Immunate - instructions for use, dose, side effects, contraindications

Component	Number / bottle
Component	250 ME	500 ME	1000 ME
Active substances:
Coagulation factor VIII *	250 ME	500 ME	1000 ME
Willebrand Factor **	190 ME	375 ME	750 ME
Excipients:
Human albumin	5.8-15 mg	11.7-30 mg	23.3-60 mg
Glycine	25 mg	25 mg	50 mg
Lysine hydrochloride	25 mg	25 mg	50 mg
Sodium chloride	10 mg	10 mg	20 mg
Sodium citrate dihydrate	25 mg	25 mg	50 mg
Calcium chloride dihydrate	3.1 mg	3.1 mg	6.2 mg

One bottle of solvent contains:

Component	Number / bottle
Component	250 ME	500 ME	1000 ME
Water for injections	5 ml	5 ml	10 ml

* Factor VIII (ME) activity is determined by the chromogenic substrate method of the European Pharmacopoeia using the International WHO Standard for Factor VIII concentrates.

Specific activity is 70 ± 30 IU / mg protein without stabilizer (albumin).The maximum specific activity is 100 IU of factor VIII per mg of protein at a ratio of 1: 1 of factor VIII activity to von Willebrand factor antigen.

** Von Willebrand factor (ME) activity is determined by the ristocetin-cofactor analysis of the European Pharmacopoeia (vWF: RCo) using the International WHO Standard for von Willebrand factor.

Description:Powder or brittle solid mass of white or light yellow color.

Pharmacotherapeutic group:Hemostatic agent

ATX: & nbsp

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

Pharmacodynamics:

Complex factor VIII/ von Willebrand factor consists of two molecules (factor VIII and von Willebrand factor) with different physiological functions.

Activated factor VIII is a cofactor of factor IX activation, which accelerates the transfer of factor X to activated factor X. Activated factor X is necessary for the conversion of prothrombin into thrombin. Thrombin, in turn, turns fibrinogen into fibrin, and a clot forms. Hemophilia A is a hereditary sex-linked disorder of the blood coagulation system due to a deficiency of factor VIII, which results in profuse bleeding or joint hemorrhage in patients,muscles or internal organs as a result of injuries and surgical interventions, and spontaneously. Substitution therapy increases the level of factor VIII in the plasma and, thus, temporarily corrects the deficiency of the factor and reduces the tendency to bleeding.

The von Willebrand factor, in addition to the function of the protein stabilizing factor VIII in the plasma, promotes the adhesion of platelets to the site of vascular damage, participates in platelet aggregation and is necessary for replacement therapy in patients with von Willebrand disease.

Pharmacokinetics:

All pharmacokinetic parameters of IMMUNAT were measured in patients with severe hemophilia A (factor VIII level ≤1%). Analysis of plasma samples was carried out in the central laboratory by the method of chromogenic analysis of factor VIII.

Pharmacokinetic parameters obtained as a result of cross-examination of IMMUNAT in 18 previously treated patients older than 12 years are listed in the table.

Pharmacokinetic parameters of IMMUNAT preparation in 18 patients with severe hemophilia A (dose = 50 IU / kg):

Parameter	Average	Standard deviation	Median	Trustee interval 90%
AUC_0-∞ ([ME x h / ml])	12,2	3,1	12,4	11,1-13,2
FROM_m_Oh (IU / ML)	1,0	0,3	0,9	0,8-1,0
T_m_Oh (H)	0,3	0,1	0,3	0,3- 0,3
The final elimination half-life T_1/2(h)	12,7	3,2	12,2	10,8-15,3
Clearance (ml / h)	283	146	232	199-254
Average circulation time MRT (h)	15,3	3,6	15,3	12,1-17,2
Volume of distribution V_ss (ml)	4166	2021	3613	2815-4034
Gradual recovery ([IU / mL] / (IU / kg))	0,020	0,006	0,019	0,016-0,020

Preclinical safety data

The human blood coagulation factor VIII in the IMMUNAT preparation is a normal component of human plasma and acts as an endogenous factor VIII.

Preclinical data obtained in traditional studies on the pharmacology of safety, toxicity of repeated doses, local tolerance and immunogenicity, studies do not indicate the existence of a special risk to humans.

Indications:

Treatment and prevention of bleeding in hereditary (haemophilia A) and acquired deficiencies of factor VIII.

