Innonafaktor

General characteristics. Structure:

Active ingredient: 250 ME, 500 ME or 1000 ME nonakog alpha (rFIX).

Excipients: histidine, sucrose, glycine, sodium chloride, polysorbate 80.

Solvent: water for injections.

Pharmacological properties:

Pharmacodynamics. Characteristic of drug. Innonafaktor is active agent of drug the recombinant blood-coagulation factors of IX (нонаког an alpha) representing the one-chained glycoprotein with a molecular weight about 55 kd consisting of 415 amino-acid remains. Нонаког the alpha belongs to family of serinovy proteases and vitamin is K-dependent blood-coagulation factors.

The recombinant blood-coagulation factors of IX are produced by the modified intertwined line of cells of ovaries of the Chinese hamster of CHO 1E6 with use of technologies of recombinant DNA.

Pharmakodinamichesky properties. Structural and functional properties of recombinant blood-coagulation factors of IX are similar to an internal cause of a blood coagulation of IX. In the course of a blood coagulation the factor of IX is activated by VIIa blood-coagulation factors in a complex with a fabric factor on the external mechanism of a blood coagulation, and also HIA blood-coagulation factors on the internal mechanism of a blood coagulation. The activated blood-coagulation factors of IX in a combination with the activated blood-coagulation factors of VIII are led to activation of blood-coagulation factors of X which provide transformation of a prothrombin into thrombin. Thrombin activates process of transformation of fibrinogen to fibrin with formation of a blood clot.

At the patients suffering from a Cristmas disease, activity of blood-coagulation factors of IX is considerably reduced that demands performing replacement therapy which provides temporary normalization of maintenance of a factor of IX and elimination of hemorrhagic displays of a disease.

Pharmacokinetics. Value of extent of recovery of activity of K-value is in range from 32,2 to 55,9% and averages 42±8,4%. The indicator of increase in activity of K-value makes from 0,77 to 1,41 ME/dl on ME/kg and is on average equal to 1,05±0,21 ME/dl on ME/kg. The maximum concentration (Cmax) of K-value makes 53,18 ME/dl (from 41,6 to 70,3 ME/dl). AUC0-96ch makes 1069,9 îà*þ/dl. The elimination half-life of K-value varies from 16,5 to 33 hours (on average - 24 ±7,7 hours). Average value of clearance makes 3,62 dl/h.

Indications to use:

Treatment and prevention of bleedings at patients with a Cristmas disease (inborn insufficiency of blood-coagulation factors of IX) at the age of 18 years are also more senior.

Route of administration and doses:

Innonafaktor is entered intravenously struyno slowly within 2-5 minutes, after lyophilisate recovery by the enclosed solvent. Rate of administering is defined by the doctor and can depend on portability of drug the patient.

The drug should not be administered kapelno or to mix with infusion solutions, in view of lack of information on long infusional introduction of blood-coagulation factors of IX.

The dose of blood-coagulation factors of IX is expressed in the international units (ME). 1 ME blood-coagulation factors of IX it is equivalent to quantity of a factor of IX in 1 ml of a blood plasma of the healthy person.

Activity of a factor of coagulation of IX in a blood plasma is expressed or as a percentage (corresponds to normal values of a blood plasma of the person), or in the international units per unit of volume (ME/dl).

Calculation of a required dose of blood-coagulation factors of IX is based on empirical researches according to which introduction 1 ME nonakog the alpha on kg of body weight increases activity of a factor of coagulation of FIX in a blood plasma on average on 0,8 - 1,0 ME/dl (variation range - from 0,7 to 1,4 ME/dl) at adult patients.

The necessary dose of introduction of Innonafaktor is calculated by the following formula:

The necessary number of ME of a factor of coagulation of IX = Body weight (in kg) x Necessary increase in activity of a factor of coagulation of IX (% or ME/dl) x the Inverse value of extent of increase in activity of a factor of coagulation of IX.

Thus, at average increase in activity of a factor of coagulation of IX, the corresponding 0,8 ME/dl:

The necessary number of ME of a factor of coagulation of IX = Body weight (in kg) x Necessary increase in activity of a factor of coagulation of IX (% or ME/dl) x 1,3 ME/kg on ME/dl.

At development of the hemorrhagic states given below in the table, activity of a factor of IX in a blood plasma should not fall below the specified levels (to % from normal or to ME/dl) during the corresponding span.

At extensive operative measures replacement therapy nonakogy an alpha needs to be controlled by means of the coagulative analysis (definition of activity of blood-coagulation factors of IX in a blood plasma). Specific features of reaction of patients to treatment by blood-coagulation factors of IX, owing to different indicators of recovery of activity of in vivo and an elimination half-life of drug are possible. Use of recombinant blood-coagulation factors IX more than 1 once a day, as a rule, is not required.

