Esperoct
UkraineTable of Contents
INSTRUCTION for medical use of the medicinal product Esperoct (Esperoct)
Composition:
Active substance: turoctocog alfa pegol;
500 IU
One vial of powder contains a nominal quantity of 500 IU turoctocog alfa pegol*.
After reconstitution of the product, 1 ml of solution contains approximately 125 IU turoctocog alfa pegol.
1000 IU
One vial of powder contains a nominal quantity of 1000 IU turoctocog alfa pegol*.
After reconstitution of the product, 1 ml of solution contains approximately 250 IU turoctocog alfa pegol.
1500 IU
One vial of powder contains a nominal quantity of 1500 IU turoctocog alfa pegol*.
After reconstitution of the product, 1 ml of solution contains approximately 375 IU turoctocog alfa pegol.
2000 IU
One vial of powder contains a nominal quantity of 2000 IU turoctocog alfa pegol*.
After reconstitution of the product, 1 ml of solution contains approximately 500 IU turoctocog alfa pegol.
3000 IU
One vial of powder contains a nominal quantity of 3000 IU turoctocog alfa pegol*.
After reconstitution of the product, 1 ml of solution contains approximately 750 IU turoctocog alfa pegol.
Activity (in international units, IU) is determined by a chromogenic assay method according to the European Pharmacopoeia. The specific activity of turoctocog alfa pegol is approximately 9500 IU/mg protein.
The active substance, turoctocog alfa pegol, is a covalent conjugate of the protein turoctocog alfa* with polyethylene glycol (PEG) of 40 kDa size.
* Human Factor VIII produced by recombinant DNA technology using a Chinese hamster ovary cell line, with no human or animal-derived additives used in this cell line, during purification, conjugation, or formulation of the components of Esperoct.
Excipients:
powder: L-histidine; sucrose; polysorbate 80; sodium chloride; L-methionine; calcium chloride, dihydrate; sodium hydroxide (for pH adjustment); hydrochloric acid (for pH adjustment);
solvent: sodium chloride; water for injections.
Pharmaceutical form. Powder and solvent for solution for injection.
Main physicochemical properties: lyophilized powder appears as a lyophilisate ranging from white to practically white.
Solvent is clear and colourless; pH 6.9; osmolality 590 mOsmol/kg.
Pharmacotherapeutic group. Haemostatics. Coagulation factor VIII.
ATC code B02BD02.
Pharmacological Properties.
Pharmacodynamics.
Mechanism of action
Turoctocog alfa pegol is a purified recombinant human factor VIII (rFVIII) conjugated with a 40 kDa polyethylene glycol (PEG) molecule attached to the protein. The PEG is linked to the O-linked glycan in the truncated B-domain of rFVIII (turoctocog alfa). The mechanism of action of turoctocog alfa pegol is based on replacement of deficient or absent factor VIII in patients with haemophilia A.
When turoctocog alfa pegol is activated by thrombin at the site of injury, the B-domain containing the PEG moiety and the a3-region are cleaved off, resulting in formation of activated recombinant factor VIII (rFVIIIa), which is structurally similar to native factor VIIIa.
The factor VIII complex with von Willebrand factor consists of two molecules (factor VIII and von Willebrand factor) that have distinct physiological functions. Upon administration of the product to a patient with haemophilia, factor VIII binds to von Willebrand factor in the bloodstream. Activated factor VIII acts as a cofactor to activated factor IX, accelerating the conversion of factor X to activated factor X.
Activated factor X converts prothrombin into thrombin. Thrombin then converts fibrinogen into fibrin, after which a clot can form. Haemophilia A is an X-linked inherited bleeding disorder caused by reduced levels of factor VIII:C and leads to severe bleeding into joints, muscles, or internal organs either spontaneously or following trauma or surgical procedures. By means of factor VIII replacement therapy, factor VIII levels in blood plasma are increased, thereby enabling temporary correction of the deficiency and counteracting the tendency to bleed.
Clinical efficacy in prophylaxis and treatment of bleeding episodes
The clinical efficacy of Esperoct in prophylaxis and treatment of bleeding was evaluated in seven multicentre prospective clinical studies. All patients had severe haemophilia A.
It should be noted that annual bleeding rates (ABR) obtained from different factor concentrates and different clinical trials should not be directly compared.
Prophylaxis in adults/children aged 12 years and older
The efficacy of Esperoct in preventing and treating bleeding episodes was assessed in an open-label, uncontrolled study involving adult patients and children aged 12 years and older with severe haemophilia A. Prophylactic efficacy of Esperoct was demonstrated using a dose of 50 IU/kg administered every 4 days or every 3–4 days (twice weekly) in 175 patients. The mean annual bleeding rate (ABR) in adults and children aged 12 years and older receiving Esperoct was 1.18 (interquartile range (IQR): 0.00; 4.25), with ABR for spontaneous bleeds being 0.00 (IQR: 0.00; 1.82), for trauma-related bleeds 0.00 (IQR: 0.00; 1.74), and joint bleed ABR being 0.85 (IQR: 0.00; 2.84). When imputed values (replacing missing data from patients who discontinued from the study) were included, the calculated mean ABR for all bleeds was 3.70 (95% CI: 2.94; 4.66). Of the 175 adults/children aged 12 years and older on prophylaxis, 70 (40%) patients had no bleeding episodes. The mean annual exposure to the medicinal product for prophylaxis was 4,641 IU/kg.
