Nuvik - instructions for use, doses, side effects, contraindications

1 bottle contains active substance Simotoctog alpha (clotting factor VIII human recombinant) 250 IU or 500 IU, or 1000 IU, or 2000 IU. Excipients: sodium chloride 45 mg, sucrose 13.5 mg, arginine hydrochloride 13.5 mg, calcium chloride dihydrate 0.75 mg, poloxamer 188 3.0 mg, sodium citrate dihydrate 3.0 mg.
In 1 syringe contains water for injection 2.5 ml.

Description:

The weight is white, a small amount of white powder is possible. The reconstituted solution is a clear or slightly opalescent colorless solution.

Pharmacotherapeutic group:Hemostatic agent.

ATX: & nbsp

Coagulation factor VIII

Pharmacodynamics:

Simotoctog alpha, coagulation factor VIII human (rDNA), is a highly purified protein, consisting of 1440 amino acids. The sequence of amino acids is comparable to that of clotting factor VIII (factor VIII) from human plasma consisting of two chains with a molecular weight of 90 kD and 80 kD and not containing a B-domain.The preparation is obtained by recombinant DNA technology from the human embryonic kidney cell lines (HEK 293F cells). No substances of human or animal origin in the production process and in the finished product are added.

Post-translational modifications of Novik are similar to those in endogenous factor VIII in healthy people, and unlike the drug from hamster cell lines, the recombinant factor VIII drug from human cell lines does not have carbohydrate epitopes that possess antigenic properties.

Complex factor VIII / vWF consists of two molecules (factor VIII and von Willebrand factor) with different physiological functions. When administered to patients with hemophilia, factor VIII binds to von Willebrand factor in the bloodstream. Activated factor VIII acts as a cofactor for activated factor IX, accelerating the conversion of factor X to activated factor X. Activated factor X converts prothrombin to thrombin. Then thrombin converts fibrinogen into fibrin, and a thrombus can form. Hemophilia A is a sex-related hereditary blood clotting disorder,associated with a decrease in the level of factor VIII and leading to profuse bleeding in the joints, muscles or internal organs, both spontaneously, and as a result of accidental trauma or surgical interventions. When carrying out substitution therapy, a temporary correction of factor VIII deficiency in plasma and correction of bleeding are achieved.

Immunogenicity of the drug Nuwick was studied in clinical studies, in which 135 patients with severe haemophilia A, previously treated (74 adults and 61 children) participated. None of the patients showed inhibitors.

In a clinical study in 32 adult patients with severe haemophilia A, the average Nuvik drug use for prevention was 468.7 IU / kg per month. The average dose for the treatment of acute bleeding was 33.0 IU / kg for patients receiving Nuwick for prophylactic purposes. In another clinical study, 22 adult patients were treated as needed. A total of 986 cases of bleeding required treatment with an average dose of 30.9 IU / kg. In general, small bleeding requires the use of slightly smaller doses of the drug, and more severe bleeding requires the administration of the drug in doses, up to three times the average dose of the drug.

Pharmacodynamics in children

Data were obtained from 29 previously treated children aged 2 to 5 years, 31 between the ages of 6 to 12 and one older than 14 years. The average dose of preventive infusions was 37.8 IU / kg. Twenty patients received an average dose of more than 45 IU / kg. The average Nuvik drug consumption for prevention was 521.9 IU / kg per month. Studies have shown that for the treatment of bleeding in children, the average dose of Nuwick (43.9 IU / kg) is higher than that of adults (33.0 IU / kg), and that the average dosage required to stop from medium to severe bleeding is higher than for weak bleeding (78.2 IU / kg vs 41.7 IU / kg). For young children, a large average dose is generally required (6-12 years: 43.9 IU / kg, 2-5 years: 52.6 IU / kg).

