptide chain with a truncated B-domain that provides a covalent bond between the heavy and light chains of blood coagulation factor VIII. It has a higher affinity for von Willebrand factor than full-length recombinant human blood coagulation factor VIII. Von Willebrand factor stabilizes blood coagulation factor VIII and protects it from degradation.

The functional characteristics of single-chain human blood coagulation factor VIII are similar to those of endogenous blood coagulation factor VIII, the activity of which is significantly reduced in patients with hemophilia A, which requires replacement therapy.

Hemophilia A is a sex-linked hereditary blood coagulation disorder due to a reduced level of blood coagulation factor VIII, leading to massive hemorrhages into joints, muscles and internal organs, both spontaneously and as a result of injuries and surgical interventions.

During replacement therapy, the level of blood coagulation factor VIII in plasma increases, resulting in temporary correction of the factor deficiency in the blood plasma and a reduction in the tendency to increased bleeding.

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

When administered intravenously to patients with hemophilia, blood coagulation factor VIII binds to the patient’s endogenous von Willebrand factor in the circulatory system. Activated blood coagulation factor VIII acts as a co-factor for activated blood coagulation factor IX, accelerating the conversion of blood coagulation factor X to activated blood coagulation factor X.

Activated blood coagulation factor X promotes the conversion of prothrombin to thrombin. Thrombin in turn promotes the conversion of fibrinogen to fibrin, leading to clot formation.

Pharmacokinetics

The assessment of pharmacokinetic parameters was based on the activity of blood coagulation factor VIII in blood plasma, measured using a chromogenic substrate assay (when using a one-stage coagulation activity assay, the result should be multiplied by a conversion factor of 2 to determine the patient’s blood coagulation factor VIII activity).

The pharmacokinetic profile obtained after 3-6 months of repeated administration of lonoctocog alfa was comparable to the pharmacokinetic profile obtained after the first dose administration.

Pharmacokinetic parameters of lonoctocog alfa after a single injection at a dose of 50 IU/kg in patients with severe hemophilia A measured using a chromogenic substrate assay.

In adults: C_max – 106 (62.4; 151) IU/dL, AUC_0-inf – 1910 (932; 4090) IU×h/dL, T_1/2 – 13.7 (7.54; 23.9) h, mean residence time – 20.2 (10.8; 35.1) h, clearance – 2.67 (1.26; 5.79) ml/h/kg, V_ss – 53.2 (32.4; 99.6) ml/kg.

In children aged 0 to 18 years: C_max – 78.6 (59.3; 138) – 92.4 (45.5; 131) IU/dL, AUC_0-inf – 985 (561; 2010) – 1520 (683; 380) IU×h/dL, T_1/2 – 10.1 (5.19; 17.8) – 13.5 (6.32; 3.8) h, mean residence time – 13.0 (6.05; 17.9) – 18.6 (9.17; 31.7) h, clearance – 5.08 (2.52; 8.92) – 3.31 (2.10; 7.32) ml/h/kg, V_ss – 70.7 (57.3; 88.3) – 62.0 (45.9; 121) ml/kg.

Compared to adolescents and adults, children under 12 years of age may have higher clearance and shorter T_1/2, which is consistent with data for other coagulation factor preparations.

Indications

Treatment and prevention of bleeding in patients with hemophilia A (congenital deficiency of blood coagulation factor VIII), previously treated with replacement therapy.

Lonoctocog is indicated for use in all age groups.

ICD codes

Dosage Regimen

For intravenous administration.

The calculation of the required dose of blood coagulation factor VIII is based on empirical data that 1 IU of blood coagulation factor VIII per kg of body weight increases the activity of this factor in blood plasma by 2 IU/dL. The required dose is calculated using the following formula:

Dose (IU) = body weight (kg) x desired increase in blood coagulation factor VIII level (IU/dL or % of normal) x 0.5 (IU/kg per IU/dL).