Adults/children aged 12 years and older who had a low bleeding frequency (0–2 bleeding episodes in the previous 6 months) and who had received at least 50 doses of Esperoct were eligible for randomization into prophylactic treatment groups receiving either the product every 7 days (75 IU/kg every 7 days) or every 4 days (50 IU/kg every 4 days). Overall, 55 out of 120 eligible patients agreed to be randomized (17 to the 50 IU/kg every 4 days group and 38 to the every 7 days group). The ABR in randomized patients was 1.77 (0.59; 5.32) with dosing every 4 days and 3.57 (2.13; 6.00) with weekly prophylaxis. During the randomized phase of the study, nine of these patients returned to prophylaxis every 4 days. Overall, considering all extension phases of the study, 31 out of 61 patients receiving prophylaxis every 7 days returned to the treatment regimen of dosing every 4 days.
Prophylaxis in previously treated patients (aged under 12 years)
The efficacy and safety of Esperoct for prophylaxis and on-demand treatment of bleeding episodes were evaluated in an open-label, single-arm, uncontrolled study involving 68 children under 12 years of age with severe haemophilia A.
Prophylactic efficacy of Esperoct was demonstrated with a prophylactic dose of 64.7 IU/kg administered twice weekly. The median and calculated mean annual bleeding rates (ABR) in children under 12 years receiving Esperoct twice weekly were 1.95 and 2.13, respectively (95% CI: 1.48; 3.06), while ABR for spontaneous bleeds was 0.00 and 0.58 (95% CI: 0.24; 1.40), for trauma-related bleeds 0.00 and 1.52 (95% CI: 1.07; 2.17), and for joint bleeds 0.00 and 1.03 (95% CI: 0.59; 1.81), respectively. Among the 68 children under 12 years receiving prophylactic Esperoct, 29 patients (42.6%) had no bleeding episodes.
The mean annual requirement of the product for prophylaxis was 6,475 IU/kg.
Due to the long duration of the study, several patients moved out of the age group to which they were initially assigned: some patients aged < 6 years also entered the 6–11 years age group, and some patients from the 6–11 years age group transitioned into the adolescent category. The main efficacy results in patients aged < 12 years, obtained during the main and extension phases of the study, are summarized in Table 1.
Table 1. Annual bleeding rate (ABR) in the study of previously treated paediatric patients by current age groups (main and extension phases of the study) – full analysis set
| Main Phase |
Extended Phase |
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| Patients’ age* |
0–5 years (N = 34) |
6–11 years (N = 34) |
0–5 years (N = 27) |
6–11 years (N = 53) |
| Number of bleeding episodes |
30 |
32 |
41 |
134 |
| Main treatment period (years) |
0.46 |
0.51 |
4.79 |
4.86 |
| Overall annual bleeding rate (ABR) |
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| Mean Poisson |
1.94 |
1.84 |
0.32 |
0.52 |
| Median |
1.94 |
1.94 |
0.22 |
0.21 |
* Some patients were included in two age groups.
Prophylaxis in previously untreated patients (PUPs) (children up to 6 years of age)
The efficacy and safety of Esperoct were evaluated in a multinational, non-randomized, open-label, phase 3 study. Prior prophylaxis (optional on-demand treatment of bleeding episodes and/or dosing of 60 IU/kg administered at intervals greater than one week until the patient reached 20 exposure days (ED) or age 24 months) and ongoing prophylaxis were assessed in 81 previously untreated patients up to 6 years of age with severe haemophilia A. Of the 81 patients, 55 patients initiated prior prophylaxis, of whom 42 subsequently transitioned to prophylaxis. Overall, 69 patients received prophylaxis with a prophylactic dose of 68.9 IU/kg twice weekly.
The prophylactic effect of Esperoct in previously untreated children up to 6 years of age with severe haemophilia A was demonstrated by a median and calculated mean annualized bleeding rate (ABR) of 1.35 and 1.76, respectively (95% CI: 1.26; 2.46).
The mean annual requirement for the 69 previously untreated patients receiving prophylaxis was 5,395 IU/kg.
The key efficacy outcomes in previously untreated patients receiving prophylaxis, summarized by the main and extension phases of the study, are presented in Table 2.
Table 2. Annualized Bleeding Rate (ABR) in the study of previously untreated paediatric patients (main and extension phases of the study) – full analysis set
| Main phase |
Extension phase |
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| Number of bleeding episodes |
124 |
223 |
| Treatment period (years) |
0.60 |
2.83 |
| Overall annual bleeding rate (ABR) |
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| Mean Poisson (95% CI) |
2.98 (2.16; 4.10) |
1.43 (0.98; 2.10) |
| Median |
2.49 (0.00; 5.22) |
0.73 (0.00; 2.57) |
During the study, 56 adverse reactions were reported in 43 out of 81 patients, and a total of 80 serious adverse reactions were reported in 48 patients following administration of Esperoct.
