�?ннонафактор - instructions for use, doses, side effects, contraindications

Active substanceNonacog AlphaNonacog Alpha

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Benefiks®

lyophilizate in / in

WAYET, LLC Russia

InnovaFactor

lyophilizate in / in

GENERIUM, CJSC Russia

Dosage form: & nbsplyophilizate for the preparation of a solution for intravenous administration

Composition:1 the vial containing the preparation contains:

active substance: nonag (rFIX)	250 ME	500 ME	1000 ME;
Excipients:
histidine	3.88 mg,	7.76 mg,	15.52 mg;
sucrose	25.0 mg,	50.0 mg,	100.0 mg;
glycine	48.8 mg,	97.6 mg,	195.2 mg;
sodium chloride	5.85 mg,	11.7 mg.	23.4 mg;
polysorbate 80	0.14 mg,	0.28 mg,	0.56 mg.

1 bottle of solvent contains: water for injection 5 ml or 10 ml

Description:Amorphous mass of white color.

Pharmacotherapeutic group:hemostatic agent.

ATX: & nbsp

B.02.B.D.09 Nonacog Alpha

Pharmacodynamics:

Characteristics of the preparation

The active substance of the drug Innonafactor is recombinant coagulation factor IX (nonag), which is a single-chain glycoprotein with a molecular weight of about 55 kDa, consisting of 415 amino acid residues. Nonacog Alpha belongs to the family of serine proteases and is a vitamin K-dependent clotting factor.

Recombinant coagulation factor IX is produced by a modified transplantable line of Chinese hamster CHO 1E6 ovary cells using recombinant DNA technology.

Pharmacodynamic properties

The structural and functional properties of the recombinant coagulation factor IX are similar to the endogenous coagulation factor IX. In the process of blood clotting, factor IX is activated by a blood coagulation factor VIIa in combination with the tissue factor in the external mechanism of blood coagulation, as well as the clotting factor XIa by the internal mechanism of blood coagulation. Activated coagulation factor IX in combination with an activated blood coagulation factor VIII lead to the activation of the coagulation factor X, which ensures the conversion of prothrombin into thrombin. Thrombin activates the process of converting fibrinogen into fibrin with the formation of a blood clot.

In patients with hemophilia B, the activity of coagulation factor IX is significantly reduced, which requires replacement therapy, which provides temporary normalization of the content of factor IX and elimination of hemorrhagic manifestations of the disease.

Pharmacokinetics:

The value of the degree of restoration of the activity of the Innafactor is in the range from 32,2 before 55,9 % and on average is 42±8,4 %. The index of increasing the activity of the Innovator (K-value) is from 0,77 before 1,41 IU / dl per IU / kg and on average is 1,05±0,21 IU / dl per IU / kg. The maximum concentration (Cmax) of the Innafactor is 53,18 IU / dl (from 41,6 before 70,3 IU / dL). AUC_0-96h is 1069,9 ME * h / dl. The half-life of Innonafactor varies from 16,5 before 33 hours (on average - 24 ±7,7 hours). The average clearance value is 3,62 dl / h.

Indications:

Treatment and prevention of bleeding in patients with hemophilia B (congenital insufficiency of the coagulation factor IX) aged 18 years and older.

Contraindications:

Hypersensitivity to hamster proteins or intolerance to any of the components that make up the drug. Age under 18 years (no experience of use).

Dosing and Administration:

Innonafactor is injected intravenously slowly for 2-5 minutes, after reconstitution of the lyophilisate with the applied solvent. The rate of administration is determined by the physician and may depend on the patient's tolerability of the drug.

The drug should not be administered drip or mixed with infusion solutions, because of the lack of information about prolonged infusion of coagulation factor IX.

The dose of coagulation factor IX is expressed in international units (ME). 1 ME coagulation factor IX is equivalent to the amount of factor IX in 1 ml of healthy human blood plasma.

The activity of coagulation factor IX in the blood plasma is expressed either as a percentage (corresponds to the normal values of human blood plasma), or in international units per unit volume (IU / dl).

