Nuvik / nuwiq®
Ukraine
Table of Contents
- INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT NUWIQ® (NUWIQ®)
- Composition:
- Pharmacological Properties
- Clinical characteristics.
- Special precautions for use.
- Administration and Dosage
- Adverse Reactions
- Frequency is based on studies with all factor VIII products that included patients with severe hemophilia A.
INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT NUWIQ® (NUWIQ®)
Composition:
Active substance: simoctocog alfa (recombinant coagulation factor VIII);
One vial of powder for solution for injection contains simoctocog alfa (recombinant coagulation factor VIII) 1500 IU, or 2500 IU, or 3000 IU, or 4000 IU;
Excipients: sodium chloride; sucrose; L-arginine hydrochloride; calcium chloride dihydrate; poloxamer 188; sodium citrate dihydrate.
Solvent: water for injections.
Pharmaceutical form. Powder and solvent for solution for injection.
Main physicochemical characteristics:
Powder: white cake. A small amount of white powder may be present.
Solvent: clear, colorless liquid, free from particles.
Pharmacotherapeutic group. Antihemorrhagics. Coagulation factor VIII.
ATC code B02BD02.
Pharmacological Properties
Pharmacodynamics
Coagulation factor VIII binds to von Willebrand factor in the patient's circulation. Activated factor VIII acts as a cofactor for activated factor IX, reducing the time required for conversion of factor X into activated factor X. Activated factor X then converts prothrombin into thrombin. Thrombin subsequently converts fibrinogen into fibrin, leading to clot formation.
Hemophilia A is a hereditary, sex-linked disorder caused by congenital deficiency of coagulation factor VIII:C, resulting in hemorrhages into joints, muscles, and internal organs, occurring spontaneously or following accidental or surgical trauma. With replacement therapy, plasma levels of factor VIII increase, thereby temporarily correcting the deficiency of blood coagulation factor VIII and reducing the tendency to bleed.
Adult and adolescent population aged 12–65 years
Prophylaxis: In a clinical study involving 32 adult patients with severe hemophilia A, the mean prophylactic dose of the medicinal product Nuwiq was 468.7 IU/kg/month.
Bleeding treatment: The mean dose used to treat bleeding episodes in patients receiving prophylaxis was 33.0 IU/kg. In another clinical study, 22 adult patients were treated on-demand. A mean dose of 30.9 IU/kg was administered in a total of 986 bleeding episodes. Overall, minor bleeds required lower doses, while major bleeds required approximately three times higher mean doses.
Individualized prophylaxis: Individualized prophylaxis based on pharmacokinetic (PK) assessment was evaluated in 66 previously treated adult patients (PTPs) with severe hemophilia A. After a 1- to 3-month standard prophylaxis phase (receiving doses every other day or three times weekly), 44 (67%) patients transitioned to a dosing regimen individualized based on their PK assessment, and 40 patients completed 6 months of prophylaxis according to the prescribed dose and regimen. Of these patients, 34 (85%) received treatment twice weekly or less frequently. Thirty-three (82.5%) patients had no bleeding episodes, and 36 (90.0%) patients had no spontaneous bleeding episodes. The mean + SD annualized (calculated on a yearly basis) bleeding rate (ABR) was 1.2 + 3.9, and the mean + SD dose was 52.2 + 12.2 IU/kg per injection and 99.7 + 25.6 IU/kg per week.
It should be noted that the annualized bleeding rate (ABR) is not comparable across different factor concentrates or between different clinical trials.
Pediatric population
Data were obtained from 29 previously treated children aged 2 to 5 years, 31 children aged 6 to 12 years, and one 14-year-old adolescent. The mean prophylactic injectable dose was 37.8 IU/kg. Twenty patients received mean doses exceeding 45 IU/kg. The mean monthly prophylactic dose of Nuwiq was 521.9 IU/kg. Children required a higher mean dose of Nuwiq for bleeding treatment (43.9 IU/kg) compared to adults (33.0 IU/kg), as well as higher mean doses for treatment of both minor and major bleeding episodes (78.2 IU/kg vs. 41.7 IU/kg). Younger children generally required higher mean doses (6–12 years: 43.9 IU/kg; 2–5 years: 52.6 IU/kg). These findings were confirmed during long-term follow-up of 49 such children treated over an additional mean period of approximately 30 months (range: 9.5 to 52 months); during this period, 45% of children had no spontaneous bleeding episodes.
Data from 108 previously untreated patients (PUPs) with severe hemophilia A (FVIII:C < 1%) were obtained in a prospective, open-label clinical trial. In most patients, prophylactic treatment was initiated after the first bleeding episode requiring treatment.