Pharmacokinetics:

Pharmacokinetics

Table 1. The pharmacokinetics of the drug Nuwick (50 IU / kg) in adults 18 to 65 years of age with severe haemophilia A who were previously treated (n = 20)

Pharmacokinetic parameter	Chromogenic analysis
Pharmacokinetic parameter	The mean ± SD	Median (interval)
AUC (h * IU / mL)	22,6 ± 8,0	22,3 (8,4-38,1)
T ½ (h)	14,7 ± 10,4	12,5 (5,4-55,6)
IVR (% / IU / kg)	2,5 ± 0,4	2,50,7-3,2)
CL (ml / h / kg)	3,0 ± 1,2	2,70,5-6,4)

Table 2. Pharmacokinetics of the drug Nuwick (50 IU / kg) in children aged 6 to 12 years with severe haemophilia A who were previously treated (n = 12)

Pharmacokinetic parameter	Chromogenic analysis
Pharmacokinetic parameter	The mean ± SD	Median (interval)
AUC (h * IU / mL)	13,2 ±3,4	12,8 (7,8-19,1)
T½ (h)	10,0 ± 1,9	9,9 (7,6-14,1)
IVR (% / IU / kg)	1,9 ±0,4	1,90,2-2,6)
CL (ml / h / kg)	4,3 ± 1,2	4,2 (2,8 - 6,9)

Table 3. Pharmacokinetics of the drug Nuwick (50 IU / kg) in children aged 2 to 5 years with severe haemophilia A who were previously treated (n = 13)

Pharmacokinetic parameter	Chromogenic analysis
Pharmacokinetic parameter	The mean ± SD	Median (interval)
AUC (h * IU / mL)	11,7 ±5,3	10,5 (4,9-23,8)
T½ (h)	9,5 ± 3,3	8,2 (4,3-17,3)
IVR (% / IU / kg)	1,9 ±0,3	1,8 0,5-2,4)
CL (ml / h / kg)	5,4 ± 2,4	5,1 (2,3-10,9)

AUC = area under the curve (FVIII: C), T1 - half life, IVR = factor recovery in vivo, CL = clearance, CO = standard deviation

Pharmacokinetics in children

According to the published data, the recovery time and half-life are somewhat lower in children than in adults, while the clearance of the drug in children is higher, which may be due to the well-known fact that children have a plasma volume per kilogram of body weight higher than adults.

Sub-division by weight

Table 4. Pharmacokinetics of the drug Nuwick (50 IU / kg), depending on the weight in adults aged 18 to 65 years with severe haemophilia A, previously treated (n = 20)

Normal weight: body mass index (BMI) 18.5-25 kg / m²Fatigue: BMI 25-30 kg / m²Obesity: BMI> 30 kg / m²

Indications:

Treatment and prevention of bleeding in children older than 3 years and adults with hemophilia A (congenital deficiency of the coagulation factor VIII).

Contraindications:

Hypersensitivity to the active ingredient or any of the components of the drug.

Pregnancy and lactation:Since hemophilia A is rarely seen in women, experience with factor VIII treatment during pregnancy and lactation is not available. Therefore, Nuuk must be used during pregnancy and during breastfeeding only in the presence of absolute indications.

Dosing and Administration:

Treatment should be performed by a doctor who has experience in treating patients with hemophilia. The drug is administered intravenously after dissolution in the attached solvent (water for injections). Only the attached dissolution and administration devices should be used, since the adsorption of factor VIII on the inner surface of any other containers and devices for injection may lead to ineffective treatment.
The rate of administration of the solution should not exceed 4 ml / min.
The dose and duration of replacement therapy depend on the degree of factor VIII deficiency, localization and severity of bleeding, as well as on the patient's objective condition.

The number of units of factor VIII in the preparation is expressed in International Units (IU), established by the current WHO standard for preparations of factor VIII.The activity of factor VIII in plasma is expressed as a percentage (relative to the content of factor VIII in normal human plasma) or in IU (relative to the International Factor VIII standard).
1 MU of factor VIII activity is equivalent to the content of factor VIII in 1 ml of normal human plasma.