The calculation of the required dose of coagulation factor IX is based on empirical studies, according to which the introduction of 1 ME Nonocyanate alpha per kg of body weight increases the activity of the clotting factor FIX in blood plasma, on average 0.8 to 1.0 IU / dL (range of variation - from 0.7 to 1.4 IU / dL) in adult patients.

The required dose of the introduction of Innonafactor is calculated by the following formula:

Necessary
quantity ME
factor a
coagulation of IX

Body weight (in kg)

Necessary
rise
factor activity
coagulation
IX (% or IU / dl)

Return value
degree of improvement
factor activity
coagulation of IX

Thus, with an average increase in coagulation factor IX activity corresponding to 0.8 IU / dl:

Necessary
quantity ME
factor a
coagulation of IX

Body weight (in kg)

Necessary
rise
factor activity
coagulation
IX (% or IU / dl)

1.3 IU / kg per IU / dL

With the development of the hemorrhagic conditions listed below, the activity of factor IX in blood plasma should not fall below these levels (in% of normal or in ME / dL) for an appropriate period of time.

With extensive surgical interventions, nonakogam alpha substitution therapy should be monitored by coagulation analysis (determination of coagulation factor IX in the blood plasma). Individual peculiarities of patients' response to treatment with coagulation factor IX are possible, due to different rates of activity recovery in vivo and half-life of the drug. The use of recombinant coagulation factor IX more than 1 time per day, as a rule, is not required.

Innonafactor can be used as a long-term prophylaxis for bleeding in patients with severe hemophilia B. The average dose of the drug when used as a secondary prophylaxis in patients previously treated with coagulation factors is on the average 40-50 IU / kg with an interval of administration of 3 to 4 days.In young patients, it may be necessary to shorten the intervals between administrations or increase the dose of the drug.

Table calculation of doses of the drug for various bleeding and in surgical practice

Severity of bleeding or type of surgical intervention	The necessary activity of factor IX (% or IU / dl)	Periodicity of administration (hours) / duration of therapy (days)
Bleeding:
Early hemarthrosis, muscle hemorrhage or bleeding in the oral cavity	20-40	Repeated injections of the drug every 24 hours, at least 1 day before the bleeding stops, which is determined by resolution of the pain syndrome or healing of the wound.
More severe hemarthrosis, muscle hemorrhage or hematoma	30-60	Repeated injections every 24 hours for 3-4 days or more, before the resolution of pain and acute impairment of function.
Life-threatening bleeding	60- 100	Repeated injections every 8-24 hours until life threatened.
Operative intervention:
Small, including tooth extraction	30-60	Repeated injections every 24 hours, for at least 1 day, until the wound is healed.
Extensive	80-100 (before and after surgery)	Repeated injections every 8-24 hours, until adequate healing of the wound, then therapy for at least 7 days to maintain factor IX activity at the level 30-60 % or IU / dl.

Use in patients with liver and kidney disease

The need to change the dose Innonafaktor drug in patients with liver disease and kidney failure in the clinical studies have not been studied.

Pediatric Use

The experience of using the drug Innonafactor in patients younger than 18 years is absent.

Application in pregnancy and lactation

The effect of the drug Innonafactor on the reproductive system during preclinical studies in animals was not evaluated. Given the rarity of hemophilia B in women, data on the use of coagulation factor IX drugs during pregnancy andin the lactation period are absent. In this connection, the drug Innonafactor in pregnant women should be used only if there are life indications.

Rules for the preparation of solution for injection

1. Wash hands thoroughly before performing the following procedures. Follow the rules of asepsis during the preparation and introduction of the solution.

2. Use the open components of the kit as quickly as possible to minimize the time of contact with atmospheric air.

3. Heat the flasks with the drug and the solvent to room temperature (not above 37 ° C), e.g. by holding them in his hands. Place the solvent bottle on a flat surface.

4. Remove the protective plastic cover from each vial.

5. Process the rubber stoppers of the vials with the supplied alcohol wipes. Allow them to dry before use.

6. Open the blister pack of the syringe by bending the paper cover to the middle.

7. Open the blister pack of the needle, bending the paper cover to the middle.

8. Put the sterile needle on the syringe without removing the protective cap. Be careful that the tip of the syringe does not come into contact with the hand or other surfaces.