Innonafaktor can be applied as long-term prevention of bleedings at the patients suffering from a severe form of a Cristmas disease. The average dose of drug at use as secondary prevention for the patients who were earlier receiving therapy by coagulation factors averages 40 - 50 ME/kg with an interval of introduction from 3 to 4 days. At patients of young age reduction of intervals between introductions or increase in a dose of drug can be required.

The table of calculation of doses of drug at various bleedings and in surgical practice:

Use for patients with diseases of a liver and kidneys. Need of change of a dose of drug Innonafaktor at patients with diseases of a liver and kidneys in clinical trials was not studied.

Use in pediatrics. Experience of use of drug Innonafaktor at patients is younger than 18 years is absent.

Use at pregnancy and in the period of a lactation. Drug influence Innonafaktor on reproductive system during preclinical trials on animals was not estimated. Considering a rarity of emergence of a Cristmas disease at women, given about use of drugs of blood-coagulation factors of IX at pregnancy willows the period of a lactation are absent. In this connection, it is necessary to use drug Innonafaktor at pregnant women only in the presence of vital indications.

Rules of preparation of solution for an injection:

1. Carefully wash up hands before performance of the following procedures. Carry out rules of an asepsis in the course of preparation and administration of solution.

2. Use open components of a set whenever possible quickly to reduce time of their contact with atmospheric air to a minimum.

3. Heat bottles with drug and solvent to room temperature (but not above 37 °C), for example, having taken them at themselves in hands. Put a bottle with solvent on a flat surface.

4. Remove a protective plastic slip from each bottle.

5. Process rubber bungs of bottles the enclosed napkin spirit. Let's them dry before use.

6. Open the blister packaging of the syringe, having unbent a paper covering to the middle.

7. Open the blister packaging of a needle, having unbent a paper covering to the middle.

8. Put on a sterile needle the syringe, without removing a protective cap. You watch that the tip of the syringe did not adjoin to a hand or other surfaces.

9. Remove a protective cap from a needle.

10. Enter a needle into a rubber bung of a bottle and gain the amount of solvent provided below in the syringe:

- for a dosage of 250 ME - 2,5 ml;

- for a dosage of 500 ME - 5 ml;

- for a dosage of 1000 ME-10 ml.

11. Postpone the syringe with a needle in a bottle stopper until the following manipulation.

12. Open the blister packaging of the second needle, having unbent a paper covering to the middle.

13. Remove the syringe from a needle (see item 11), having left it in a bottle stopper with solvent.

14. Put on the second sterile needle the syringe with solvent, without removing a protective cap. You watch that the tip of the syringe did not adjoin to a hand or other surfaces. Remove a protective cap from a needle.

15. Enter a needle into a bottle stopper with drug, directing it to a sidewall, and, slowly pressing a piston rod, enter the corresponding volume of solvent (see item 10) on a bottle wall, avoiding foaming and contact of a needle with drug solution. "Foaming" appears if solvent gets directly on lyophilisate.

16. Carefully shake a bottle until all substance is dissolved. Do not stir up a bottle. Make sure that powder was completely dissolved. In the presence of inclusions or a turbidity solution cannot be used.

17. Keeping a bottle in slightly inclined situation, gather from it solution in the syringe, slowly and smoothly delaying the piston. Make sure that all prepared solution passed into the syringe. Postpone the syringe with a needle in a bottle stopper until the following manipulation.

18. Open the blister packaging of a catheter for peripheral veins.

19. Open the blister packaging of the filter injection, having unbent a paper covering to the middle.

20. Without changing position of the piston (see item 17), remove the syringe from a needle, having left it in a stopper of an empty bottle. Remove air from the syringe. Put on the filter injection (the open end) the syringe after removal of the blister packaging. You watch that the filter injection did not adjoin to foreign surfaces.

21. Remove a protective cap from a catheter tube. Attach the free end of the filter of a catheter, injection to a tube, having turned the filter clockwise against the stop. Be convinced of connection density.

22. Open packaging of the plaster fixing process the place of an injection the enclosed napkin spirit.

23. Remove a protective cap from a catheter needle. Remove air from the syringe and the attached system for intravenous administration and enter drug solution intravenously struyno slowly (within 2-5 minutes), previously having fixed a catheter needle on skin by the fixing plaster. After the termination of an intravenous injection carefully remove a needle.

24. Provide safe destruction of all used dressing materials. If it is necessary to enter more than one dose, similarly prepare solution in other bottle of drug, using the enclosed solvent, and then connect solutions in the syringe of bigger volume it (is not applied) and administer the drug as it is described above.

It is recommended to use the prepared solution right after cultivation or within 3 hours. Solution unused during this time has to be utilized.