Pharmacokinetics
Adult population
Table 1.
Pharmacokinetic parameters of Nuwiq (50 IU/kg dose) in adults aged 18 to 65 years with severe hemophilia A who were previously treated (n=20).
| Pharmacokinetic parameters |
Chromogenic assay |
|
| Mean ± SD |
Median (range) |
|
| AUC (hr*RU/mL) |
22.6 ± 8.0 |
22.3 (8.4 – 38.1) |
| T 1/2 (hr) |
14.7 ± 10.4 |
12.5 (5.4 – 55.6) |
| IVR (%/RU/kg) |
2.5 ± 0.4 |
2.5 (1.7 – 3.2) |
| CL (mL/hr/kg) |
3.0 ± 1.2 |
2.7 (1.5 – 6.4) |
AUC - area under the curve (FVIII:C), T½ - half-life
IVR - in vivo recovery, CL - clearance, SD - standard deviation
Table 2.
Pharmacokinetic parameters of Nuwiq administered at a dose of 50 IU/kg in children aged 6 to 12 years with severe haemophilia A, who had been previously treated (n=12).
| Pharmacokinetic parameters |
Chromogenic assay |
|
| Mean ± SD |
Median (range) |
|
| AUC (hr*MO/mL) |
13.2 ± 3.4 |
12.8 (7.8 – 19.1) |
| T 1/2 (hr) |
10.0 ± 1.9 |
9.9 (7.6 – 14.1) |
| IVR (%/MO/kg) |
1.9 ± 0.4 |
1.9 (1.2 – 2.6) |
| CL (mL/hr/kg) |
4.3 ± 1.2 |
4.2 (2.8 – 6.9) |
AUC - area under the curve (FVIII:C), T½ - half-life
IVR - in vivo recovery, CL - clearance, SD - standard deviation
Table 3.
Pharmacokinetic parameters of Nuwiq after administration of 50 IU/kg in children aged 2 to 5 years with severe haemophilia A, who were previously treated (n=13).
| Pharmacokinetic parameters |
Chromogenic assay |
|
| Mean ± SD |
Median (range) |
|
| AUC (hr*MU/mL) |
11.7 ± 5.3 |
10.5 (4.9 – 23.8) |
| T 1/2 (hr) |
9.5 ± 3.3 |
8.2 (4.3 – 17.3) |
| IVR (%/MU/kg) |
1.9 ± 0.3 |
1.8 (1.5 – 2.4) |
| CL (mL/hr/kg) |
5.4 ± 2.4 |
5.1 (2.3 – 10.9) |
AUC - area under the curve (FVIII:C), T½ - half-life
IVR - in vivo recovery, CL - clearance, SD - standard deviation
Paediatric population
According to published data, recovery values and half-life were lower in younger children than in adults, while the clearance value was higher, which may be partly explained by the larger plasma volume per kilogram of body weight in younger patients.
Subgroups by body weight
Table 4.
Pharmacokinetic parameters of the medicinal product Nuwiq (dose 50 IU/kg) in adults aged 18 to 65 years with severe haemophilia A, previously treated (n=20), by patient body weight
| Pharmacokinetic parameters |
All patients (n =20) |
Normal body weight (n =14) |
Pre-obesity (n =4) |
Obesity (n =2) |
| Chromogenic assay, mean ± SD |
||||
| AUC (h*IU/mL) |
22.6 ± 8.0 |
20.4 ± 6.9 |
24.9 ± 8.9 |
33.5 ± 6.5 |
| T 1/2 (h) |
14.7 ± 10.4 |
14.7 ± 12.1 |
13.4 ± 5.9 |
17.2 ± 4.8 |
| IVR (%/IU/kg) |
2.5 ± 0.4 |
2.4 ± 0.4 |
2.7 ± 0.4 |
2.8 ± 0.3 |
| CL (mL/h/kg) |
3.0 ± 1.2 |
3.2 ± 1.3 |
2.6 ± 1.0 |
1.8 ± 0.4 |
| Chromogenic assay, median (range) |
||||
| AUC (h*IU/mL) |
22.3 (8.4 – 38.1) |
21.2 (8.4– 32.6) |
23.3 (17.4 – 35.5) |
33.5 (28.9 – 38.1) |
| T 1/2 (h) |
12.5 (5.4 – 55.6) |
12.3 (5.4– 55.6) |
11.2 (9.3 – 22.0) |
17.2 (13.8 – 20.6) |
| IVR (%/IU/kg) |
2.5 (1.7 – 3.2) |
2.4 (1.7 – 3.1) |
2.8 (2.3 – 3.2) |
2.8 (2.6 – 3.0) |
| CL (mL/h/kg) |
2.7 (1.5 – 6.4) |
2.8 (1.7 – 6.4) |
2.5 (1.6 – 3.7) |
1.8 (1.5 – 2.0) |
Normal body weight BMI - 18.5 – 25 kg/m², Increased body weight: BMI 25 – 30 kg/m², Obesity: BMI > 30 kg/m², SD - standard deviation
Clinical characteristics.