9. Remove the protective cap from the needle.

10. Insert the needle into the rubber stopper of the vial and fill the syringe with the following amount of solvent:

- for dosage 250 ME - 2.5 ml;

- for dosage 500 ME 5 ml;

- for a dosage of 1000 ME -10 ml.

11. Put the syringe with the needle in the vial stopper until the next manipulation.

12. Open the blister pack of the second needle, bending the paper cover to the middle.

13. Remove the syringe from the needle (see item 11), leaving it in the stopper of the vial with the solvent.

14. Put the second sterile needle on the syringe with the solvent, without removing the protective cap. Be careful that the tip of the syringe does not come into contact with the hand or other surfaces. Remove the protective cap from the needle.

15. Insert the needle into the stopper of the vial with the drug, directing it to the side wall, and slowly pushing the piston rod, enter the appropriate volume of the solvent (see item 10) along the wall of the vial, avoiding foaming and contact of the needle with the solution of the drug. "Foaming" appears if the solvent falls directly on the lyophilizate.

16. Gently shake the bottle until all the substance has dissolved. Do not shake the bottle. Make sure that the powder is completely dissolved. In the presence of inclusions or turbidity, the solution can not be used.

17. While holding the bottle in a slightly inclined position, draw a solution from it into the syringe, slowly and slowly pulling the piston. Make sure that the entire prepared solution has passed into the syringe. Put the syringe with the needle in the vial stopper until the next manipulation.

18. Open the blister pack of the catheter for peripheral veins.

19. Open the blister pack of the injection filter, bending the paper coating to the middle.

20. Without changing the position of the piston (see clause 17), remove the syringe from the needle, leaving it in the cork of an empty vial. Remove air from the syringe. Put the injection filter (open end) on the syringe after removing the blister pack. Ensure that the injection filter does not come into contact with foreign surfaces.

21. Remove the protective cap from the catheter tube. Attach the free end of the injection filter to the catheter tube by turning the filter clockwise until it stops. Make sure the connection is tight.

22. Open the package of the fixative patch, treat the injection site with the attached alcohol sponge.

23. Remove the protective cap from the catheter needle. Remove air from the syringe and attached system for intravenous administration and inject the drug solution intravenously slowly (for 2-5 minutes), pre-fixing the catheter needle on the skin with a fixing plaster. After the end of the intravenous injection, gently remove the needle.

24. Ensure the safe disposal of all materials used.

If more than one dose is needed, similarly, prepare the solution in another vial of the preparation using the supplied solvent, and then connect the solutions in a larger syringe (not supplied) and enter the preparation as described above.

It is recommended to use the prepared solution immediately after dilution or for 3 hours. The solution not used during this time should be disposed of.

Side effects:

The use of nonacarpalpha in some cases may be accompanied by the development of a number of side effects with the following frequency: infrequent (at a frequency of ≥1/1000 to <1/100) and rare (with a frequency of ≥1/10000 to <1/1000). The most significant side effects are: anaphylaxis, phlegmon, phlebitis and the formation of neutralizing antibodies.

Within each frequency category, side effects are listed in order of decreasing severity.

Disturbances from the nervous system

Infrequent: dizziness, headache, pre-syncope, change taste perception.

Rare: tremor, drowsiness, a violation of taste.

Ondigestive system disorders

Infrequent: nausea.

Rare: vomiting, diarrhea.

Systemic disorders and complications at the site of administration

Infrequent: phlegmon in the area of administration, phlebitis in the area of administration, cutaneous and other reactions at the injection site (including burning and tightening sensation), discomfort at the injection site, pain at the injection site.

Rare: fever.

Immune system disorders

Infrequent: the formation of neutralizing antibodies (inhibitors of the coagulation factor IX) for a short time in a low titer (see section "Special instructions").