Mode of therapy "on demand"

The calculation of the required dose is based on empirically obtained results, according to which 1 IU of the factor VIII/ kg of body weight increases the plasma factor VIII activity level by about 2% of normal activity (or 2 IU / dl). Calculation of the required dose is carried out according to the formula:

Necessary dose = body weight (kg) x desired increase in factor VIII level (%) (IU / dl) x 0.5 (IU / kg per IU / dl)
Expected increase in factor VIII level (% of norm):
2 x amount of introduced factor VIII (ME)
body weight (kg)

The dose and frequency of the drug should always be targeted at achieving a clinical effect in each individual case.

In the event of subsequent bleeding, the level of activity of factor VIII should not decrease below a predetermined level of plasma activity (% of normal content) at the appropriate time period. The table below can be used as a a guideline for the choice of doses for various bleeding and surgical interventions.

Table 5. Recommended doses of Novik for various types of bleeding and surgical interventions

Heaviness of bleeding / type surgical intervention	Necessary level of factor VIII (%)	Frequency of administration (hours) / Duration of treatment (days)
Bleeding
Early hemarthrosis, intramuscular hemorrhage, oral bleeding	20-40	Every 12-24 hours for at least 1 day, until the bleeding episode (determined by the presence of pain) is resolved or until the source of bleeding is healed.
More extensive hemarthrosis, intramuscular bleeding or bruising	30-60	Every 12-24 hours for at least 3-4 days before the disappearance of pain and acute functional disorders.
Life threatening bleeding.	60- 100	Every 8-24 hours until the threat of bleeding disappears completely.
Surgical interventions
Small interventions, including tooth extraction	30-60	Every 24 hours at least 1 day before the healing is achieved.
Major Interventions	80-100 (pre- and post-operation)	Every 8-24 hours to adequate healing of the source of bleeding, then at least 7 days to maintain the activity of factor VIII at a level of 30-60%

Mode of therapy "prevention"

For the long-term prophylaxis of bleeding in patients with severe hemophilia A, the average dose of factor VIII is 20-40 IU / kg body weight at intervals of 2-3 days.

In some cases, especially in younger patients, it may be necessary to reduce the gap between the administrations or increase the dose.

During the course of treatment it is recommended to determine the level of factor VIII in order to correct the dose and frequency of repeated injections. In the case of large surgical interventions careful monitoring of replacement therapy by monitoring blood clotting is necessary (factor VIII activity in plasma). The response to treatment may be different for individual patients, which indicates differences in half-life and recovery.

Patients who were not previously treated
Information about the safety and efficacy of the drug Nuwick in patients who have not previously received treatment, at the moment there.

Use in children
The use of the drug in children corresponds to that in adults, but children may need shorter intervals of administration or higher doses.

Preparation of the preparation for administration
The lyophilizate is diluted with the applied solvent (2.5 ml of water for injection) and dissolution and administration devices. The solution after reconstitution should be colorless,transparent or slightly opalescent, pH 6.5 to 7.5.
The reconstituted drug is used immediately.

Instructions for preparation and introduction

1. Bring the syringe with the solvent (water for injections) and a closed vial with lyophilizate to room temperature. You can warm them in your hand. Do not use any other heating methods. Keep the room temperature of the drug in the process of recovery.

2. Remove the plastic flip-off lid from the lyophilized bottle. Do not remove the aluminum cap and do not remove the rubber plug.

3. Wipe the top of the vial with a disinfectant alcohol wipe. Allow the alcohol to dry.

4. Remove the paper cover from the adapter package for the vial. Do not remove the adapter from the package.

5. Place the vial with lyophilizate on a flat surface and hold it. Place the packaging with the adapter pointing down the center of the rubber stopper. Push the adapter with force so that the needle pinches the plug. When the adapter has reached the desired position, a click will be heard.

6. Remove the paper cover from the syringe package. Hold the piston rod by the end and do not touch the pin. Insert the piston rod with the threaded end into the plunger of the syringe with the solvent.Turn the piston rod clockwise until you feel a slight resistance.

7. Break off the plastic cap with the tamper indication from the syringe with the solvent on the perforation of the cap. Do not touch the inside of the cap or the opened end of the syringe. If the solution is not immediately used, close the syringe with a plastic cap for the duration of storage.