Features of use:

At the patients who were earlier receiving therapy by drugs of blood-coagulation factors IX formation of active neutralized antibodies (inhibitors) is sometimes noted. The analysis on availability of inhibitors to blood-coagulation factors of IX which caption is measured in Betezd's (BE) units is carried out at impossibility to reach the expected level of activity of blood-coagulation factors IX or to stop bleeding at introduction of the calculated dose, by adequate tests. With high concentration of inhibitors to blood-coagulation factors the IX therapy nonakogy the alpha can be inefficient. In this case use of alternative methods of treatment can be required. Maintaining such patients has to be carried out by the doctors having experience of treatment of patients with a Cristmas disease.

In clinical trials of drug Innonafaktor it was not included enough patients at the age of 65 years and is more senior that does not allow to estimate distinction of the response to treatment in comparison with younger age. At Innonafaktor's appointment individual dose adjustment of drug can be required by patients of various age.

Intravenous administration of any proteinaceous drugs, including recombinant blood-coagulation factors of IX, can be followed by development of reaction of the hypersensitivity connected with existence of trace residual amounts of the proteins of a strain producer postponed during technological process of production. When using recombinant blood-coagulation factors of IX also development of anaphylactic and anaphylactoid reactions is possible.

Besides, allergic reactions can be connected with emergence of inhibitors to blood-coagulation factors of IX in this connection patients with allergic reactions in the anamnesis have to be inspected on availability of inhibitors. It is necessary to consider that at the patients having inhibitors to blood-coagulation factors of IX increase in risk of anaphylactic reactions can be noted and at the subsequent introductions of blood-coagulation factors of IX. Development of acute reactions of hypersensitivity in patients with deletion of a gene of blood-coagulation factors of IX is had educated about higher risk of inhibitory antibodies, and also. In case of identification at patients of deletion of the gene coding synthesis of blood-coagulation factors of IX careful observation of possible development of clinical manifestations of acute reactions of hypersensitivity, especially during an initial phase of therapy is necessary.

Patients need to be informed on precursory clinical signs of reactions of hypersensitivity, including emergence of difficulty of breath, a small tortoiseshell, skin itch, edematization, feelings of a prelum of a thorax, a bronchospasm, a laryngospasm, goose breathing, arterial hypotension, decrease in clearness of sight and an anaphylaxis. At development of allergic reaction or an acute anaphylaxis it is necessary to stop immediately administration of drug Innonafaktor and to begin the corresponding standard therapy. At development of heavy allergic reactions it is necessary to consider a question of purpose of alternative haemo static therapy. The principles of treatment depend on a look and weight of side effects.

In view of existence of risk of development of allergic reactions, Innonafaktor it is reasonable to carry out the first administrations of drug under medical observation in institutions where there are conditions for rendering the appropriate emergency assistance.

Doses and duration of replacement therapy depend on degree of deficit of blood-coagulation factors of IX, localization and expressiveness of bleeding, the general condition of the patient, clinical effect of the carried-out therapy and individual parameters of pharmacokinetics of the patient. The drug dose Innonafaktor can differ from doses of plasma drugs of blood-coagulation factors of IX. For ensuring necessary activity of a factor of IX in blood at replacement therapy it is recommended to control level of a factor of a blood coagulation of IX in plasma by means of the coagulative analysis.

In spite of the fact that drug Innonafaktor does not contain other active agents, it must be kept in mind risk of development of thromboses and a syndrome of the disseminated intravascular coagulation (DIC). As purpose of earlier applied blood-coagulation factors of II, IX, X in a combination and a prothrombin complex was associated with development of tromboembolic episodes, the risk of their development will increase at treatment by drugs of blood-coagulation factors of the IX patients suffering from DVS a syndrome and patients with fibrinolysis signs.

Considering potential risk of thromboembolisms at introduction of recombinant blood-coagulation factors to the IX patients having liver diseases, in the postoperative period, having risk of development of thromboses or the IDCS, implementation of observation is necessary for identification of early manifestations of trombotichesky complications with use of the corresponding tests, and at their development - performing the corresponding treatment. In each of these situations it is necessary to estimate a ratio of potential advantage of therapy by recombinant blood-coagulation factors of IX and risk of development of these complications.

For the purpose of decrease in probability of development of agglutination in the syringe or system for intravenous administration it is reasonable to limit hit of blood in them at administration of drug. In case of development of agglutination of erythrocytes in system or the syringe it is necessary to utilize the used expendables (system for intravenous infusions, the syringe and solution of drug Innonafaktor) and to repeat introduction with use of new packaging of drug.

In attempts of induction of immune tolerance at the patients with a Cristmas disease who are producing inhibitors of blood-coagulation factors IX and having allergic reactions in the anamnesis, cases of development of a nephrotic syndrome were noted. Safety and efficiency of use of drug Innonafaktor for the purpose of induction of immune tolerance are not defined.

Influence on ability to manage vehicles and mechanisms. Researches of influence of drug on ability to driving and work with the mechanisms demanding the increased concentration of attention were not conducted.