In 31 out of 59 previously untreated patients without inhibitors, a transient decrease in incremental recovery (IR) of factor VIII was observed after exposure to Esperoct. There were 17 previously untreated patients with consecutive measurements showing reduced IR; all of these patients had IgG antibodies to PEG. A relationship between anti-PEG antibodies and low IR cannot be excluded.
Clinical efficacy of Esperoct in the treatment of bleeding episodes and on-demand use
The clinical efficacy of Esperoct in the treatment of bleeding episodes was demonstrated in all previously treated patients across all age groups.
The majority of bleeding episodes treated with Esperoct were of mild to moderate severity.
The overall success rate of hemostatic therapy for treatment of bleeding episodes in previously treated patients was 84.4%.
The success rates of hemostatic therapy in age groups of previously treated patients were 89.4% (0−5 years), 82.6% (6−11 years), 78.9% (12−17 years), and 84.9% (≥ 18 years), respectively; 94.2% were successfully treated, with bleeding resolved after administration of 1–2 injections.
The efficacy of Esperoct in treating bleeding episodes was demonstrated in previously untreated patients aged < 6 years. The overall success rate of hemostatic therapy was 91.9%; 93.3% were successfully treated, with bleeding resolved after administration of 1–2 injections.
In the core study, 12 patients aged 18 years and older chose to remain on demand treatment. In these patients, 1,270 bleeding episodes were treated with a mean dose of 37.5 IU/kg (range: 20–75 IU/kg). After administration of 1–2 doses of Esperoct, 97% of all bleeding episodes were stopped.
Clinical efficacy of Esperoct in surgical procedures
The hemostatic effect of Esperoct during surgical procedures was evaluated in four studies, one of which was a dedicated surgical procedure study.
In the dedicated surgical study, 49 major surgical procedures in 35 previously treated adolescent and adult patients were analyzed. On the day of surgery, patients received a preoperative mean dose of 55.7 IU/kg (range: 27.2–86.2 IU/kg), and the postoperative mean dose was 30.7 IU/kg (range: 10.1–58.8 IU/kg). The overall success rate of hemostatic therapy with Esperoct during major surgical procedures was 95.9%, with hemostatic efficacy rated as excellent or good in 47 out of 49 major surgical procedures performed.
In two studies involving previously treated pediatric patients (under 12 years of age), 24 patients underwent 46 surgical procedures, of which only one was a major surgery with a successful hemostatic response. Minor surgeries in these patients did not result in any complications, although hemostatic efficacy and factor VIII levels were not monitored during these procedures. In 26 previously untreated pediatric patients (under 6 years of age) in the study involving previously untreated patients, successful hemostatic effect was recorded in all 4 major surgical procedures and in 25 out of 30 minor surgeries. Esperoct was administered according to recommended dosing guidelines.
Pharmacokinetics
Overall, 129 pharmacokinetic (PK) profiles obtained after single-dose administration of Esperoct in 86 patients (including 24 pediatric patients aged 0 to 12 years) were evaluated.
All pharmacokinetic studies of Esperoct were conducted in patients with severe hemophilia A (factor VIII level < 1%) who had previously received treatment. Patients received a single dose of 50 IU/kg, with blood sampling performed prior to administration and multiple times over 96 hours post-administration.
In adult patients, the half-life of Esperoct was 1.6 times longer than that of conventional unmodified factor VIII products.
Pharmacokinetic parameters
A total of 108 pharmacokinetic profiles obtained after single-dose administration of 50 IU/kg Esperoct in 69 patients were evaluated. Pharmacokinetic parameters after single-dose administration were comparable in younger children (0 to 6 years), middle-aged children (6 to 12 years), older children (12 to 17 years), and adults (≥ 18 years).
As expected, incremental recovery (IR) was lower in children under 12 years of age compared to adults and children aged 12 years and older, while body weight-adjusted clearance was higher. Overall, a trend toward increasing incremental recovery (IR) and decreasing clearance (mL/h/kg) with increasing age was observed. This is consistent with a higher volume of distribution per kilogram of body weight in children under 12 years compared to adults (Table 1).
Pharmacokinetic parameters of Esperoct after single-dose administration, determined at week 28 of prophylactic treatment, were consistent with initial pharmacokinetic parameters.
Table 3 presents the pharmacokinetic parameters of Esperoct after single administration.