Indications.
Treatment and prevention of bleeding in patients with hemophilia A (congenital factor VIII deficiency).
Nuvig may be used in patients of all age groups.
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.
No studies have been conducted on interactions between Nuvig and other medicinal products.
Special precautions for use.
Traceability
To improve traceability of biological medicinal products, the name and batch number of the administered product should be clearly recorded.
The specific activity of the medicinal product Nuwiq is approximately 9500 IU/mg protein.
Simocotocog alfa (recombinant DNA coagulation factor VIII) is a pure protein consisting of 1440 amino acids. The amino acid sequence is similar to the 90+80 kDa form of human factor VIII plasma (i.e., with the B-domain deleted). Nuwiq is produced using recombinant DNA technology from genetically modified human embryonic kidney (HEK) 293F cells. No materials of animal or human origin are added during the manufacturing process or to the final medicinal product.
Hypersensitivity
As with any intravenous protein-containing medicinal product, there is a possibility of developing allergic reactions and hypersensitivity. Nuwiq contains trace amounts of human cell proteins that differ from factor VIII. If symptoms of hypersensitivity occur, administration of the medicinal product should be stopped immediately and medical advice sought. Patients should be informed about early signs of hypersensitivity reactions such as urticaria, generalized urticaria, sensation of chest tightness, difficulty breathing, wheezing, arterial hypotension, and anaphylaxis.
In the event 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 IgG immunoglobulins directed against the procoagulant activity of factor VIII and are quantified in Bethesda Units (BU) per 1 mL of plasma using a modified assay. The risk of inhibitor formation correlates with the severity of the disease and depends on exposure to factor VIII, being highest during the first 50 exposure days but persisting throughout life, although the risk is rare.
Cases of recurrent inhibitor formation (low titer) have been observed when switching from one recombinant factor VIII product to another in patients who had previously received treatment for more than 100 days and had a history of inhibitor development. Therefore, careful monitoring of all patients for inhibitor formation is recommended following any change in medicinal product.
The clinical significance of inhibitor formation depends on the inhibitor titer: low-titer inhibitors, whether transient or persistently low, pose a lower risk of inadequate clinical response compared to high-titer inhibitors.
Careful monitoring of all patients receiving treatment with recombinant coagulation factor VIII is required for inhibitor development through appropriate clinical observation and laboratory testing. If expected plasma factor VIII activity levels are not achieved or if bleeding persists despite administration of an appropriate dose, tests should be conducted to determine the presence of factor VIII inhibitors. In patients with high-titer inhibitors, factor VIII therapy may be ineffective, and alternative therapeutic options such as immune tolerance induction (ITI) should be considered. Treatment of such patients should be managed by physicians experienced in the treatment of hemophilia and factor VIII inhibitor development.
Cardiovascular complications
In patients with existing cardiovascular risk factors, replacement therapy with FVIII may increase the risk of cardiovascular events.
Complications associated with catheter use
If a central venous access device (CVAD) is required, the risks of complications related to its use, including local infections, bacteremia, and catheter-related thrombosis, should be considered.
It is strongly recommended that the name and batch (lot) number of the medicinal product be recorded each time Nuwiq is administered to establish a link between the patient's condition and the batch of the administered medicinal product.
All warnings apply to both adults and children.
Information on excipients (sodium content)
1 mL of reconstituted solution contains 7.35 mg (18.4 mg sodium per vial), which is essentially "sodium-free."
However, depending on body weight and dosage, a patient may receive more than one vial. This information should be taken into account by patients following a sodium-controlled diet.
Use during pregnancy or breastfeeding
Studies on the effects of Nuwiq on reproductive function in animals have not been conducted. Since hemophilia A is rare in women, there is no experience with the use of Nuwiq during pregnancy and breastfeeding. Therefore, Nuwiq may be prescribed during pregnancy and breastfeeding when clinically indicated and necessary. Data on effects on fertility are lacking.
Ability to affect reaction speed when driving or operating machinery
No effects on the ability to drive or operate machinery have been observed.