Rare: hypersensitivity, allergic reactions, including anaphylaxis (see section "Special instructions"), laryngospasm, bronchospasm or respiratory distress syndrome (dyspnea), wheezing, lowering of arterial pressure, angioedema, laryngeal edema, tachycardia, chest tightness cage, urticaria, skin rashes, burning sensation in the lower jaw and skull area, chills (shivering), tingling sensation, blood flushes to the face, inhibition, anxiety, dry coughing or sneezing, decreased vision clarity (see section "Special instructions"), allergic rhinitis, weakness, anaphylaxis.

Respiratory, thoracic and mediastinal disorders

Infrequent: cough, leading to hypoxia.

Other

Rare: trembling, photosensitivity reactions.

Changes in laboratory indicators

Infrequent: increased activity of aspartate aminotransferase, increased activity of alanine aminotransferase, increased bilirubin concentration, increased activity of creatine phosphokinase, increased activity of alkaline phosphatase.

There is evidence of the possibility of developing cyanosis and lowering blood pressure.

Disorders from the urinary system

There are data on the development of a kidney infarction 12 days after the administration of nonacarpal alpha about a hemorrhagic condition in 1 patient with antibodies to the hepatitis C virus.

Thrombotic complications

Against the background of treatment with nonacom alfa, cases of thrombosis development, including life-threatening syndrome of the inferior vena cava in newborns who were in serious condition and who received nonag in the form of a long infusion through a central venous catheter. Also, cases of peripheral vein thrombophlebitis and deep vein thrombosis have been reported, mainly after prolonged intravenous infusions not registered as a method of administration of this drug.

Inadequate response and inadequate degree of recovery of coagulation factor IX activity

There is information about cases of inadequate response and inadequate degree of recovery of coagulation factor IX activity when using nonacarpal alpha.

With the development of any side effects, which, presumably, may be associated with the administration of the drug, it is necessary to reduce the rate of administration or to suspend it.

Overdose:

Cases of overdose Innonafactor is not described.

Interaction:

Drug interaction is not described.

Special instructions:

Patients previously treated with coagulation factor IX drugs sometimes develop active neutralizing antibodies (inhibitors). The analysis for the presence of inhibitors to the coagulation factor IX, whose titer is measured in Bethezd (BY) units, is performed if it is not possible to achieve the expected level of activity of the coagulation factor IX or stop bleeding when the calculated dose is administered, using adequate tests. In the presence of high concentrations of inhibitors to the coagulation factor IX, therapy with nonakogam alfa may not be effective. In this case, alternative therapies may be required. Such patients should be administered by physicians with experience in the treatment of patients with hemophilia B.

In clinical studies of Innonafactor, a sufficient number of patients aged 65 years and older were not included, which makes it impossible to assess the difference in response to treatment compared to a younger age. When prescribing Innonafactor, patients of different ages may require an individual dose adjustment.

Intravenous administration of any protein preparations, including the recombinant factor of blood clotting IX, may be accompanied by the development of a hypersensitivity reaction associated with the presence of trace residual quantities of protein-producer proteins transferred during the manufacturing process. When using recombinant coagulation factor IX, it is also possible to develop anaphylactic and anaphylactoid reactions.

In addition, allergic reactions may be associated with the appearance of inhibitors to the coagulation factor IX, and therefore patients with allergic reactions in the history should be examined for the presence of inhibitors. It should be taken into account that in patients who have inhibitors to the coagulation factor IX, there may be an increased risk of anaphylactic reactions and subsequent injections of the coagulation factor IX. There is evidence of a higher risk of formation of inhibitory antibodies, as well as the development of acute hypersensitivity reactions in patients with deletion of the coagulation factor gene IX. If the deletion of the gene encoding the synthesis of coagulation factor IX is detected in patients,it is necessary to closely monitor the possible development of clinical manifestations of acute hypersensitivity reactions, especially during the initial phase of therapy.

Patients should be informed of early clinical signs of hypersensitivity reactions, including the occurrence of difficulty breathing, urticaria, skin itching, edema development, chest compressions, bronchospasm, laryngospasm, wheezing, arterial hypotension, decreased vision and anaphylaxis. With the development of an allergic reaction or anaphylactic shock, it is necessary to immediately stop the injection of the drug Innonafactor and begin the appropriate standard therapy. With the development of severe allergic reactions, consideration should be given to the appointment of alternative hemostatic therapy. The principles of treatment depend on the type and severity of side effects.

