Когенэйт FS

General characteristics. Structure:

Active agent:   250 ME, 500 ME, 1000 ME, 2000 ME октоког alpha (anti-hemophilic (recombinant) blood-coagulation factors of VIII). According to the standard for blood-coagulation factors established by World Health Organization VIII one ME is approximately equal to the level of a prothrombokinase (AGF) found in 1,0 ml of a pool of fresh human plasma. Excipients: sucrose, histidine, glycine, sodium chloride, Calcii chloridum, polysorbate 80.

Description:
Lyophilisate: powder, white with a yellowish shade.
Description of solution: transparent liquid from colourless till slightly yellowish color.

Pharmacological properties:

Когенэйт FS represents the sterile, stable, cleared, not pyrogenic dried-up concentrate made with use of technology of recombinant DNA. Когенэйт FS is intended for use in therapy of classical hemophilia (hemophilia And) and is developed by cells of kidneys of cubs of hamsters (VNK) into which the gene of human blood-coagulation factors of VIII (FVIII) was entered. The environment of cellular culture contains solution of proteins of plasma of the person (HPPS) and recombinant insulin, however does not contain the proteins received from animal sources. Когенэйт FS is the high cleaning glycoprotein consisting of several peptides including one with a molecular weight of 80 cd and various expanded subunits with a molecular weight of 90 cd. It has the same biological activity, as the factor of VIII received from a blood plasma of the person.
Process of cleaning includes a stage of a virus inactivation effective solvent / detergent in addition to classical methods of cleaning by means of ion-exchange chromatography, an immunoaffine chromatography with monoclones, along with other hromatografichesky stages intended for cleaning of a recombinant factor of VIII and removal of the infecting substances. Besides, production was investigated regarding its ability to reduce an infektivnost of the experimental agent of the tranmissionny spongy encephalopathy (TSE) who was considered as model of agents KJD (Kreyttsfelda-Jacob's disease) and BKYa option. It was shown that a number of separate production phases and preparation of initial raw materials in the course of Kogeneyt's production of FS reduces an infektivnost of this experimental model of the agent. Stages of reduction of an infektivnost of TGE included a stage of division of fraction II + III in solution of proteins of plasma of the person (6.0 logio), and a stage of anion-exchange chromatography (3.6 logio). These researches give a reasonable guarantee that low degree of an infektivnost of the agent BKYa/variant of BKYa if it was present at a starting material, would be eliminated.
Kogeneyt's introduction provides to FS increase in maintenance of a factor of VIII in a blood plasma and temporarily eliminates defect of coagulation at patients with hemophilia And (the hereditary bleeding which is characterized by insufficient activity of specific protein of plasma, the VIII blood-coagulation factors).
In each bottle of Kogeneyt of FS contains the quantity of a recombinant factor of VIII specified on the label in the international units (IU). One ME, according to the standard for blood-coagulation factors of the person of VIII established to WHO, is approximately equal to the level of activity of a factor of VIII of 1 ml of a pool of fresh plasma of the person.

Pharmacokinetics. The average recovery of activity of a factor of VIII measured in 10 minutes after infusion at Kogeneyt FS made 2,1±0,3% / ME/kg. The average biological elimination half-life at the recombinant factor of VIII (rFVIII-FS) containing sucrose was equal to about 13 hours and is similar to an elimination half-life of a prothrombokinase (AGF) received from a blood plasma of the person. Когенэйт FS shortened time of the activated partial thromboplastin. Recovery of activity of a factor rFVIII-FS and its elimination half-life did not change 24 weeks of treatment later only this drug that indicates preservation of efficiency and lack of formation of antibodies to a factor of VIII. The average recovery of activity of a factor of VIII measured in 10 minutes after introduction of a dose of rFVIII-FS to 37 patients (in 24 weeks of treatment of rFVIII-FS), made 2,1% / ME/kg that did not differ from an indicator of recovery of activity of a factor of VIII which was defined at the initial level, and also by 4 and 12 weeks of treatment.

Indications to use:

Prevention and treatment of episodes of bleedings at hemophilia And.

Route of administration and doses:

Each bottle of Kogeneyt of FS contains the level of activity of a recombinant factor VIII designated on the label in the international units determined by method of the single-stage analysis. After preparation solution has to be entered within 3 hours. For introduction it is recommended to use the enclosed system. General approach to treatment and assessment of efficiency of therapy
The dosages provided below are given as the general management. It is necessary to emphasize that Kogeneyt's dose of FS necessary for recovery of a hemostasis has to be selected individually, depending on needs of the patient, expressiveness of deficit, intensity of bleeding, availability of inhibitors and desirable level of a factor of VIII. Often happens it is necessary to trace the therapy course by means of the analyses defining level of a factor of VIII. The clinical effect of a factor of VIII is the most important in assessment of efficiency of treatment. For achievement of satisfactory clinical result introduction of a bigger dose of a factor of VIII can be required, than it was calculated. If after introduction of the calculated dose it is not possible to provide the expected concentration of a factor of VIII or to control bleeding, at the patient it is necessary to suspect presence of the circulating inhibitor to a factor of VIII. Its existence and quantity (caption) has to be confirmed with the corresponding laboratory tests. In the presence of inhibitor the required dose of a factor of VIII at different patients can significantly vary, and the optimum scheme of treatment is defined only proceeding from the clinical answer.
Some patients with low credits of inhibitors (<10 Betezda of units) can successfully be treated by drugs of a factor VIII without anamnestic increase in a caption of inhibitors. For providing the adequate answer it is necessary to check level of a factor of VIII and the clinical response to treatment. A factor of VIII and/or with higher credits of inhibitors use of alternative medicines, such as concentrates of a complex of a factor of IX, a prothrombokinase (pork), recombinant factor of VIb or an anti-inhibitory complex of a blood coagulation can be required by patients with the anamnestic response to treatment.

Calculation of a dosage
Percentage increase in level of a factor VIII in vivo can be estimated, having increased Kogeneyt's dose of FS of the Prothrombokinase (recombinant) per kg of the body weight (ME/kg) by 2% / ME/kg. This method of calculation is based on the clinical data on use received from plasma and recombinant products of AGF7-9 and is illustrated on the following examples:
Quantity of the entered units x 2% / ME/kg
The expected % of increase in a factor of VIII =        
body weight (kg)

1400 ME x 2% / ME/kg
Example of calculation of a dose for the adult weighing 70 kg:        = 40%
70 kg
Or

body weight (kg) x desirable % of increase in a factor of VIII
Required dose (ME) =      2% / ME/kg
15 kg x 100%
Example of calculation of a dose for the child weighing 15 kg:  = 750 ME is required
2% / ME/kg

The dose necessary for achievement of a full-fledged hemostasis is defined by type and weight of a hemorrhagic episode, according to the following general recommendations:

Bleeding type                            Therapeutic              Kogeneyt's Dose of FS,
                                                        necessary                  necessary for
                                                       level of activity         of maintenance
                                                        factor of VIII in plasma     of therapeutic
                                                                                               level of a factor of VIII in
                                                                                                to plasma
Small bleedings                             of 20-40%                      of 10-20 ME/kg of body weight                             
(superficial                                                                        to Enter a repeated dose,
hemorrhages, early                                                                  if remain symptoms
bleedings,                                                                           the proceeding bleeding.
bleedings in joints)
The expressed                         30-60% of moderate                     15-30 ME/kg of body weight.
bleedings (hemorrhages                                                 If it is necessary, to repeat
in muscles, bleedings in                                                        introduction in the same dose in 12-24 hours.
oral cavity, explicit hemarthrosis,
obvious injury)
Small surgical
interventions
The expressed and zhizneugrozhayushchy        80-100%                      the Initial dose 40k50 body weight ME/kg.
bleedings (intracranial                                                Repeated dose of 20-25 ME/kg
bleedings, bleedings in                                                   body weights every 8-12 hours
belly or chest cavities,
gastrointestinal bleedings,
bleedings in TsNS,
retropharyngeal or
retroperitoneal space,
capsule of iliolumbar
muscles)
Head Injury changes
Extensive surgical                      ~ 100%                     Preoperative dose of-50 ME/kg of body weight.
interventions                                                                         to be convinced in 100% of activity before operation. 
                                                                                           To repeat introduction originally later 
                                                                                                   6-12 hours after operation, and then 
                                                                                            to continue treatment within 10-14 days
                                                                                                     before full healing.

Prevention
Concentrates of AGF can be also entered on a regular basis for prevention of bleedings.
Drug preparation, its introduction and all manipulations with system for administration of drug have to be carried out extremely attentively. Когенэйт FS with the adapter for a bottle represents needleless system which allows to warn injuries as a result of pricks a needle in preparation time of solution. At injury of skin by the needle contaminated by blood viruses of various infections, including HIV (AIDS) and hepatitis can be transmitted. In case of an injury immediately ask for medical care. Needles should be placed in the enclosed containers at once after use, all devices for preparation and administration of drug, including the remains of the prepared Kogeneyt's solution of FS of the Prothrombokinase (rekombinatny), it is necessary to throw out in the corresponding container.