When selecting the dose and frequency of administration, one should always be guided by clinical effectiveness in each individual case.

Adverse Reactions

Blood and lymphatic system disorders uncommon – formation of factor VIII inhibitors.

Immune system disorders common – hypersensitivity.

Nervous system disorders common – dizziness, paresthesia.

Skin and subcutaneous tissue disorders common – rash; uncommon – erythema, pruritus.

General disorders and administration site conditions common – pyrexia; uncommon – injection site pain, chills, feeling hot.

Contraindications

Hypersensitivity to lonoctocog alfa, history of hypersensitivity to proteins of animal origin.

With caution

Patients over 65 years of age.

Use in Pregnancy and Lactation

Use is possible only if there are strict indications.

Pediatric Use

The drug is approved for use in children and adolescents under 18 years of age.

Geriatric Use

Use with caution in patients over 65 years of age.

Special Precautions

If symptoms of hypersensitivity appear, the use of the drug containing Lonoctocog alfa should be stopped immediately and medical attention should be sought.

Patients should be informed about the early symptoms of hypersensitivity reactions, such as localized urticaria, generalized urticaria, chest tightness, wheezing, hypotension and anaphylaxis.

In patients with previous hypersensitivity reactions, appropriate premedication should be administered.

In case of shock development, standard anti-shock therapy should be carried out.

In patients receiving therapy with lonoctocog alfa, monitoring for the formation of neutralizing antibodies (inhibitors) to blood coagulation factor VIII should be performed using laboratory and clinical methods.

Typically, these inhibitors are immunoglobulins IgG directed against the procoagulant activity of blood coagulation factor VIII, which are quantified in Bethesda units (BU) per ml of blood plasma using a modified assay.

The risk of inhibitor formation correlates with the severity of the disease, as well as with the exposure to blood coagulation factor VIII and is highest during the first 20 days of administration. In rare cases, inhibitor formation is possible after the first 100 days of drug administration.

The appearance of inhibitors should also be monitored when transferring patients from one blood coagulation factor VIII preparation to another, as cases of re-formation of inhibitors (in low titer) have been observed in patients who received therapy with blood coagulation factor VIII preparations for more than 100 days.

In this regard, careful monitoring of all patients for inhibitor formation after any drug change is recommended.

A low titer of inhibitors, which is detected over a short period or is constantly present, is associated with a lower risk of insufficient clinical response compared to a high titer of inhibitors.

In general, careful monitoring should be carried out for all patients receiving therapy with blood coagulation factor VIII preparations regarding inhibitor formation through appropriate clinical observations and laboratory tests.

If the expected level of blood coagulation factor VIII activity is not achieved, or if bleeding does not stop after administration of an appropriate dose of the drug, the patient should be examined for the presence of inhibitors to blood coagulation factor VIII.

In patients with a high inhibitor content, therapy with blood coagulation factor VIII may be ineffective, and in such cases, other treatment options should be considered. Therapy for such patients should be carried out by physicians experienced in the treatment of patients with hemophilia and inhibitors to blood coagulation factor VIII.

If a one-stage coagulation test is used to determine the patient’s blood coagulation factor VIII activity, its result should be multiplied by a conversion factor of 2. The chromogenic assay is recommended for determining the patient’s blood coagulation factor VIII activity.

In patients with pre-existing cardiovascular risk factors, the use of blood coagulation factor VIII preparations may increase the risk of cardiovascular complications.

When central venous access (CVA) is required, the risk of complications associated with CVA, including local infections, bacteremia, and catheterization site thrombosis, should be considered.

Effect on the Ability to Drive and Operate Machinery

Lonoctocog alfa does not affect the ability to drive vehicles and operate machinery. However, some adverse reactions associated with the drug’s action may affect concentration and the speed of psychomotor reactions. Patients with such impairments should refrain from driving and other potentially hazardous activities.

Storage Conditions

Store at 2°C (36°F) to 8°C (46°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.