Table 3. Pharmacokinetic parameters of Esperoct 50 IU/kg after single administration in previously treated patients, determined by chromogenic method [geometric mean (CV% – coefficient of variation)]
| PK parameter, |
Patients aged 0 to 6 years (N = 13) |
Patients aged 6 to 12 years (N = 11) |
Patients aged 12 to 18 years (N = 3) |
Patients aged 18 years and older (N = 42) |
| Number of PK profiles |
13 |
11 |
5 |
79 |
| IR (IU/dL per IU/kg)a |
1.80 (29) |
1.99 (25) |
2.79 (12) |
2.63 (22) |
| Maximum Factor VIII activity (IU/dL)a |
101.2 (28) |
119.6 (25) |
133.2 (9) |
134.4 (23) |
| t1/2 (hours) |
13.6 (20) |
14.2 (26) |
15.8 (43) |
19.9 (34) |
| AUCinf (IU*hour/dL) |
2,147 (47) |
2,503 (42) |
3,100 (44) |
3,686 (35) |
| CL (mL/hour/kg) |
2.6 (45) |
2.4 (40) |
1.5 (43) |
1.4 (32) |
| Vss (mL/kg) |
44.2 (34) |
41.2 (25) |
33.4 (10) |
37.7 (27) |
| MRT (hours) |
17.0 (22) |
17.3 (31) |
21.7 (45) |
25.2 (29)b |
Abbreviations: AUC – area under the pharmacokinetic curve describing the time course of factor VIII activity; t1/2 – terminal half-life; MRT – mean residence time; CL – clearance; Vss – volume of distribution at steady state; IR – incremental recovery.
a Incremental recovery (IR) and factor VIII activity were determined 30 minutes after administration in patients aged 12 years and older, and 60 minutes after administration (first sample collection) in children under 12 years of age.
b Calculations based on data from 67 profiles.
In a study involving previously untreated pediatric patients, the incremental recovery (IR) of factor VIII was assessed in 46 patients under 6 years of age after the first dose, yielding a geometric mean (CV %) of 1.76 (34) [IU/dL]/[IU/kg]. In 17 out of 59 previously untreated patients without inhibitors, consecutive measurements (i.e., two or more) showed transiently reduced incremental recovery (IR) of factor VIII within the range of 5–10 exposure days (further details provided in section "Special Warnings and Precautions for Use").
Mean values of minimum factor VIII activity in previously treated and previously untreated patients by age groups are summarized in Table 4.
Table 4. Mean calculated values of minimum factor VIII activity in previously treated and previously untreated patients by age groups
| Minimum Factor VIII Activity |
Previously treated patients, 60 IU/kg of Esperoct for prophylaxis twice weekly |
Previously treated patients, 50 IU/kg of Esperoct for prophylaxis every 4 days |
Previously untreated patients, 60 IU/kg of Esperoct for prophylaxis twice weekly |
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| Age groups at study entry |
0–5 years |
6–11 years |
12–17 years |
≥ 18 years |
0–5 years |
| Number of patients included in the analysis |
31 |
34 |
23 |
143 |
81 |
| Number of minimum values included in the analysis |
144 |
161 |
112 |
722 |
355 |
| Number of minimum values below LLOQ |
62 |
43 |
16 |
107 |
128a |
| Mixed model resultsb: |
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| 1.2 |
2.0 |
2.7 |
3.0 |
1.5 |
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| 0.8; 1.6 |
1.5; 2.7 |
1.8; 4.0 |
2.6; 3.5 |
1.1; 1.9 |
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LLOQ – lower limit of quantification
a Factor VIII activity levels in plasma below the lower limit of quantification (LLOQ) of 0.009 IU/mL were set at half the LLOQ (0.0045 IU/mL).
b Mixed model of log-transformed factor VIII activity levels in plasma, with age group as a fixed effect and patient as a random effect. Separate modeling was performed for each prophylactic treatment regimen (i.e., for each dosing frequency). The minimum level was back-transformed to the natural scale.
Only pre-dose measurements obtained at steady state for this prophylactic regimen were included in the analysis.
Preclinical safety data
Preclinical study data indicate no special hazard for humans, considering the results of standard safety and repeat-dose toxicity studies.
Clinical characteristics.
Indications.
Treatment and prevention of bleeding in patients with haemophilia A (hereditary factor VIII deficiency).
Esperoct can be used in all age groups of patients.
Contraindications.
Hypersensitivity to the active substance or to any of the excipients of the medicinal product (see section "Composition").
Known allergic reaction to hamster proteins.
Interaction with other medicinal products and other forms of interaction.
There are no reports of interactions between recombinant human coagulation factor VIII (rDNA) and other medicinal products.
Special precautions for use.
Traceability
In order to improve the traceability of biological medicinal products, the name and batch number of the administered product must be clearly documented.
Hypersensitivity
Hypersensitivity reactions of allergic type may occur during administration of Esperoct. This medicinal product contains traces of hamster proteins which may cause allergic reactions in some patients. Patients should be advised to immediately discontinue use of this medicinal product and contact their physician if symptoms of hypersensitivity occur. Patients should be informed about early signs of hypersensitivity, including allergic rash, generalized urticaria, chest tightness, wheezing, hypotension, and anaphylaxis.
In the event of shock, standard treatment for shock should be initiated.
Inhibitors
A known complication in the treatment of patients with haemophilia A is the development of neutralizing antibodies (inhibitors) to factor VIII. These inhibitors are typically immunoglobulins IgG directed against the procoagulant activity of factor VIII, quantified in Bethesda units (BU) per 1 mL of plasma using a modified quantitative assay method. The risk of inhibitor development depends on the severity of the disease and the level of exposure to factor VIII, with the highest risk occurring during the first 50 exposure days. However, the risk persists throughout life, although it is infrequent.
