Kogenate FS - instructions for use, dose, side effects, contraindications

Active substanceOktokog alfaOktokog alfa

Similar drugsTo uncover

Adv

lyophilizate in / in

Baxter AG Austria

Kogenate FS

lyophilizate in / in

Bayer Helscher LLS USA

Recombinant

lyophilizate in / in

Baxter, C.A. Belgium

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

Composition:

Active substance: 250 ME, 500 ME, 1000 ME, 2000 ME octokog alpha (anti-hemophilic (recombinant) coagulation factor VIII).

According to the World Organization for Blood Coagulation VIII one ME is approximately equal to the level of antihemophilic factor (AHF) found in 1.0 ml of a pool of fresh human plasma.

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

Description:

Lyophilizate: white with a yellowish tinge powder.

Solution: Clear liquid from colorless to slightly yellowish color.

Pharmacotherapeutic group:Hemostatic agent

ATX: & nbsp

B.02.B.D.02 Coagulation factor VIII

Pharmacodynamics:

Kogenate FS is a sterile, stable, purified, non-pyrogenic dried concentrate made using recombinant DNA technology. Kogenate FS is designed for use in the treatment of classical hemophilia (hemophilia A) and is produced by kidney cells of baby hamsters (BHK),in which the human blood coagulation factor gene VIII (FVIII). The cell culture medium contains a solution of human plasma proteinsHPPS) and recombinant insulin, but does not contain proteins derived from animal sources. Kogenate FS is a highly purified glycoprotein consisting of several peptides, including one with a molecular weight of 80 kD and various dilated subunits with a molecular weight of 90 kD. It has the same biological activity as factor VIII, obtained from human blood plasma.

The purification process includes a viral inactivation step with an effective solvent / detergent in addition to the classical purification methods by ion exchange chromatography, immunoaffinity chromatography with monoclonal antibodies, along with other chromatographic steps for purifying recombinant factor VIII and removing contaminants.

In addition, the manufacturing process was investigated for its ability to reduce the infectivity of the experimental agent with transmission spongiform encephalopathy (TGE), which was considered as a model of CJD (Creutzfeldt-Jakob disease) agents and CJD variant.It was shown that a number of separate stages of production and preparation of the feedstock in the process of manufacturing Kogenate FS reduces the infectivity of this experimental model of the agent. Steps to reduce infectivity TGE included the stage of separation of fraction II + III in the solution of human plasma proteins (6.0 log₁₀), and anion exchange chromatography step (3.6 log₁₀). These studies provide a reasonable assurance that a low degree of infectivity of the CJES / CJE variant, if present in the starting material, would be eliminated.

Introduction Coagenate FS provides an increase in the content of factor VIII in blood plasma and temporarily eliminates the coagulation defect in patients with haemophilia A (hereditary bleeding, characterized by insufficient activity of a specific plasma protein, VIII coagulation factor).

Each Kogenate FS bottle contains the amount of recombinant factor VIII indicated on the label in international units (ME). One ME, according to WHO's standard for the coagulation factor of human blood VIII, is approximately equal to the level of activity of factor VIII in 1 ml of a pool of fresh human plasma.

Pharmacokinetics:

The mean recovery of factor VIII activity, measured 10 minutes after infusion, was 2.1 ± 0.3% (IU / kg) in Kogenate FS. The mean biological half-life of the sucrose-containing recombinant factor VIII (rFVIII-FS) was approximately 13 hours and is similar to the half-life of the anti-hemophilic factor (AHF) obtained from human plasma. Kogenate FS shortened the time of activated partial thromboplastin. Restore the activity of the factor rFVIII- FS and its half-life did not change after 24 weeks of treatment with this preparation alone, which indicates the preservation of efficacy and the absence of formation of antibodies to factor VIII. The mean recovery of factor VIII activity, measured 10 minutes after dosing rFVIII-FS 37 patients (after 24 weeks of treatment rFVIII-FS), was 2.1% / IU / kg, which did not differ from the recovery factor of factor VIII activity, which was determined at baseline, and after 4 and 12 weeks of treatment.