8. Remove the packaging from the bottle adapter and place it in the waste container.

9. Reliably connect the syringe with the solvent with the bottle adapter, turning it clockwise until you feel resistance.

10. Pressing the piston rod, carefully insert the solvent into the vial with lyophilizate.

11. Without removing the syringe, gently rotate the vial or move in a circle until the lyophilizate is completely dissolved. Do not shake the bottle.

12. Before proceeding, be sure to inspect the solution for particles and discoloration. The solution should be clear and colorless. Do not use a cloudy solution or solution in which there are particles.

13. Turn the bottle with the attached syringe upside down and slowly pour the solution back into the syringe. Make sure that the entire contents of the vial are transferred to the syringe.

14.Disconnect the filled syringe from the vial adapter by turning it counter-clockwise, place the empty vial into the waste container.

15. The solution in the syringe is ready for administration. Do not store in the refrigerator after dilution. The prepared solution should be used immediately after dilution.

16. Clean the place of administration of one of the disinfecting napkins that come with it.

17. Connect the supplied insertion system ("butterfly needle") to the syringe. Enter the "butterfly needle" into the selected vein. When using a tourniquet to facilitate the introduction of a needle into the vein before the injection of the solution, it is necessary to remove the tourniquet. It should be ensured that blood does not enter the syringe to avoid the risk of fibrin clots.

18. Slowly inject the solution into the vein (at a rate of no more than 4 ml / min).

If you plan to use several vials with the drug for one procedure of administration, you can use the same needle to introduce the reconstituted product from other vials.
The vial adapter and syringe are for single use only. Unused product or waste should be disposed of in accordance with existing regulations.

Side effects:

General characteristics of the security profile

Hypersensitivity or allergic reactions (which may include angioedema, burning and itching at the injection site, chills, reddening of the face, generalized urticaria, headache, local urticaria, hypotension, inhibition, nausea, anxiety, tachycardia, chest tightness, ringing in ears, vomiting, wheezing) with the use of preparations of factor VIII were rare, but in some cases progressed with the development of severe anaphylaxis (including shock).

In clinical trials using Novik in pre-treatment children (2 to 11 years, n = 58), adolescents (12 to 17 years, n = 3), and adult patients (n = 74) with severe hemophilia A in A total of 8 adverse reactions (NLR) were recorded (6 in adults and 2 in children) in 5 patients (3 adults and 2 children). In adolescents, NLDs were not observed. The total number of patients in the study was 135.

Table 6. Information on the incidence of adverse reactions in clinical studies of patients with severe hemophilia A who received previous treatment

	Unwanted reactions	Frequency * in children from 2 to 11 years (n = 58)	Frequency * in patients older than 18 years (n = 74)
From the nervous system	Paresthesia Headache	- 1,72%	1,35% -
From the organs of hearing and balance	System dizziness (vertigo)	-	1,35%
From the side gastrointestinal tract	Dry mouth	-	1,35%
From the musculoskeletal system and connective tissue	Backache	1,72%	-
Local Reactions	Inflammation at the injection site	-	1,35%
Local Reactions	Pain at the injection site	-	1,35%
From the side laboratory indicators	Positive the result of the determination of non-neutralizing antibodies to factor VIII	-	1,35%

* All these unwanted reactions occurred once.

Description of individual adverse reactions

Non-neutralizing antibodies to factor VIII were determined in one adult patient. The test was performed in a central laboratory at eight dilutions. The result was positive only at a dilution ratio of 1, with the antibody titer being very low. Inhibitory activity according to the modified Bethesda-test was not determined. Clinical efficacy and recovery of Novik invivo in this patient did not change.

Use in children

It is assumed that the frequency, type and severity of adverse reactions in children are similar to those in adults.

Overdose:

No cases of overdose have been reported.

Interaction:

Investigations of drug interactions with other drugs have not been conducted. Due to the lack of compatibility studies, this drug should not be mixed with other drugs.