Administration and Dosage
Treatment should be administered 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 control the required dose and frequency of repeat infusions. Individual patients may respond differently to factor VIII administration, showing variable half-lives and recovery rates. Dose adjustments based on body weight may be necessary in patients with significantly low or high body weight. During major surgical procedures, careful monitoring of replacement therapy using coagulation assays (plasma factor VIII activity) is mandatory.
When using a one-stage clotting activity assay based on activated partial thromboplastin time (aPTT) in vitro to determine factor VIII activity in patient plasma samples, both the type of aPTT reagent and the reference standard used in the assay may significantly influence the measured factor VIII activity. Moreover, considerable discrepancies may occur between results obtained by the one-stage aPTT-based clotting assay and those from chromogenic assays, as defined by the European Pharmacopoeia. This is particularly important when changing laboratories and/or reagents used in testing.
Administration Method
The dosage and duration of replacement therapy depend on the severity of factor VIII deficiency, the location and extent of bleeding, and the patient's clinical condition.
The amount of factor VIII administered is expressed in International Units (IU), calibrated against the WHO International Standard for factor VIII-containing medicinal products. Factor VIII activity in plasma is measured either as a percentage (relative to normal human plasma) or, preferably, in International Units (according to the International Standard for factor VIII in plasma).
1 International Unit (IU) of factor VIII activity is equivalent to the amount of factor VIII present in 1 ml of normal human plasma.
On-demand Treatment
Dose calculations for factor VIII are based on empirical data indicating that 1 International Unit (IU) of factor VIII per 1 kg of body weight raises plasma factor VIII activity by approximately 2% (or 2 IU/dL) from baseline. The required dose can be calculated using the following formula:
I.
Required units = body weight (kg) × desired factor VIII increase (%) (IU/dL) × 0.5 (IU/kg per IU/dL)
II.
| Expected rise in factor VIII (% of normal) = |
2 × administered IU |
| body weight (kg) |
II.
The dose to be administered and the frequency of administration must always be adjusted according to the clinical response in each individual case.
In the hemorrhagic situations listed below, factor VIII activity should not fall below the specified plasma activity level (% of normal or IU/dL) during the corresponding period. Table 5 can be used to determine dosing during bleeding episodes and surgery.
Table 5
| Severity of bleeding/ Type of surgical procedure |
Required level of factor VIII (%) (IU/dl) |
Dosing frequency (hours)/ duration of therapy (days) |
| Bleeding Early haemarthrosis, muscle or oral bleeding |
20–40 |
Repeat every 12 – 24 hours for at least 1 day until bleeding associated with pain is controlled or until complete healing |
| More extensive haemarthrosis, muscle bleeding or haematoma |
30–60 |
Repeat every 12 – 24 hours for 3 – 4 days or more until pain and acute symptoms resolve |
| Life-threatening bleeding |
60–100 |
Repeat injections every 8 – 24 hours until the threat is resolved |
| Surgery Minor surgery, including tooth extraction Major surgery |
30–60 |
Every 24 hours for at least 1 day until complete healing |
| 80–100 (before and after surgical intervention) |
Repeat injections every 8 – 24 hours until substantial wound healing; thereafter therapy for at least 7 days to maintain factor VIII activity between 30% and 60% (IU/dl) |
Prophylaxis
For long-term prevention of bleeding in patients with severe hemophilia A, the usual dose is 20 to 40 IU of factor VIII per kg of body weight every 2–3 days. In some cases, particularly in younger patients, higher doses or more frequent administration of the drug may be required.
It is recommended to monitor factor VIII levels throughout the treatment course to adjust the dose and frequency of repeat infusions. Precise monitoring of replacement therapy by measuring factor VIII activity in plasma is especially necessary during major surgical procedures. Depending on factor VIII, individual patients may exhibit different half-lives and recovery rates. The dosing regimen may be adjusted based on the patient's response.
The route of administration is the same for adults, children, and adolescents; however, shorter intervals between doses or higher doses may be required for children and adolescents. There are no data available regarding use in children under 2 years of age.
Method of administration
Nuvic is intended for intravenous use.
It is recommended to administer no more than 4 ml per minute.
Instructions for reconstitution of the medicinal product prior to administration.
The powder must be reconstituted only with the provided diluent (2.5 ml of water for injections) using the enclosed injection preparation kit. The vial should be gently swirled until the powder is completely dissolved. After reconstitution, the solution should be drawn into the syringe that contained the diluent.
The prepared solution should be inspected visually for particulate matter and discoloration prior to administration. The reconstituted solution should be clear, colorless, free of foreign particles, and have a pH between 6.5 and 7.5. Solutions that are cloudy or contain precipitate must not be used.
Instructions for preparation and administration of the drug.
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