Indications:

Prevention and treatment of bleeding episodes in hemophilia A.

Contraindications:

Known hypersensitivity or allergic reactions to the components of the drug.

Known hypersensitivity to mouse or hamster proteins.

Carefully:

In the literature, cases of arterial hypotension, urticaria and chest tightness are described in connection with hypersensitivity reactions in patients treated with antigemophilic factor concentrates. With the development of serious anaphylactic reactions, immediate emergency treatment with resuscitation, such as epinephrine and oxygen, is required.

Pregnancy and lactation:

Studies of the effect of Kogenate FS on reproductive function in animals have not been conducted. It is also unknown whether Kogenate FS is able to cause harm to the fetus in the case of the administration of this drug to a pregnant woman or adversely affect the ability to reproduce. During pregnancy and lactation, Kogenate FS should be used only in the presence of absolute indications.

Dosing and Administration:

Each flask of Kogenate FS contains the level of recombinant factor VIII activity in international units indicated on the label, determined by the one-step analysis method. After preparation, the solution should be introduced within 3 hours. For the introduction it is recommended to use the enclosed system.

General approach to treatment and evaluation of the effectiveness of therapy

The following dosages are given as general guidance. It should be emphasized that the dose of Kogenate FS necessary to restore hemostasis must be selected individually, depending on the patient's needs, the severity of the deficit, the intensity of bleeding, the presence of inhibitors and the desired level of factor VIII. It is often necessary to monitor the course of therapy through analyzes that determine the level of factor VIII. The clinical effect of factor VIII is the most important in assessing the effectiveness of treatment. To achieve a satisfactory clinical result, a higher dose of factor VIII may be required than was calculated. If, after the administration of the calculated dose, the expected concentration of factor VIII can not be achieved or bleeding can be controlled, the patient should be suspected of the presence of a circulating inhibitor to factor VIII. Its presence and quantity (titer) should be confirmed by appropriate laboratory tests. In the presence of an inhibitor, the required dose of factor VIII in different patients can vary significantly, and the optimal treatment regimen is determined only on the basis of the clinical response.

Some patients with low titer inhibitors (<10 Betezda units) can be successfully treated with preparations of factor VIII without anamnestic increase in titer inhibitors. To ensure an adequate response, it is necessary to check the level of factor VIII and the clinical response to treatment. Patients with an anamnestic response to treatment with factor VIII and / or with higher inhibitor titers may require the use of alternative medications such as factor IX complex concentrates, antihemophilic factor (porcine), recombinant factor Vila or anti-inhibitory complex of blood coagulation.

Calculation of dosage

The percentage increase in the level of factor VIII in vivo can be estimated by multiplying the dose of Cohenate FS with an anti-hemophilic factor (recombinant) per kg body weight (IU / kg) by 2% / IU / kg. This method of calculation is based on clinical data on the use of plasma-derived and recombinant AHF products^7-9 and is illustrated in the following examples:

Expected % increase in factor VIII = Number of administered units x 2% / IU / kg / body weight, kg

Example of calculating the dose for an adult weighing 70 kg: 1400 ME x 2% / IU / kg / 70 kg = 40%

Required dose (ME) = body weight, kg x desired% increase factor VIII / 2% / IU / kg

Example of calculating the dose for a child weighing 15 kg: 15 kg x 100% / 2% / IU / kg = 750 required ME

The dose needed to achieve full hemostasis is determined by the type and severity of the haemorrhagic episode, according to the following general recommendations:

Type of bleeding	Therapeutically necessary activity level of the factor VIII in plasma	The dose of Cohenate FS, necessary for maintenance of the therapeutic level of the factor VIII in plasma
Small bleeding (superficial hemorrhages, early bleeding, bleeding in the joints)	20-40%	10-20 IU / kg body weight. Introduce a second dose if symptoms persist of bleeding.
Moderately severe bleeding (hemorrhage in the muscles, bleeding in the mouth, obvious hemarthrosis, obvious trauma)	30-60%	15-30 IU / kg body weight. If necessary, repeat the administration at the same dose after 12-24 hours.
Small surgical interventions
Expressed and life-threatening bleeding (intracranial bleeding, bleeding to the abdominal or thoracic cavity, gastrointestinal bleeding, bleeding in the central nervous system, retrofaringealnoe or retroperitonealnoe space capsule ileo-lumbar muscle)	80-100%	The initial dose is 40-50 IU / kg body weight. Repeated dose 20-25 IU / kg body weight every 8-12 hours
Fractures Head injuries
Extensive surgery	~100%	The preoperative dose is 50 IU / kg body weight. Ensure 100% activity before surgery. Repeat the introduction initially 6-12 hours after the operation, and then continue treatment for 10-14 days until complete healing.

Prevention

Concentrates of AGF can also be administered on a regular basis to prevent bleeding.

Preparation of the drug, its administration and all manipulations with the system for the administration of the drug should be carried out with the utmost care. Kogenate FS with adapter for the bottle is a needleless system that allows you to prevent injuries as a result of pricking with a needle during the preparation of the solution. If the skin is damaged by a needle contaminated with blood, viruses of various infections, including HIV (AIDS) and hepatitis can be transmitted. In case of injury, immediately seek medical help. Needles should be placed in the enclosed containers immediately after use, all preparations for preparation and administration of the preparation, including residues of the prepared Kogenate FS solution of the Antigemophilic factor (recombinant), should be disposed of in the appropriate container.

Preparation of the solution

A solution for infusions should be prepared in aseptic conditions.

When preparing and administering the Kogenate FS solution, the components included in the kit should be used.

Do not use an open or damaged component of the kit.

Before use, it is necessary to check the solution for foreign matter content and discoloration. Do not use the drug in the presence of foreign particles or the appearance of turbidity.

Before use, filter the solution with the adapter to the vial to remove any foreign particles from the solution.

1. Wash your hands thoroughly with warm water and soap.

2. Heat the closed vial and syringe in the hands to room temperature (no higher than 37 ° C)

3. Remove the protective cap (A) from the vial. Disinfect the rubber stopper with alcohol, trying not to touch the rubber stopper with your hands.

4. Place the vial on the drug on a hard, non-slippery surface. Remove the paper coating from the plastic adapter cartridge for the vial. Do not remove the adapter from the plastic cartridge. Take the cartridge with the adapter, place it on the bottle with the drug and press firmly (B). The adapter snaps into place on the lid of the vial.Do not remove the cartridge from the adapter at this point.

5. Carefully open the blister pack of the syringe by bending the paper cover to the middle. Remove the pre-filled syringe with the solvent. Take the piston rod for the top nozzle, remove it from the package. Try not to touch the sides and threads of the piston rod. Holding the syringe straight, take the plunger by the top nozzle and attach the rod, tightly screwing it clockwise into the threaded plug (C).

6. Having taken a syringe for the case, break off a cover (D) from a tip of a syringe. Take care that the tip of the syringe does not come into contact with the hand or any other surface. Set the syringe to the next manipulation.

7. Now remove the adapter cartridge and discard it (E).

8. Attach the pre-filled syringe by turning it clockwise to the threaded adapter of the vial (F).

9. Insert the solvent by slowly pressing the piston rod (G).

10. Carefully rotate the vial until all of the substance has dissolved (H). Do not shake the bottle. Make sure that the powder is completely dissolved. Do not use the solution if it is cloudy or contains visible particles.

11. Draw the solution into the syringe, holding the bottle over the edge above the vial adapter and the syringe (I), and then slowly and smoothly pull the piston rod.Make sure that the entire contents of the vial are typed into the syringe.