Special instructions:

Hypersensitivity

As with any protein preparation for intravenous administration, it is possible to develop allergic hypersensitivity reactions. Nuwick contains traces of human host proteins other than factor VIII. If symptoms of hypersensitivity reaction appear, the patient should immediately stop using the drug and consult a doctor. Patients should be informed of early signs of hypersensitivity reactions, including allergic rash, generalized urticaria, chest tightness, wheezing, hypotension and anaphylaxis.
In case of shock, standard treatment should be performed.

Inhibitors

The formation of neutralizing antibodies (inhibitors) to factor VIII is a known complication in the treatment of patients with hemophilia A. Typically, these inhibitors are directed against procoagulant activity of factor VIII immunoglobulins IgG, the content of which is determined in modified Betezda units (BU) per ml plasma using a modified method.
The risk of the appearance of inhibitors correlates with the number of times (days) of administration of factor VIII and is highest during the first 20 days of administration. In rare cases, inhibitors may appear after the first 100 days of administration.

Cases of recurrent appearance of inhibitors (with a low titer) were observed after switching from treatment with a single factor VIII drug to treatment with another factor VIII drug in patients who had previously received the drug (introduction more than 100 days), who had history of occurrence of inhibitors. Therefore, it is recommended to carefully monitor patients for the appearance of inhibitors after switching from one preparation of factor VIII to another.

In general, the condition of patients receiving treatment with preparations of factor VIII,should be carefully monitored for the appearance of inhibitors by appropriate clinical observation and laboratory tests (it is necessary to periodically determine the level of activity of factor VIII). If the expected level of activity of factor VIII in the plasma is not achieved, or if an adequate dose does not manage to control bleeding, an appropriate analysis should be performed to identify the inhibitors of factor VIII. In patients with high levels of inhibitors, treatment with factor VIII may not be effective, and consideration should be given to the use of alternative therapies (eg, induction of immune tolerance). Treatment of such patients should be performed by a doctor who has experience in the treatment of hemophilia in the presence of inhibitors to factor VIII.

Complications associated with the use of a catheter

If a device for central venous access is required, the risk of complications associated with its use should be considered, including local infections, bacteremia and thrombosis at the site of insertion of the catheter.
With each introduction of Novik, the patient is strongly recommended to register the name of the drug and the number of the series,so that it is possible to trace the relationship of the patient's condition with the administration of the drug of a particular series.

Use in children

The above instructions apply equally to both adults and children. Limitations associated with excipients One bottle of the drug contains <1 mmol (23 mg) of sodium.
However, depending on body weight and indications, the patient may use more than one vial of the drug. This should be taken into account for patients who adhere to a sodium-restricted diet.

Effect on the ability to drive transp. cf. and fur:

Nuvik no effect on the ability to road management and the performance of potentially hazardous activities that require high concentration and psychomotor speed reactions.

Form release / dosage:

Lyophilizate for solution for intravenous administration 250 ME, 500 ME, 1000 ME and 2000 ME.

Packaging:

250 each ME or 500 ME or 1000 ME or 2000 ME vial of clear, colorless glass (type I, Eur. F.), a sealed rubber stopper (Eur. F.) coated aluminum cap and a plastic break-lid type flip-off (it is allowed to scroll the lid).

For 2.5 ml of the solvent (water for injection) into a disposable syringe made of clear, colorless glass (type I, Hebrew F.).

1 bottle with lyophilizate, 1 syringe with solvent in blister pack, 1 adapter for bottle in blister pack, 1 system for insertion ("needle-butterfly") in blister pack, 2 disinfecting napkins in individual sealed packages together with instructions for use in cardboard pack with cardboard insert.

Storage conditions:

Store at a temperature of 2 to 8 ° C in a dark place. Do not freeze.
Keep out of the reach of children.

Shelf life:

2 years. Do not use after the expiration date.

Terms of leave from pharmacies:On prescription

Registration number:LP-003522

Date of registration:24.03.2016

Expiration Date:24.03.2021

The owner of the registration certificate:Octapharma ABOctapharma AB Sweden

Manufacturer: & nbsp

OCTAPHARMA, AB Sweden

Representation: & nbspOKTAPHARMA NORDIC AB OKTAPHARMA NORDIC AB Sweden