Solution preparation
Solution for infusions should be prepared in aseptic conditions.
At preparation and administration of solution of drug of Kogeneyt of FS it is necessary to use the components entering set.
Do not use the opened or damaged set component.
Before use it is necessary to check solution for the maintenance of foreign particles and discoloration. It is not necessary to use drug in case of existence of foreign particles or emergence of a turbidity.
Before use it is necessary to filter solution by means of the adapter to a bottle for the purpose of removal from solution of possible foreign particles.
1. Carefully wash up hands warm water with soap.
2. Warm in hands the closed bottle and the syringe to room temperature (it is not above 37 °C)
3. Remove a protective cap from a bottle (And). Disinfect alcohol a rubber bung, trying not to touch a rubber bung hands.

4. Put a bottle with drug on a firm nonslipping surface. Remove a paper covering from a plastic cartridge of the adapter for a bottle. Do not take out the adapter from a plastic cartridge. Take a cartridge with the adapter, place it on a bottle with drug and strongly press (In). The adapter will be latched on a bottle cover. Do not remove a cartridge from the adapter at this stage.
5. Carefully open the blister packaging of the syringe, having unbent a paper covering to the middle. Take out previously filled syringe with solvent. Having taken a piston rod for an upper nozzle, get it from packaging. Try not to concern the parties and a carving of a piston rod. Holding the syringe directly, take the piston for an upper nozzle and attach a core, having densely twisted it clockwise in a stopper with a carving (C).
6. Having taken the syringe for the case, break off a cover (D) from a syringe tip. You watch that the tip of the syringe did not adjoin to a hand or any other surface. Postpone the syringe until the following manipulation.
7. Now remove a cartridge of the adapter and throw out it (Е).
8. Attach previously filled syringe, turning it clockwise
to arrow, to the cut adapter of a bottle (F).
9. Enter solvent, slowly pressing a piston rod (G).
10. Carefully rotate a bottle until all substance is dissolved (N). Do not stir up a bottle. Make sure that powder was completely dissolved. Do not use solution if it muddy or contains visible particles.
11. Gather solution in the syringe, holding a bottle for edge over the adapter of a bottle and the syringe (I), and then slowly and smoothly delay a piston rod. Make sure that all contents of a bottle are gathered in the syringe.
12. Without changing position of the piston, take out the syringe from the bottle adapter (the last has to remain attached to a bottle). Attach the syringe to the enclosed system for administration of drug and enter solution intravenously (J). NOTE: follow instructions for use of the enclosed infusional system.
13. If the patient needs to enter more than one bottle, prepare solution in each bottle by means of the enclosed syringe with solvent, and then connect solutions in larger syringe it (is not applied) and administer the drug regularly.
14. Parenteral medicines if it solution and a container allow, before introduction have to look round attentively regarding existence of foreign particles or discoloration.

Rate of administering
Rate of administering is defined according to individual reaction of the patient. As a rule, introduction of all dose within 5-10 min. and even quicker, is transferred well.

Features of use:

Когенэйт FS is intended for treatment of the episodes of bleeding caused by deficit of a factor of VIII. Existence of this deficit has to be established before Kogeneyt's introduction to FS.
Когенэйт FS does not contain Villebrand's factor therefore it is not shown for treatment of an angiohemophilia.
At introduction of Kogeneyt of FS by means of devices of the central venous access development of the infections connected with use of a catheter is possible. To communication between developing of infections and drug of Kogeneyt of FS it was not established. During treatment of patients with hemophilia And formation of the circulating neutralized antibodies to a factor of VIII is possible. Inhibitors especially often appear in the first years of treatment at the children of early age suffering from a severe form of hemophilia or at those patients who received limited quantity of a factor of VIII earlier. However emergence of inhibitors can take place at any time in the course of treatment of the patient with hemophilia And. The patients receiving treatment by any drug AGF including Kogeneyty FS, need careful monitoring for the purpose of identification of possible antibodies to a factor of VIII by means of appropriate clinical observation and laboratory researches according to recommendations of the Center for treatment of patients with hemophilia. During clinical trials with participation of the patients who were previously receiving treatment the 109th was registered undesirable the phenomena on 4160 infusions (2,6%). Existence, at least, of the remote communication with the studied drug was noted by the researcher only at 13 of these phenomena. 7 more undesirable phenomena did not give in to assessment. Thus, 20 undesirable phenomena at 11 patients were considered or as not giving in to assessment or as, at least, remotely FS connected using Kogeneyt with rate of 0,5% concerning number of the made infusions. 72 previously treated patients with a severe form have hemophilias And which received Kogeneyt of FS, on average, within 54 days, inhibitors of a factor VIII it was not found. Antibody formation to proteins of mice and hamsters
During clinical trials at all patients analyses regarding identification of seroconversion concerning proteins of mice and hamsters were carried out. After an initiation of treatment of specific antibodies to these proteins it was not developed at one of patients, and any serious allergic reactions connected with animal protein, against the background of infusions of rFVIII-FS it was not noted. Despite it, patients have to be warned about a possibility of development of hypersensitivity reaction to proteins of mice and/or hamsters in the form of the urticaria localized or generalized urtikarny rash, goose breathing and arterial hypotension). In these cases patients should recommend to stop use of drug and to see the attending physician. Use in pediatrics
Когенэйт FS is suitable for treatment of children. Researches of safety and efficiency   were preposted     with participation of the pediatric patients (n=62) who were not receiving treatment and receiving the minimum treatment. Use for elderly patients
Clinical trials of Kogeneyt of FS did not include enough patients at the age of 65 years and are more senior that it was possible to define whether their response to treatment for the answer of younger patients differs. As well as for any patients receiving Kogeneyt of FS, the dose for elderly patients is required to be selected individually. Oncogenicity, mutagenicity
The analysis of mutagen potential of rFVIII which is carried out by in vitro in the doses considerably exceeding the maximum therapeutic dose did not reveal reverse mutation or aberation chromosomes. The research rFVIII in vivo on animals with use of doses, at 10-40 times exceeding the expected therapeutic maximum also showed that rFVIII has no mutagen potential. Long-term researches regarding cancerogenic potential with use of animals were not conducted.