12. Without changing the position of the piston, remove the syringe from the bottle adapter (the latter must remain attached to the vial). Attach the syringe to the attached system to administer the drug and inject the solution intravenously (J). NOTE: Follow the instructions for using the supplied infusion system.

13. If the patient needs to enter more than one vial, prepare the solution in each vial with the supplied syringe with the solvent, and then connect the solutions in a larger syringe (not supplied) and enter the drug in the usual manner.

14. Parenteral drugs, if allowed by the solution and container, should be carefully inspected for foreign particles or discoloration before administration.

The rate of administration

The rate of administration is determined according to the individual reaction of the patient. Typically, the entire dose for 5-10 minutes and even faster, is tolerated well.

Side effects:

The most common adverse reaction to the administration of Cohenate FS was the formation of antibodies that neutralize factor VIII (mainly in patients who had not previously been treated with factor VIII drugs or who received minimal treatment).

The frequency of side effects is classified as follows: very often - ≥1/10 (≥10%), often - ≥1/100 and <1/10 (≥1% <10%), infrequently - ≥1/1000 and <1/100 (≥0.1% <1%), rarely - ≥1/10000 and <1/1000 (≥0.01% <0.1%). "Frequency unknown" is indicated for undesirable effects detected during post-marketing observations and for which it is not possible to reliably estimate the frequency or establish a causal relationship with taking the drug.

Violations of the blood and lymphatic system: andinhibition of factor VIII: very often - it is revealed in patients, who did not receive medication factor VIII previously, or whose treatment was minimal; infrequently - is revealed in patients, who received preparations of factor VIII earlier.

General pathology and changes in the place of administration: often - reactions at the injection site; frequency unknown: febrile reaction during infusion.

Immune system disorders: often - skin reactions hypersensitivity (including urticaria, itching, rash); frequency is unknown - systemic reactions hypersensitivity (including anaphylactic reactions, nausea, deviation of blood pressure from norms, dizziness).

Impaired nervous system: frequency unknown - dysgeusia (unusual smack in the mouth).

Overdose:

Symptoms of overdose are not known.

Interaction:

Not known.

Do not mix Kogenate FS with other drugs or solvents.

Special instructions:

Kogenate FS is designed to treat episodes of bleeding caused by a deficiency of factor VIII. The presence of this deficiency should be established before the introduction of Kogenate FS. Kogenate FS does not contain vWF, so it is not indicated for the treatment of von Willebrand disease.

With the introduction of Kogenate FS with the help of central venous access devices, the development of infections associated with the use of a catheter is possible. The relationship between the occurrence of infections and the drug Kogenate FS is not established.

During treatment of patients with hemophilia A, circulating neutralizing antibodies to factor VIII can be formed. Inhibitors are especially frequent in the early years of treatment in young children with severe hemophilia or in those who previously received a limited amount of factor VIII. However, the appearance of inhibitors can occur at any time during the treatment of a patient with hemophilia A.Patients receiving any drug treatment AGF, including Kogenate FS need careful monitoring to detect possible antibodies to factor VIII by appropriate clinical observations and laboratory studies in accordance with the recommendations of the Center for the treatment of hemophiliacs.

In clinical studies, Kogenate drug used for the treatment of bleeding episodes in 60 patients who had not previously received treatment, and pediatric patients receiving treatment for a minimum (maximum 4dney). In 9 (15%) of 60 patients, inhibitors appeared: in 6 (10%) of 60 patients, the titre of data of antibodies was greater than 10 Bethesda units, and 3 out of 60 (5%) patients had less than 10 Bethesda units. The average number of days of treatment at the time of detection of inhibitors was 9 days (range - from 3 to 18 days). Four out of five patients who did not reach the end of the 20 days of treatment at the end of the study, had accumulated more than 20 days of treatment during follow-up after the study. One of these 4 patients showed the appearance of inhibitory antibodies (low titer). The fifth patient dropped out of observation.