Villebrand disease with factor VIII deficiency.

Contraindications:

Hypersensitivity to the components of the drug.

Carefully:

The drug should be used with caution for children under 6 years of age, who have limited use of coagulation factor VIII preparations, due to limited data for this group of patients.

Pregnancy and lactation:

Studies of the effect of factor VIII on reproductive function in animals have not been conducted.Given that hemophilia A in women is rare, there is no evidence of the use of factor VIII in pregnancy and breastfeeding. Therefore, the IMMUNAT should be used during pregnancy and during breastfeeding only if there are strong indications.

Regarding parvovirus information, see the "Special instructions and precautions for use" section.

Dosing and Administration:

The drug after the preparation of the solution is administered intravenously slowly. The maximum infusion rate should not exceed 2 ml per minute.

Therapy should begin under the supervision of a doctor with experience in the treatment of hemophilia.

Calculation of dose for hemophilia A

Doses and duration of substitution therapy depend on the degree of factor VIII deficiency, localization, bleeding intensity and severity of the clinical condition of the patient.

The number of units of factor VIII administered is expressed in International Units (ME), which corresponds to the generally accepted WHO standard for preparations containing factor VIII. The activity of factor VIII in plasma is expressed either as a percentage (relative to normal human plasma) or in International Units (relative to the International Standard for Factor VIII concentrates).

One International Unit (ME) of factor VIII activity is equivalent to the amount of factor VIII that is contained in 1 ml of normal human plasma.

The calculation of the required dose of factor VIII is based on the empirically established fact that 1 ME factor VIII per kg of body weight increases the activity of factor VIII in plasma by approximately 2% of normal activity.

The dose of the drug is calculated by the following formula:

Necessary number of units = body weight (kg) x desired increase in factor VIII (%) x 0.5

The amount of the drug and the frequency of administration should always be guided by clinical effectiveness in each individual case.

Bleeding and surgical interventions

In the case of the hemorrhagic episodes listed below, the activity of factor VIII in plasma should not decrease below this level of activity (in% of normal or in IU / dl) in the relevant period.

Degree of severity

bleeding /
type of surgical
interventions

Required level

factor VIII in plasma
(% of normal)
(IU / dl)

Frequency of administration (hours) /

duration of therapy (days)

Bleeding

Initial signs

hemarthrosis,

hemorrhage in the muscles

or bleeding in

oral cavity

20-40

Enter every 12-24 hours. Not

less than 1 day; before cupping

bleeding, which

the lack of

pain, or healing.

Expressed hemarthrosis,

muscle hemorrhage

or hematoma

30-60

Enter every 12-24 hours in

for 3-4 days or more to

complete relief of pain and

recovery

activity.

Threatening lives

bleeding

60-100

Enter every 8-24 hours to

elimination of the threat of life.

Surgical interventions

Small, including extraction of teeth

30-60

Enter every 24 hours, no less than

1 day, until healing.

Large

80-100

(before and after surgery)

Enter every 8-24 hours to

adequate wound healing,

then therapy for at least

7 days to maintain

factor VIII activity on

level of 30% -60% (IU / dl)

The amount of the drug and the frequency of administration should be correlated with clinical efficacy in an individual case. In some cases (for example, if there is a low titer of inhibitors), it may be necessary to administer the drug at doses higher than the calculated ones.

During the course of treatment it is recommended to determine the levels of factor VIII in the plasma for the purpose of dose correction and the frequency of repeated infusions. Accurate monitoring of substitution therapy based on coagulation data (activity of factor VIII in plasma) is especially needed in large surgical interventions.Among patients, individual features of the response to the introduction of factor VIII are possible, which is manifested in differences in recovery rates in vivo and elimination half-life.

Prolonged prevention

For long-term prophylaxis in severe forms of hemophilia A, doses of 20-40 ME factor VIII per kg of body weight with an interval of 2-3 days. In some cases, especially in young patients, it may be necessary to reduce the intervals between administrations or increase the dose of the drug.

Inhibitory forms of hemophilia A

Patients should be monitored for the development of antibodies to Factor VIII. If it is not possible to achieve the expected increase in factor VIII activity in the patient's plasma or to stop bleeding by administering the calculated doses of the drug, a study should be conducted for the presence of inhibitors to factor VIII. In patients with a high level of inhibitors, factor VIII therapy may be ineffective and other treatment options should be considered. The management of such patients should be performed by physicians with experience in the treatment of patients with hemophilia.