Side effects:

Use of a nonakog an alpha in certain cases can be followed by development of a number of side effects with the following frequency: infrequent (with a frequency from ≥1/1000 to <1/100) and rare (with a frequency from ≥1/10000 to <1/1000). The most significant side effects are: anaphylaxis, phlegmon, phlebitis and formation of neutralized antibodies.

In each category of frequency side effects are given in an order of decrease in degree of their gravity.

Disturbances from a nervous system. Infrequent: dizziness, headache, preunconscious condition, change of flavoring perception. Rare: tremor, drowsiness, disturbance of flavoring feelings.

Disturbances from the alimentary system. Infrequent: nausea. Rare: vomiting, diarrhea.

System disturbances and complications in an injection site. Infrequent: phlegmon in the field of introduction, phlebitis in the field of introduction, skin and other reactions in an injection site (including burning and feeling of tightening), discomfort in an injection site, pain in an injection site. Rare: fever.

Disturbances from immune system. Infrequent: formation of neutralized antibodies (inhibitors of blood-coagulation factors IX) is short-term in a low caption (see the section "Special Instructions"). Rare: hypersensitivity, allergic reactions, including an anaphylaxis (see the section "Special Instructions"), a laryngospasm, a bronchospasm or a respiratory distress syndrome (диспноэ), the whistling cough, a lowering of arterial pressure, a Quincke's disease, throat hypostasis, tachycardia, feeling of constraint in a thorax, urticaria, skin rashes, a burning sensation in the field of a mandible and a skull, a fever (shiver), feeling of a pricking, "inflows" of blood to the person, block, concern, dry cough or sneezing, decrease in clearness of sight (see the section "Special Instructions"), allergic rhinitis, weakness, an anaphylaxis.

Respiratory, thoracic and mediastinal disturbances. Infrequent: the cough leading to a hypoxia.

Others. Rare: shiver, photosensitivity reactions.

Changes of laboratory indicators. Infrequent: increase in activity of aspartate aminotransferase, increase in activity of alaninaminotranspherase, increase in concentration of bilirubin, increase in activity of a kreatinfosfokinaza, increase in activity of an alkaline phosphatase.

There is development of cyanosis given about an opportunity and a lowering of arterial pressure.

Disturbances from an urinary system. Are available germinated about development a heart attack in 12 days after introduction of a nonakog an alpha concerning a hemorrhagic state at 1 patient with antibodies to a hepatitis C virus.

Trombotichesky complications. Against the background of treatment nonakogy an alpha it was reported about cases of development of thromboses, including, a life-threatening syndrome of an upper vena cava at the newborns who were in a serious condition and receiving нонаког an alpha in the form of long infusion through the central venous catheter. Cases of thrombophlebitis of peripheral veins and a deep vein thrombosis preferential after the long intravenous infusions which are not registered as a method of administration of this drug are also registered.

Inadequate answer and inadequate extent of recovery of activity of blood-coagulation factors of IX. There is information on cases of the inadequate answer and inadequate extent of recovery of activity of blood-coagulation factors of IX at use of a nonakog an alpha.

At development of any side effects which, presumably, can be connected with administration of drug it is necessary to lower rate of administering or to suspend it.

Interaction with other medicines:

Medicinal interaction is not described.

Contraindications:

Hypersensitivity to proteins of hamsters or intolerance of any of the components which are a part of drug. The age is younger than 18 years (experience of use is absent).

Overdose:

Cases of overdose of Innonafaktor are not described.

Storage conditions:

In the place protected from light, at a temperature from 2 to 8 °C. Not to freeze. To store in the places unavailable to children. Period of validity: drug - 2 years, solvent - 2 years 6 months. Not to use after the term specified on packaging.

Issue conditions:

According to the recipe

Packaging:

Lyophilisate for preparation of solution for intravenous administration on 250 ME, 500ME or 1000 ME in the glass bottles corked by rubber bungs with a running in caps aluminum-plastic with control of the first opening. On 5 or 10 ml of solvent (water for injections) in the glass bottles corked by the caps combined with elements elastomeric. 1 bottle with drug and 1 bottle with solvent - in a blister strip packaging from a film polyvinyl chloride or polietilentereftalatny. 1 blister strip packaging complete with account medical materials: by the syringe without needle with a capacity of 5 or 10 ml, 2 needles for cultivation, the filter injection, a catheter for peripheral veins, the plaster fixing 2 napkins spirit and the application instruction are placed in a pack from a cardboard. Each component of account medical materials is placed in sterile one-time packaging from a film polyvinyl chloride and the paper laminated. The napkin spirit is packed into the multilayer material consisting of aluminum foil and a film polyethylene. On joints of a cover and a bottom with front and back sides of a pack self-adhesive unmarked labels for control of the first opening are pasted.