The clinical significance of inhibitor development depends on the inhibitor titer, with lower titers indicating a lower risk of inadequate clinical response compared to higher titers. Overall, all patients receiving factor VIII clotting factor products should be closely monitored through appropriate clinical observation and laboratory testing to detect inhibitor formation. If expected plasma factor VIII activity levels are not achieved or if bleeding cannot be controlled with an appropriate dose, the presence of factor VIII inhibitors should be investigated. In patients with high inhibitor titers, therapy with factor VIII may be ineffective, and alternative treatment options should be considered.
Management of such patients should be performed by physicians experienced in the treatment of haemophilia and factor VIII inhibitor cases.
Decreased factor VIII activity in previously treated patients
Post-marketing reports have described decreased factor VIII activity in the absence of detectable factor VIII inhibitors in previously treated patients. Decreased factor VIII activity has been observed during transition to Esperoct and, in some cases, may be associated with antibodies to PEG. Appropriate assessment of factor VIII activity after transition should be considered. For additional information, see section "Adverse reactions".
Cardiovascular events
In patients with existing cardiovascular risk factors, replacement therapy with factor VIII may increase cardiovascular risk.
Complications related to catheter use
If a central venous access device (CVAD) is required, the potential risk of CVAD-related complications, including local infections, bacteremia, and catheter site thrombosis, should be considered.
Children
The aforementioned warnings and precautions apply to both adult and pediatric patients.
Decreased incremental recovery (IR) of factor VIII levels in previously untreated patients
In clinical studies, decreased incremental recovery (IR) of factor VIII levels in the absence of apparent factor VIII inhibitors was observed in 31 out of 59 previously untreated patients. Among them, 14 patients had only one measurement of low incremental recovery (IR), while 17 patients had two or more consecutive measurements of low incremental recovery (IRs) within 5–10 exposure days. The decreased incremental recovery (IR) was transient, and within 15–70 exposure days, incremental recovery (IR) returned to a level > 0.6 (IU/dL)/(IU/kg). Decreased incremental recovery (IR) was associated with increased titers of antibodies to polyethylene glycol (anti-PEG IgG) in previously untreated patients without development of factor VIII inhibitors. Repeated low incremental recovery (IR) values may potentially be associated with reduced efficacy of the medicinal product during this period. Monitoring of pediatric patients, including monitoring of factor VIII activity after administration of the medicinal product, is recommended. If bleeding is not controlled or expected factor VIII activity levels are not achieved with the recommended dose of Esperoct in the absence of factor VIII inhibitors, dose adjustment, increased dosing frequency, or discontinuation of the medicinal product should be considered.
Excipients
This medicinal product contains 30.5 mg of sodium per reconstituted vial, equivalent to 1.5% of the WHO recommended maximum daily intake of sodium – 2.0 g – for an adult.
Use during pregnancy or breastfeeding.
Reproductive toxicity studies with factor VIII in animals have not been conducted. Haemophilia A in women is rare; therefore, experience with the use of factor VIII during pregnancy and lactation is lacking. Consequently, factor VIII should be used during pregnancy and lactation only if clearly indicated.
Ability to affect reaction speed when driving or operating machinery.
Esperoct has no effect or has a negligible effect on the ability to drive or operate machinery.
Administration and Dosage
Treatment should be initiated under the supervision of a physician experienced in the management of hemophilia.
Monitoring during treatment
Appropriate monitoring of factor VIII activity levels is recommended throughout treatment to allow for adjustment of the ESOCTAVE dosing regimen if necessary. Individual patients may respond differently to factor VIII, resulting in varying half-life and incremental recovery (IR) values. Dose adjustments based on body weight may be required for patients with low or high body weight. During major surgical procedures, replacement therapy with factor VIII should be monitored by measuring factor VIII activity in plasma.
Factor VIII activity in ESOCTAVE can be measured using standard chromogenic and one-stage clotting factor VIII quantitative assays. When using the one-stage clotting assay based on activated partial thromboplastin time (aPTT) in vitro for measuring factor VIII activity in patient plasma samples, the results may vary significantly depending on both the type of aPTT reagent and the reference standard used in the assay.
When using the one-stage clotting assay, certain silica-based reagents should be avoided, as they may lead to falsely low results. Furthermore, significant discrepancies may occur between results obtained by the one-stage aPTT-based clotting assay and the chromogenic assay according to the European Pharmacopoeia. This is particularly important when changing analytical laboratories and/or reagents used for testing.
Dosage
The dose, dosing interval, and duration of replacement therapy depend on the severity of factor VIII deficiency, the location and severity of bleeding, the target factor VIII activity level, and the patient's clinical condition. The amount of factor VIII administered is expressed in International Units (IU), which are referenced to the WHO International Standard for factor VIII concentrate. Factor VIII activity in plasma is expressed either as a percentage (relative to the normal human plasma level) or in International Units per deciliter (relative to the established 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 human plasma.
On-demand treatment and treatment of bleeding episodes
The calculation of the required factor VIII dose is based on empirical findings indicating that 1 IU of factor VIII per kilogram of body weight raises plasma factor VIII activity by 2 IU/dL.