It was reported that inhibitors appeared primarily in untreated patients.See also "Special instructions and precautions for use").

Disease of vWF with a deficiency of factor VIII

IMMUNE is indicated as a substitution therapy for patients with von Willebrand disease with reduced factor VIII activity. Substitution therapy with IMMUNAT for the purpose of stopping and preventing bleeding associated with surgical interventions is carried out in accordance with the recommendations for patients with hemophilia A.

Since the IMMUNAT preparation contains relatively high amounts of factor VIII with respect to von Willebrand factor, the attending physician should take into account the fact that prolonged treatment with the drug may cause coagulation factor VIII, which may lead to an increased risk of thrombosis.

Preparation of the drug solution

To dissolve, use only the kit contained in the package. The drug solution IMMUNAT is prepared immediately before the introduction, since the drug does not contain preservatives. The solution should be clear or slightly opalescent.
Turbid solutions or solutions with sediment should not be used.

Dissolution

Observe the rules of asepsis!

1. Heat an unopened vial of solvent (sterile water for injection) to room temperature (no higher than 37 ° C).

2. Remove the protective caps from the vials with the preparation and the solvent (Figure A) and disinfect the rubber stoppers of both bottles.

3. Set, and then with the pressure put on the wavy edge of the needle-filter for transfer to the bottle with a solvent (Figure B).

4. Remove the protective cap from the other end of the needle-filter for transfer. Do not touch the exposed end of the needle.

5. Turn the needle adapter with the attached solvent vial over the vial of the preparation and insert the free end of the needle into the center of the vial of the vial with the drug (Figure B). Due to the vacuum, the solvent will flow into the vial with the drug. Wait for about 1 minute.

6. Separate the vials by pulling the needle filter to transfer from the vial of the vial to the preparation (Figure D). As the drug dissolves easily, lightly, if necessary, shake the bottle. DO NOT REDUCE THE VAPOR WITH THE PREPARATION. DO NOT RETURN THE VAPOR WITH THE PREPARATION BEFORE DELIVERING ITS CONTENT.

7. The prepared solution should be inspected visually for foreign inclusions and discoloration before administration.Even if the instructions for preparing the solution are carefully observed, small particles can occasionally be seen. They are removed with the supplied needle filter. At the same time, the nominal activity of the drug does not decrease.

Introduction

Observe the rules of asepsis!

1. When collecting the prepared solution in a syringe, use the supplied filter needle to avoid particles of the rubber plug (risk of microembolism). Install the needle filter on the supplied disposable syringe and pierce the rubber plug (Fig. D).

2. Remove the syringe from the filter needle for a short time. The air will get inside the vial with the solution and the formed foam will settle. Then, draw the solution through the needle filter into the syringe (Fig. E).

3. Remove the syringe from the filter needle and inject the solution intravenously slowly (maximum injection rate is 2 mL / min) with the supplied "butterfly" needle (or the supplied disposable needle).

Any unused residue of the drug must be disposed of in accordance with established requirements.

Side effects:

Unfavorable adverse reactions, possible with the use of drugs factor aVIII derived from human plasma

Hypersensitivity reactions or allergic reactions that may include angioedema, burning sensation in the infusion site, chills, flushing, generalized rash, headache, hives, lowering blood pressure, drowsiness, nausea, anxiety, tachycardia, chest tightness, vomiting, Stridoroznoe breath. In some cases, severe anaphylaxis may develop (up to a shock). If these symptoms occur, patients should consult a doctor (see also "Special instructions and precautions for use").

In rare cases, an increase in body temperature is possible.

In patients with hemophilia A, neutralizing antibodies (inhibitors) can be developed to factor VIII, which is clinically manifested by an insufficient clinical response. In such cases, the patient should be counseled in a specialized hemophilia center.

In response to the administration of high doses of the drug in patients with blood groups A (II), B (III) or AB(IV) can be noted hemolysis.

In patients with von Willebrand's disease, especially type III, neutralizing antibodies (inhibitors) can be developed to the von Willebrand factor.The presence of inhibitors is characterized by an insufficient clinical response. The appearance of an inhibitor can be closely associated with anaphylactic reactions. Therefore, patients who have had anaphylactic reactions should be tested for inhibitors. In all such cases it is necessary to contact a specialized center of hemophilia.