Influence on ability to drive the car and mechanisms
It is not revealed

Side effects:

The most frequent undesirable reaction to administration of drug of Kogeneyt of FS was antibody formation, neutralizing a factor of VIII (it is preferential at patients, earlier not treated drugs of a factor VIII, or receiving the minimum treatment). Frequency of side effects is classified as follows: often-> 1/100 and <1/10, infrequently-> 1/1000 and <1/100, it is rare-> 1/10000 and <1/1000. "Frequency is unknown" it is specified for the undesirable effects revealed in the course of post-marketing observations and for which it is not possible to estimate reliably frequency or to establish a causal relationship with administration of drug. Disturbances from blood and lymphatic system Inhibition of a factor of VIII:
Often - it is revealed during clinical trials at patients who did not receive
treatment by a factor of VIII earlier, or treatment of which was minimum;
Infrequently - it is revealed at the patients receiving drugs of a factor VIII earlier or in the course
post-market researches.
General pathology and changes in an injection site
Often: reactions in a drug injection site;
Frequency is unknown: febrile reaction at infusion.
Disturbances from immune system
Often: skin reactions of hypersensitivity (including urticaria, an itch, rash);
Frequency is unknown: system reactions of hypersensitivity (including anaphylactic reactions, nausea, a deviation of arterial pressure from norm, dizziness).
Disturbances from a nervous system
Frequency is unknown: a dysgeusia (unusual smack in a mouth).

Interaction with other medicines:

Are not known.
It is not necessary to mix drug of Kogeneyt of FS with other medicines or solvents.

Contraindications:

Known hypersensitivity or allergic reactions to drug components.
The known hypersensitivity to proteins of mice or hamsters.

With care
In literature cases of arterial hypotension, small tortoiseshell and constraint in a thorax in connection with hypersensitivity reactions at the patients receiving treatment by prothrombokinase concentrates are described. At development of serious anaphylactic reactions immediate emergency treatment using resuscitation actions, such as introduction of Epinephrinum and oxygen is required.

Pregnancy and period of a lactation
Researches of influence of Kogeneyt of FS on reproductive function at animals were not conducted. It is also unknown whether Kogeneyt of FS is capable to do harm to a fruit in case of administration of this drug the pregnant woman or to influence negatively ability to reproduction. During pregnancy and in the period of a lactation of Kogeneyt of FS it is necessary to apply only in the presence of absolute indications.

Overdose:

Symptoms of overdose are not known.

Storage conditions:

At a temperature from 2 to 8 °C in the place protected from light. Not to freeze. Storage is allowed at a temperature not above 25 °C no more than 3 months, for example, at treatment in house conditions. To store in the place, unavailable to children!

Period of validity
Lyophilisate: 30 months
Solvent: 48 months.
Not to use after a period of validity!

Issue conditions:

According to the recipe

Packaging:

Lyophilisate for preparation of solution for intravenous administration: on 250 ME, 500 ME, 1000 ME, 2000 ME drugs in the bottles of transparent colourless glass of hydrolytic type I corked by a rubber bung under a running in a cap the aluminum, covered plastic protective cap.
Solvent: on 2,5 ml of water for injections for drug in dosages 250 ME, 500 ME and 1000 ME and on 5,0 ml of water for injections for drug in a dosage 2000 ME in previously filled syringe from colourless transparent glass of hydrolytic type I with a plunger and an upper cover from elastomer.
On 1 adapter for a bottle in the blister (PVC/paper). On 1 device for intravenous administration in the blister (PVC/paper). 1 bottle with drug, 1 previously filled syringe with solvent, 1 blister with the adapter for a bottle, 1 blister with the device for intravenous administration together with the application instruction is placed in a cardboard pack.