The required dose can be calculated using the following formula:
Required dose (IU) = body weight (kg) × desired increase in factor VIII activity (%) (IU/dL) × 0.5 (IU/kg per IU/dL).
The required dose and frequency of administration should always be adjusted according to the clinical response in each individual patient.
Dosage recommendations for ESOCTAVE in on-demand treatment and treatment of bleeding episodes are provided in Table 5. Factor VIII activity levels should be maintained at or above the indicated levels in plasma (in IU/dL or % of normal). For treatment of bleeding episodes, the maximum single dose of 75 IU/kg and the maximum total daily dose of 200 IU/kg/24 hours may be used.
Table 5. Recommendations for treatment of bleeding episodes with ESOCTAVE
| Severity of bleeding |
Required factor VIII level (IU/dl or % of normal) |
Dosing frequency (hours) |
Duration of therapy |
| Mild Early hemarthrosis, mild muscle or oral bleeding |
20–40 |
12–24 |
Until bleeding stops |
| Moderate More extensive hemarthrosis, muscle bleeding, hematoma |
30–60 |
12–24 |
Until bleeding stops |
| Severe or life-threatening bleeding |
60–100 |
8–24 |
Until the threat is resolved |
a The required dose is calculated using the following formula:
Required number of units (IU) = body weight (kg) × desired increase in factor VIII level (%) (IU/dL) × 0.5 (IU/kg per IU/dL).
Use in the perioperative setting
The dose level and dosing interval during surgery depend on the surgical procedure performed and local practice. The maximum single dose of Esperoct is 75 IU/kg, and the maximum total dose is 200 IU/kg/24 hours.
The dosing frequency and duration of therapy must always be individually adjusted based on the clinical response in each individual patient.
Table 6 provides general dosing recommendations for Esperoct in the perioperative setting. Maintenance of factor VIII activity at or above the target range should be ensured.
Table 6. Dosing recommendations for Esperoct in the perioperative setting
| Type of surgical procedure |
Required factor VIII level (IU/dl) (%) (IU/dl)a |
Dosing frequency (hours) |
Duration of therapy |
| Minor surgical procedure (including tooth extraction) |
30–60 |
Within one hour prior to surgery. If necessary, repeat after 24 hours. |
Single or repeated injection every 24 hours for at least one day until healing is achieved. |
| Major surgical procedure |
80–100 (before and after surgery) |
Within one hour prior to surgery to achieve factor VIII activity within the target range. Repeat every 8–24 hours to maintain factor VIII activity within the target range. |
Repeat injection every 8–24 hours as needed for adequate wound healing. Consider continuing therapy for an additional 7 days to maintain factor VIII activity between 30% and 60% (IU/dl). |
a The required dose is calculated using the following formula:
Required number of units (IU) = body weight (kg) × desired increase in factor VIII level (%) (IU/dL) × 0.5 (IU/kg per IU/dL).
Prophylaxis
The recommended dose of Esperoct for adults is 50 IU per kilogram of body weight every 4 days.
Dose and dosing interval adjustments may be considered based on achieved factor VIII levels and individual bleeding tendency in each patient.
Children
The recommended dose for children (aged 12 years and older) is the same as for adults.
The recommended dose for prophylaxis in children under 12 years of age is 65 IU per 1 kg of body weight (50–75 IU/kg) twice weekly. Dose and frequency adjustments depend on achieved factor VIII levels and individual bleeding tendency.
For more detailed information regarding pediatric patients, see the sections “Special precautions”, “Pharmacodynamics”, and “Pharmacokinetics”.
Method of administration
Esperoct is intended for intravenous use.
Esperoct should be administered by intravenous injection (over approximately 2 minutes) after reconstitution of the powder with 4 mL of diluent supplied with the medicinal product (sodium chloride, 9 mg/mL (0.9%) solution for injection).
Instructions for reconstitution of the medicinal product prior to administration are provided below in the section “Handling and disposal precautions”.
Handling and disposal precautions
Esperoct should be administered intravenously after reconstitution of the powder with the diluent contained in the syringe. After reconstitution, the solution should appear as a clear, colorless liquid without visible particles. Before administration, the reconstituted medicinal product should be visually inspected for presence of particulate matter and discoloration. The solution must be clear and colorless. Do not use the solution if it is cloudy or contains a precipitate.
Instructions for reconstitution of the medicinal product prior to administration are provided in the section “Instructions for use of Esperoct”.
The infusion rate should be determined according to patient comfort and should take approximately 2 minutes.
An infusion set (butterfly needle with tubing), sterile alcohol swabs, gauze pads, and adhesive tape will also be required. These devices are not included in the Esperoct package.
Always use aseptic technique.
Disposal
After injection, safely dispose of the syringe, infusion set, vial, and vial adapter.
