Adveit: instructions for using the medicine, structure, Contraindications

Clinical and pharmacological group: The preparation of blood coagulation factor VIII

Pharmaco-therapeutic group: Hemostat

Adveit: pharmachologic effect

Factor VIII/Willebrand factor complex consists of two molecules (factor VIII and von Willebrand factor), having different physiological functions. The drug was produced by recombinant technology in the culture of Chinese hamster ovarian cells, no added proteins of human or animal origin during the manufacturing process.

Preparation Adveit^® contains recombinant coagulation factor VIII (octocog alpha), which is a glycoprotein with the amino acid sequence, similar to human factor VIII.

Octocog alfa is a glycoprotein, consisting of 2332 amino acids with approximate molecular weight 280 kDa. When administered to patients, octocog alfa binds to endogenous von Willebrand factor.. Activated factor VIII acts as a cofactor for activated factor IX, accelerating the conversion of factor X to activated factor X. Activated factor X promotes the conversion of prothrombin to thrombin. Thrombin, in turn, promotes the conversion of fibrinogen to fibrin, which leads to the formation of a thrombus (blood clot).

Hemophilia A is hereditary, gender related, violation of the blood coagulation system with a decrease in the level of factor VIII activity. Clinically manifested by profuse bleeding into the joints, muscles or internal organs, as spontaneous, and resulting from trauma or surgery. During replacement therapy, the level of factor VIII in plasma increases, resulting in a temporary correction of the factor deficiency in the blood plasma and a decrease in the tendency to increased bleeding.

Adveit: pharmacokinetics

All pharmacokinetic studies of Adveit^® conducted with the participation of patients, previously treated for severe or moderately severe hemophilia A (baseline factor VIII ≤2%). Generally, summary pharmacokinetic data were obtained and analyzed in 195 previously treated patients, with severe hemophilia A (baseline factor VIII <1%).

Table 1. Pharmacokinetic parameters of Adveit^® in patients of various age groups with severe hemophilia A (baseline factor VIII <1%)

* Calculated as (FROM_max minus baseline factor VIII) divide by dose (IU / kg), where C_max – maximum level of factor VIII, determined after the introduction.

Safety and hemostatic efficacy of Adveit^® in children similar to the safety and hemostatic efficacy in adults.

Adjusted recovery rate and T_1/2 in the final phase in patients younger than 6 years were on 20% less, than in adults, which may in part be explained by the high plasma volume per kg of body weight in children.

Currently, there are no data on the parameters of the pharmacokinetics of the drug Adveit^® patients, previously untreated.

Indications of the drug Adveit^®

• treatment and prevention of bleeding in adults and children of all ages, people with hemophilia A (hereditary factor VIII deficiency).

Preparation Adveit^® does not contain the von Willebrand factor in the amount, necessary to achieve a pharmacological effect, therefore not indicated for the treatment of von Willebrand's disease.

Open list of ICD-10 codes

Adveit: dosing regimen

Treatment with the drug should be started under the supervision of a physician., experienced in the treatment of hemophilia, and if there is the possibility of immediate resuscitation in the event of anaphylaxis.

Doses and duration of treatment depend on the degree of factor VIII deficiency., location and intensity of bleeding, as well as the clinical condition of the patient. Careful laboratory monitoring of replacement therapy is especially important in cases of major surgery and life-threatening bleeding..

The potency of Factor VIII drugs is usually expressed in International Units. (ME), according to WHO international standards. Plasma factor VIII activity is expressed either as a percentage (relative to normal human plasma) or in ME (relative to the international standard).

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

Treatment “on demand”

The calculation of the required dose of factor VIII is based on empirical data, according to which the preparation of factor VIII, dosed 1 ME and 1 kg body weight, increases plasma factor VIII activity by 2 ME / dl.

Required dose of Adveit^® determined by the formula:

Required dose (ME) = Body weight (kg) × required % factor VIII increase × 0.5

For bleeding and clinical situations, indicated in the tables 2 and 3, factor VIII activity should not fall below a predetermined level (expressed in % from normal activity or in IU/dL) in the corresponding period. When choosing a dose and frequency of administration for episodes of bleeding and surgical interventions, you can be guided by the tables 2 and 3.