In clinical trials involving 73 patients,(duration over 100 days), during the four-year observation the formation of new inhibitors was not revealed.

In post-marketing studies of Cohenate FS with the participation of more than 1000 patients in the subgroup of previously untreated or minimally treated (less than 20 days) patients, the appearance of inhibitory antibodies was noted in less than 11% of patients. In less than 0.2% of patients treated previously, new inhibitors appeared.

According to available registers, the probability of formation of inhibitory antibodies to factor VIII preparations in previously untreated patients with severe hemophilia A is from 28 to 38%.

Formation of antibodies to mouse and hamster proteins

In clinical trials, all patients were tested for seroconversion with respect to mouse and hamster proteins. After treatment, specific antibodies to these proteins were not developed in any of the patients, and no serious allergic reactions associated with animal proteins were observed with rFVIII-FS infusions. Despite this, patients should be warned about the possibility of developing a hypersensitivity reaction to mouse and / or hamster proteins in the form of urticaria, localized or generalized urticaria rash, wheezing and arterial hypotension. In these cases, patients should be advised to stop using the drug and consult a doctor.

Pediatric Use

Kogenate FS is suitable for the treatment of children. Safety and efficiency studies were conducted with the participation of previously untreated and minimally treated pediatric patients.

Application in elderly patients

Clinical studies of Cohenate FS did not include a sufficient number of patients aged 65 years and older to determine whether their response to treatment differs from that of younger patients. As with any patient receiving Cohenate FS, the dose for elderly patients should be selected individually.

Oncogeneity, mutagenicity

An in vitro analysis of the mutagenic potential of rFVIII at doses far exceeding the maximum therapeutic dose showed no reverse mutation or chromosomal aberrations. Study of rFVIII in vivo on animals using doses 10-40 times higher than the expected therapeutic maximum, also showed that rFVIII does not have a mutagenic potential.Long-term studies for carcinogenic potential using animals have not been conducted.

Cardiovascular diseases

In patients with cardiovascular diseases or having risk factors for their development after the normalization of thrombus formation in the treatment with a factor VIII drug, the risk of complications from the cardiovascular system may be the same as in patients without hemophilia.

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

Not found.

Form release / dosage:

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

Packaging:

In the bottles of clear, colorless glass of hydrolytic type I, sealed with a rubber stopper under running-in with an aluminum cap covered with a plastic protective cap.

Solvent: 2.5 ml of water for injections for the preparation in dosages of 250 ME, 500 ME and 1000 ME and 5.0 ml of water for injection for the preparation at a dose of 2000 ME in a pre-filled syringe of clear hydrolytic type I clear glass with a plunger and the top lid of elastomer.

1 adapter for the bottle in the blister (PVC / paper).1 device for intravenous administration in a blister (PVC / paper).

1 vial with the drug, 1 pre-filled syringe with solvent, 1 blister with adapter for the bottle, 1 blister with the device for intravenous injection, together with the instruction for use, is placed in a cardboard box.

Storage conditions:

At a temperature of 2 to 8 ° C in a protected place. Do not freeze.

It is allowed to store at a temperature of no higher than 30 ° C for not more than 6 months, for example, when treating at home.

Keep out of the reach of children.

Shelf life:

Lyophilizate: 30 months.

Solvent: 48 months.

Do not use after expiry date.

Terms of leave from pharmacies:On prescription

Registration number:П N015661 / 01

Date of registration:14.09.2007 / 05.08.2010

Expiration Date:Unlimited

Date of cancellation:2018-04-09

The owner of the registration certificate:Bayer Helscher LLSBayer Helscher LLS USA

Manufacturer: & nbsp

BAYER HealthCare, LLC USA

Representation: & nbspBAYER, AOBAYER, AO

Information update date: & nbsp09.04.2018

Illustrated instructions

Instructions

Kogenate FS (Kogenate FS)