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
| Instructions for Use of Esperoct Please read this instruction carefully before using Esperoct. Esperoct is supplied as a powder. Before injection, it must be reconstituted using the diluent contained in the syringe. This diluent is 9 mg/mL (0.9%) sodium chloride solution for injection. The reconstituted preparation must be administered intravenously (IV injection). The equipment provided in this pack is intended for reconstitution and administration of Esperoct. You will also need:
These items are not included in the Esperoct packaging. Do not use the equipment unless you have received proper training from your doctor or nurse. Always wash your hands and ensure a clean environment around you. When preparing and administering a medication directly into a vein, it is essential to use aseptic techniques to maintain sterility. Failure to follow these techniques may result in microbial contamination and bloodstream infection. Do not open the equipment until you are ready to use it. Do not use the equipment if it has been dropped or damaged. In this case, use a new pack. Do not use the equipment after its expiration date has passed. In this case, use a new pack. The expiration date is printed on the carton, vial, vial adapter, and prefilled syringe. Do not use the equipment if you suspect it is contaminated. In this case, use a new pack. Do not dispose of any items until after you have completed the injection of the reconstituted solution. This equipment is intended for single use only. |
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Do not use any other method to warm the vial and prefilled syringe. |
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Do not touch the rubber stopper with your fingers, as this may introduce microbes. |
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If the protective paper membrane is not fully attached or is torn, do not use this vial adapter. Do not remove the vial adapter from under the protective cap with your fingers. If you touch the tip of the vial adapter, it may introduce microbes from your fingers. |
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Once the vial adapter is attached to the vial, do not remove it from the vial. |
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Do not disconnect the vial adapter from the vial when removing the protective cap. |
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Do not touch the tip of the syringe under the cap. Touching the syringe tip may introduce microbes from your fingers. If the plastic cap is loose or missing, do not use this prefilled syringe. |
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Do not shake the vial, as this may cause foaming.
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| Esperoct should be used immediately after reconstitution. If you cannot use the reconstituted Esperoct solution immediately, it must be used:
The reconstituted solution should be stored in the vial. Do not freeze the reconstituted solution and do not store it in syringes. Keep the reconstituted solution protected from direct sunlight. If more than one vial of Esperoct is needed to achieve your required dose, repeat steps A to J with additional vials, vial adapters, and prefilled syringes until you obtain the required dose. |
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Do not touch the tip of the syringe. Touching the syringe tip may introduce microbes from your fingers. |
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The Esperoct preparation is now ready for intravenous injection.
Do not mix Esperoct with any other intravenous injections or medications. Administration of Esperoct via needle-free connectors for intravenous (IV) catheters. Caution! The prefilled syringe is made of glass and designed for use with standard Luer-lock connections. Some needle-free connectors with internal spikes are incompatible with this prefilled syringe. Such incompatibility may prevent proper drug administration and may damage the needle-free connector. Administration of the solution via a central venous access device (CVAD), such as a central venous catheter or implanted port:
If the CVAD system needs to be flushed before or after injection of Esperoct, use 9 mg/mL (0.9%) sodium chloride injection solution. |
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| Disposal.
Do not dispose of these materials with regular household waste. |
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| Do not disassemble the equipment before disposal. Do not reuse this equipment. |
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Children
Treatment and prophylaxis of bleeding in patients with hemophilia A (hereditary factor VIII deficiency).
Esperoct can be used in all age groups.
Detailed information regarding pediatric patients is provided in the sections "Pharmacological properties" (subsections "Pharmacodynamics" and "Pharmacokinetics"), "Special precautions", "Dosage and administration".
Overdose.
No symptoms of overdose with recombinant blood coagulation factor VIII have been reported.
Side effects
Summary of safety profile
Hypersensitivity or allergic reactions (including angioedema, burning and stinging at the infusion site, chills, flushing, generalized urticaria, headache, allergic dermatitis, hypotension, somnolence, nausea, restlessness, tachycardia, chest tightness, tingling sensation, vomiting, wheezing) have been observed rarely and in some cases could progress to severe anaphylaxis (including shock).
Formation of antibodies to hamster proteins, with corresponding hypersensitivity reactions, has been observed very rarely.
In patients with haemophilia A treated with factor VIII, including Esperoct, neutralizing antibodies (inhibitors) may develop. If such inhibitors form, this may manifest as a suboptimal clinical response to treatment. In such cases, consultation with a specialized haemophilia centre is recommended.
List of adverse reactions
Data on the frequency of adverse reactions were obtained from six clinical studies involving 270 previously treated patients and 81 previously untreated patients with severe haemophilia A (< 1% endogenous factor VIII activity) and no history of factor VIII inhibitors. The adverse reactions listed below are categorized according to the MedDRA system organ classification (by system organ classes and preferred terms) as shown in Table 7.
The frequency of adverse reactions was assessed according to 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); unknown (cannot be estimated based on available data). The adverse reactions listed below occurred in patients who had previously received treatment.