Table 2. The use of the drug Adveit^® with various types of bleeding

Table 3. The use of the drug Adveit^® surgical interventions

Dose and frequency of administration should be individually tailored to clinical response.. Under certain circumstances (eg, in the presence of inhibitors in low titer) doses may be required, exceeding calculated.

During the course of treatment, the level of coagulation factor VIII in plasma should be determined in order to, to adjust the dose or frequency of administration, if necessary.

When carrying out major surgical interventions, it is mandatory to monitor replacement therapy by determining the activity of factor VIII in plasma..

Patients may differ in clinical response to factor VIII treatment., reaching different values ​​of pharmacokinetic parameters, in particular, T_1/2 and recovery rate in vivo.

Prevention of bleeding

For long-term bleeding prophylaxis in patients with severe hemophilia A, doses typically range from 20 to 40 Factor VIII ME per kg of body weight with an interval between injections from 2 to 3 days.

The use of the drug in children

When using the drug in the mode “on demand” recommended doses and frequency of administration of Adveit^® in children aged 0 to 18 years the same, as in adult patients. For long-term prevention of bleeding in patients under 6 years it is recommended to use the drug at a dose of 20 to 50 Factor VIII ME per kg body weight 3-4 times a week.

Mode of application

The drug is intended exclusively for intravenous administration.. If the drug is administered by a person, who does not have a specialized medical education, then this person should receive appropriate training on the administration of Adveit^®. The rate of administration of the drug should be selected so, to provide the patient with maximum comfort. The rate of administration should not exceed 10 ml / min. Recommended, in the interests of the patient, record the name of the drug and batch number each time a drug is administered.

Preparation Adveit^® should be administered intravenously after reconstitution of the lyophilisate with sterile water for injection. The reconstituted solution should be clear, colorless and free from mechanical inclusions. Do not use cloudy solution or solution, containing visible particles.

• For the introduction of the drug, you must use a syringe with a Luer tip.
• The drug should be used within 3 h after recovery.
• Do not place reconstituted drug in the refrigerator.
• Any unused drug or residue must be disposed of in accordance with established requirements..

Breeding using the BAXJECT II device

• Follow the rules of asepsis.
• To reconstitute the drug, use only sterile water for injection and dilution device, contained in the package.
• Do not use the BAXJECT II device, if its sterile barrier system or packaging is damaged, or if you notice any signs of damage.
• If the drug was stored in the refrigerator until the dilution, Bring the temperature of Adveit^® (lyophilisate) and sterile water for injection (solvent) up to room temperature (from 15 ° to 25 ° C).

1. Wash your hands, using soap and hot water.

2. Remove caps from lyophilisate and solvent vials.

3. Wipe the plugs with alcohol wipes. Place vials on a flat, clean surface.

4. Open the packaging of the BAXJECT II device by removing the paper membrane., without touching the contents of the package. Do not remove the device from the packaging. Do not use, if the BAXJECT II device, its sterile barrier system or packaging is damaged.

5. Invert the package and insert the clear plastic tip into the cap of the solvent vial. Grasping the edges of the package, pull up and remove it from the BAXJECT II device. Do not remove the blue cap from the BAXJECT II device.

6. To dilute the drug, use only sterile water for injection., contained in the package. By attaching BAKSJECT II to the solvent vial, flip the system like this, so that the solvent bottle is on top of the device. Insert the white plastic tip into the stopper of the Advate vial.^® (lyophilisate). Due to the vacuum, the solvent will flow into the vial with Adveit^®.

Gently rotate the vial until the drug is completely dissolved.. Check, that adveit^® (lyophilisate) completely dissolved, otherwise, the active substance will not pass through the filter of the device. The drug dissolves quickly (usually less than 1 m). The reconstituted solution should be clear, colorless and free from mechanical inclusions.

The introduction of the drug

Follow the rules of asepsis.

Before use, the reconstituted drug must be checked for the absence of mechanical impurities.. Only clear and colorless solution should be used..