For safety information on the transmission of infectious agents, see "Special instructions and precautions for use".

Adverse adverse reactions noted during clinical trials and post-marketing experience with IMMUNAT

The following adverse adverse reactions were noted during clinical trials and post-marketing studies. Their frequency was assessed based on the following criteria: very frequent (> 1/10), frequent (> 1/100; <1/10), infrequent (> 1/1000; <1/100), rare (> 1/10000 ; <1/1000), very rare (<1/10000) and the frequency of occurrence is unknown (frequency of occurrence can not be determined on the basis of available data).

1. Clinical studies

The following adverse adverse reactions were very rare (<1/10000):

Immune system disorders: allergic reactions.

2. Post-marketing experience

For the following adverse adverse reactions, the incidence is unknown:

Violations of the blood and lymphatic system: coagulation disorders, inhibition of factor VIII.

Immune system disorders: hypersensitivity.

Disturbances from the nervous system: dizziness, headache, anxiety, paresthesia.

Disturbances on the part of the organ of sight: conjunctivitis.

Heart Disease: tachycardia, heart palpitations.

Vascular disorders: lowering blood pressure, pallor.

Disturbances from the respiratory system, chest and mediastinal organs: cough, shortness of breath.

Disorders from the gastrointestinal tract: nausea, vomiting.

Disturbances from the skin and subcutaneous tissues: erythema, neurodermatitis, pruritus, rash, erythematous rash, papular rash, urticaria, increased sweating.

Disturbances from the musculoskeletal and connective tissue: myalgia.

General disorders and disorders at the site of administration: chills, irritation at the injection site, pain, chest discomfort, chest pain, fever, fever, swelling (including peripheral, eyelids and faces).

Overdose:

Cases of overdose are unknown.

Concerning the possibility of thrombosis and hemolysis in patients with groups A (II), AT(III) or AB(IVsee "Special instructions and precautions for use".

Interaction:

The interaction of preparations of the factor VIII coagulation factor with other drugs is unknown.

As with other coagulation factor concentrates, the IMMUNAT before administration can not be mixed with other drugs or solvents, with the exception of sterile water for injection, as this can impair the efficacy and safety of the drug.

Use only the supplied kit for administration, as treatment may not be effective due to the adsorption of coagulation factor VIII on the internal surfaces of certain types of infusion products.

Special instructions:

As in the case of any intravenous protein preparations, it is possible to develop hypersensitivity reactions of the allergic type. Patients should be informed of early signs of hypersensitivity reactions, including hives, generalized rash, chest tightness, wheezing, lowering blood pressure, including allergic shock.If these symptoms occur, patients should immediately stop using the drug and consult a doctor. In the event of shock, anti-shock therapy should be performed according to current medical standards.

Patients with hemophilia A

The formation of neutralizing antibodies (inhibitors) to factor VIII is a known complication in the treatment of patients with hemophilia A. These inhibitors are usually IgG immunoglobulins, are directed against procoagulant activity of factor VIII and are measured in units of Bethezd (BE) per ml of plasma (modified Bethesda method).

The risk of developing inhibitors correlates with the duration of the coagulation factor VIII, the risk being highest during the first 20 days of use. In rare cases, inhibitors can develop after the first 100 days of use.

The cases of re-formation of inhibitors in previously treated patients who had more than 100 days of administration were observed after transferring the patient from one factor VIII preparation to another. For timely detection of inhibitors, careful clinical observation and laboratory examination of patients being treated with preparations of coagulation factor VIII of a human should be carried out. See also the "Side effect" section.

Patients with Willebrand disease

In patients with von Willebrand's disease, especially type III, neutralizing antibodies (inhibitors) can be developed to the von Willebrand factor. If the desired level of vWF activity in the plasma can not be achieved, or the bleeding is not controlled by the appropriate dose of the drug, it is necessary to conduct blood plasma studies of patients for the presence of inhibitors to the von Willebrand factor. For patients with high levels of inhibitors, von Willebrand factor therapy may be ineffective, so other treatments should be considered.