In view of the risk of developing allergic reactions, the first administration of the drug Innonafactor is advisable to perform under medical supervision in institutions where there are conditions for providing appropriate emergency assistance.

Doses and duration of substitution therapy depend on the degree of deficiency of the coagulation factor IX, the localization and severity of bleeding, the general condition of the patient, the clinical effect of the therapy and individual parameters of the patient's pharmacokinetics. The dose of the drug Innonafactor can differ from the doses of plasma preparations of the coagulation factor IX. To ensure the necessary activity of factor IX in the blood with replacement therapy, it is recommended to control the level of coagulation factor IX in the plasma by means of coagulation analysis.

Despite the fact that the drug Innonafactor does not contain other active substances, it is necessary to bear in mind the risk of developing thromboses and the syndrome of disseminated intravascular coagulation (ICD). Since the appointment of previously used blood clotting factors II, IX, X in combination and prothrombin complex was associated with the development of thromboembolic complications, the risk of their development will increase with the treatment with drugs of coagulation factor IX patients suffering from DIC syndrome and patients with signs of fibrinolysis.

Given the potential risk of thromboembolism with the introduction of recombinant coagulation factor IX patients with liver disease in the postoperative period at risk of developing thrombosis or DIC syndrome, it is necessary to carry out surveillance to detect early manifestations of thrombotic complications using appropriate tests, and in their development, conduct appropriate treatment. In each of these situations, the ratio of the potential benefit of recombinant coagulation factor IX therapy and the risk of these complications should be assessed.

In order to reduce the likelihood of agglutination in a syringe or intravenous system, it is advisable to limit the ingress of blood in them when the drug is administered. If erythrocyte agglutination develops in the system or syringe, the consumables used (intravenous infusion system, syringe and Innonafactor solution) must be disposed of and the administration should be repeated using a new package of the drug.

In attempts to induce immune tolerance in patients with hemophilia B,which produce inhibitors of the coagulation factor IX and who had allergic reactions in the anamnesis, there were cases of development of a nephrotic syndrome. Security and the effectiveness of the use of the drug Innafactor for the purpose of inducing immune tolerance is not defined.

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

Studies of the effect of the drug on the ability to drive and work with mechanisms that require increased concentration of attention have not been conducted.

Form release / dosage:

Lyophilizate for the preparation of a solution for intravenous administration of 250 ME, 500 ME or 1000 ME.

Packaging:

Lyophilizate for the preparation of a solution for intravenous administration of 250 ME, 500 ME or 1000 ME in glass bottles, corked with rubber stoppers with aluminum-plastic caps with control of the first opening.

For 5 or 10 ml of solvent (water for injection) in glass bottles, capped with caps combined with elastomeric elements.

1 bottle with the preparation and 1 bottle with a solvent - in a contour acrylic package of a film of polyvinylchloride or polyethylene terephthalate.

1 blisters complete with expendable medical materials: a syringe without a needle capacity of 5 or 10 ml, 2 needles dilution filter injection, peripheral venous catheter, a fixing plaster, 2 alcohol wipes and instructions for use placed in a pile of cardboard.

Each component of consumable medical materials placed in sterile disposable packaging film of polyvinyl chloride and laminated paper. Napkin alcohol packed in a multi-layer material, consisting of aluminum foil and polyethylene film.

On the joints of the lid and the bottom with the front and back sides of the pack are glued self-adhesive unmarked labels to control the first opening.

Storage conditions:

In the dark place at a temperature of 2 to 8 C. Do not freeze.

Keep out of the reach of children.

Shelf life:

Preparation - 2 years, solvent - 2 years 6 months.

Do not use after the time specified on the package.

Terms of leave from pharmacies:On prescription

Registration number:LP-002662

Date of registration:20.10.2014

The owner of the registration certificate:GENERIUM, CJSC GENERIUM, CJSC Russia

Manufacturer: & nbsp

GENERIUM, CJSC Russia

Information update date: & nbsp07.08.2015

Illustrated instructions

Instructions

InnovaFactor (Innonafactor)