Table 7. Frequency of adverse reactions observed during clinical studies
| Organ system according to classification |
Preferred terms |
Frequency of cases (previously treated patients) |
Frequency of cases (previously untreated patients) |
| Blood and lymphatic system disorders |
Inhibition of factor VIII * |
Uncommon |
Very common** |
| Skin and subcutaneous tissue disorders |
Pruritus |
Common |
- |
| Erythema |
Common |
Common |
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| Rash |
Common |
Common |
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| General disorders and administration site reactions |
Injection site reactions*** |
Common |
Common |
| Immune system disorders |
Hypersensitivity to the medicinal product |
- |
Common |
| Hypersensitivity |
Uncommon |
- |
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| Investigations |
Decreased level of blood coagulation factor VIII |
Unknown**** |
- |
* A patient with confirmed factor VIII inhibitor was defined based on an initial inhibitor test result ≥ 0.6 Bethesda units (BU), confirmed by a second sample obtained no later than 2 weeks later.
** Includes patients with confirmed factor VIII inhibitor among patients in the risk group (at least 10 days of product exposure).
*** Preferred terms included injection site reactions: injection site reaction, vessel puncture site hematoma, infusion site reaction, injection site erythema, injection site rash, vessel puncture site pain, and injection site swelling.
**** Based on post-marketing reports.
Description of selected adverse reactions
Development of factor VIII inhibitors
One confirmed case of factor VIII inhibitor development was reported during prophylactic treatment with Esperoct in an 18-year-old previously treated patient. The patient had intron 22 inversion in the factor VIII gene and a high risk of developing factor VIII inhibitors.
There is no evidence indicating an increased risk of factor VIII inhibitor development with Esperoct compared to other factor VIII products.
Development of antibodies to the medicinal product
One case of development of persistent antibodies to the medicinal product was reported, which temporally coincided with the confirmed case of factor VIII inhibitor development (see section on factor VIII inhibitor development). In three patients, transient positive test results for antibodies to Esperoct were observed after administration, but no correlation with adverse reactions was identified.
Anti-PEG antibodies
During the clinical trial program, 37 patients had anti-PEG antibodies prior to Esperoct administration. The anti-PEG antibody test became negative in 20 out of 37 patients after treatment. Transient low-titer anti-PEG antibodies were observed in 17 patients. No correlation with adverse events was established.
According to post-marketing reports, anti-PEG antibodies have also been observed during transition to Esperoct. In some patients, anti-PEG antibodies may be associated with lower than expected FVIII activity levels.
Paediatric population
No differences in the safety profile were observed between previously treated paediatric and adult patients.
Transient decrease in factor VIII incremental recovery (IR) was observed in some previously untreated patients in the absence of factor VIII inhibitors (see section "Special warnings and precautions for use" for more details).
Reporting of suspected adverse reactions and lack of efficacy
Reporting suspected adverse reactions after marketing authorization 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 all suspected adverse reactions and lack of efficacy via the Automated Pharmacovigilance Information System at: https://aisf.dec.gov.ua.
Shelf life.
Unopened vial (prior to reconstitution):
36 months when stored refrigerated (2–8 °C).
During the shelf life, the medicinal product may be stored:
- at room temperature (≤ 30 °C) from the date of manufacture until reconstitution for no more than 12 months
or
- above room temperature (from > 30 °C to 40 °C) from the date of manufacture until reconstitution for no more than 3 months.
Once the product has been stored outside the refrigerator, it must not be returned to refrigerated storage.
The start date of storage outside the refrigerator and the storage temperature must be recorded in the designated space on the carton.
After reconstitution:
Chemical and physical in-use stability has been demonstrated:
- for 24 hours when stored refrigerated (2–8 °C), or
- for 4 hours at ≤ 30 °C, or
- for 1 hour at temperatures from > 30 °C to 40 °C, provided that prior to reconstitution the product was stored at temperatures above room temperature (from > 30 °C to 40 °C) for no longer than 3 months.
From a microbiological point of view, the product should be used immediately after reconstitution. If not used immediately, in-use storage conditions and duration are the responsibility of the user; storage should not exceed the times indicated above, except when reconstitution has been carried out under controlled and validated aseptic conditions.
The reconstituted solution should be stored in the vial.
Storage conditions.
Store in a refrigerator (2–8 °C). Do not freeze. Store in the original packaging to protect from light.
For information on storage at room temperature (≤ 30 °C) or up to 40 °C, and conditions after reconstitution, see the section "Shelf life". Keep out of the reach of children.
Incompatibilities.
As compatibility studies have not been conducted, this medicinal product must not be mixed with other medicinal products or reconstituted using other injection solutions except for the diluent provided in the pack – sodium chloride solution.
The reconstituted product must not be administered simultaneously with other medicinal products through the same infusion set or via the same container already used for other medicinal products.
Packaging.
Each carton of Esperoct contains:
- 1 glass vial (Type I glass) containing powder, stoppered with a chlorobutyl rubber stopper, sealed with an aluminium cap and a flip-off plastic cap;
- 1 sterile vial adapter for reconstitution;
- 1 pre-filled syringe of 4 ml diluent (0.9% sodium chloride solution) with a reverse plunger (polypropylene), rubber plunger (bromobutyl), and rubber cap (bromobutyl);
- 1 plunger rod (polypropylene).
Prescription status. Prescription only.
Marketing Authorisation Holder/Manufacturer.
A/T Novo Nordisk.
Address of the Marketing Authorisation Holder/Manufacturer and location of its operations.
Novo Allé,
Bagsværd, 2880,
Denmark.