For patients with Willebrand disease, there is a risk of developing thrombosis, especially in patients with known clinical and laboratory risk factors. Therefore, patients should be observed for the appearance of early signs of thrombosis. It is necessary to use prophylaxis against venous thromboembolism according to the current medical standards. Since the IMMUNAT preparation contains relatively high amounts of factor VIII in relation to the von Willebrand factor, the attending physician should take into account that prolonged treatment with the drug may cause a clotting factor VIII.Patients taking IMMUNAT should monitor the level of factor VIII to avoid prolonged levels of factor VIII in the plasma, which may increase the risk of thrombosis.

The sodium content in the maximum daily dose of the drug is 200 mg, which should be taken into account in individuals on a diet low in sodium.

The drug should be used with caution in children under 6 years of age, who have been rarely treated with factor VIII drugs, since clinical data are limited for this group of patients.

Standard measures to prevent infections that can be transmitted with drugs derived from human blood or plasma include selection of donors, screening of individual plasma portions and plasma pools for the presence of specific infection markers, and the inclusion in the production process of steps that effectively inactivate / delete viruses. Despite this, with the introduction of drugs obtained from human blood or plasma, the possibility of transmitting infectious agents can not be completely ruled out. This applies equally to unknown viruses and other pathogens.

These standard measures to prevent viral infections include two separate production stages - hot steam treatment and solvent-detergent treatment.

The measures taken are considered effective against envelope viruses, such as HIV, hepatitis B and hepatitis C virus, as well as against the non-enveloped hepatitis A virus. Measures taken may be limited in effectiveness against non-enveloped viruses such as parvovirus B19. Infection caused by parvovirus B19 can lead to serious illness in pregnant women (fetal infection) and in patients with immunodeficiency or increased disintegration of red blood cells (eg, in hemolytic anemia).

Patients who regularly or repeatedly receive Factor VIII preparations derived from human plasma are advised to receive appropriate vaccination (against hepatitis A and B).

The IMMUNAT contains the anti-A and anti-B gamagglutinins. For patients with blood groups A (II), B (III) or AB(IV), hemolysis can occur after frequent repeated doses or after the administration of very large doses of the drug.

It is strongly recommended, for the purpose of monitoring, to write down the name and serial number of the drug every time the IMMUNE is administered to the patient.

The chemical and physical stability of the prepared solution for intravenous administration is maintained for 3 hours at a temperature of 20-25 ° C. From the microbiological point of view, if the method of opening / dissolving / diluting does not exclude the risk of microbial contamination, the drug should be used immediately after dissolution. If the finished drug solution is not used immediately, then the user is responsible for the time and storage conditions. The diluted drug should not be stored in a refrigerator.

Within this expiration date, patients can store the IMMUNATE preparation at room temperature (not above 25 ° C) for 6 months. The date of storage at room temperature should be marked on the package. At the end of this period, the drug is not returned to the refrigerator, but should be immediately used or disposed of.

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

Effects on the ability to drive and work with mechanisms were not observed.

Form release / dosage:Lyophilizate for the preparation of a solution for intravenous administration, 250 ME, 500 ME or 1000 ME.

Packaging:

250 each ME, 500 ME or 1000 ME in bottles of clear, colorless glass of hydrolytic type II (Hebrew Pharm.) with a capacity of 20 ml (for 250 ME, 500 ME and 1000 ME) or 25 ml (for 1000 ME), sealed with a rubber stopper with aluminum flap and a plastic flip-off cap 5 ml (for 250 ME and 500 ME) or 10 ml (for 1000 ME) in bottles of clear, colorless glass of hydrolytic type I (Hebrew Pharm.), sealed with a rubber stopper with aluminum rolling, and plastic cover type flip-off, and a kit for the dissolution and administration of the drug (needle-filter for per enos (5 microns), disposable syringe, needle-butterfly, disposable needle for injections).

1 vial with lyophilizate, 1 vial with solvent, kit for dissolution and administration preparation together with instructions for use in a cardboard box.

Storage conditions:

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

Keep in a dark place.

Keep out of the reach of children.

Shelf life:

2 of the year.

Do not use after expiry date.

Terms of leave from pharmacies:On prescription

Registration number:П N015027 / 01

Date of registration:04.05.2008 / 01.08.2017

Expiration Date:Unlimited

The owner of the registration certificate:Baxter AGBaxter AG Austria

Manufacturer: & nbsp

BAXTER, AG Austria

Representation: & nbspBaxter Baxter USA

Information update date: & nbsp08.11.2017

Illustrated instructions

Instructions

Immunate (Immunate)