1. Remove the blue cap from the BAXJECT II device. Do not draw air into the syringe! Inject syringe into BACSJECT II.

2. Flip the system (vial with reconstituted solution should be on top). Draw the reconstituted solution into the syringe, slowly retracting the piston.

3. Disconnect the syringe.

Connect the butterfly needle to the syringe. The solution should be administered in/in, slowly. The rate of administration of the drug should not exceed 10 ml / min. Before and during administration of Adveit^® the patient's pulse rate must be monitored. With a significant increase in heart rate, reducing the rate of drug administration or temporarily stopping the administration in most cases helps to quickly stop these symptoms.

Adveit: side effects

In clinical trials of Adveit^® took part 418 patients, received, least, one administration of Adveit^®. Were registered 93 unwanted drug reactions (NLR). The most frequently reported ADRs were:: appearance of inhibitors (neutralizing antibodies to factor VIII), headache and fever.

Hypersensitivity or allergic reactions (which may include angioedema, burning and itching at the injection site, chills, redness, generalized urticaria, Headache, localized urticaria, gipotenziю, lethargy, nausea, anxiety, taxikardiju, narrowing in Gruda, pricking, vomiting, wheezing) observed infrequently, but in some cases progressed to severe anaphylaxis (including anaphylactic shock). Anti-mouse and/or hamster protein antibodies and associated hypersensitivity reactions may occur.

Patients with hemophilia A may develop neutralizing antibodies (inhibitors) Factor VIII. The appearance of such inhibitors manifests itself in the form of an insufficient clinical response.. In all such cases, it is recommended to contact a specialized hemophilia center.

Below are data on the frequency of adverse reactions, information about which was obtained in clinical studies and from spontaneous reports. Adverse reactions are classified according to the damage to organs and organ systems; names of organs and organ systems are given in accordance with MedDRA terminology.

The frequency of occurrence of adverse reactions was assessed in accordance with the WHO NLR classification according to the frequency of development: Often (≥1/10), often (≥1 / 100 to <1/10), infrequently (≥1 / 1000 to <1/100), rarely (≥1 / 10,000 to <1/1000 ), rarely (<1/10000), Frequency unknown (cannot be established from the available data). Within each frequency gradation, adverse effects are presented in decreasing order of severity.. The frequency was calculated in relation to the total number of patients, treated with Adveit^® (N=418).

Infectious and parasitic diseases: infrequently – flu, laringit.

From the blood and lymphatic system: often – emergence of factor VIII inhibitors^to; infrequently – limfangit.

On the part of the immune system: Frequency unknown – anaphylactic reaction, hypersensitivity^to.

From the nervous system: often – headache; infrequently – dizziness, memory impairment, fainting, tremor, migraine, disgevziya.

On the part of the organ of vision: infrequently – eye inflammation.

Cardio-vascular system: infrequently – palpitations, hematoma, hot flashes, paleness.

The respiratory system: infrequently – dyspnoea.

From the digestive system: infrequently – diarrhea, pain in the upper abdomen, nausea, vomiting.

Skin and subcutaneous tissue disorders: infrequently – itch, rash, hyperhidrosis, hives.

General disorders and disorders at the injection site: often – fever; infrequently – peripheral edema, chest pain, feeling of chest discomfort, chills, change in well-being, hematoma at the puncture site; Frequency unknown – fatiguability, reactions at the injection site, malaise.

Laboratory and instrumental data: infrequently – decreased levels of clotting factor VIII^and; increase in the number of monocytes, decrease in hematocrit, deviation from the norm in the results of laboratory tests.

Injuries, intoxication and complications of manipulations: infrequently – post-procedural complication, post-procedural bleeding, reaction at the site of the procedure.

^and An unexpected decrease in factor VIII levels occurred in one patient during a continuous infusion of Advate.^® on 10-14 days after surgery. During this period, hemostasis was maintained. Plasma factor VIII levels and clearance returned to normal by postoperative day 15. Factor VIII inhibitor tests, performed at the end of the continuous infusion and at the end of the study, gave negative results.

^to Information about this adverse reaction is given below..

Description of individual adverse reactions

The emergence of factor VIII inhibitors

Immunogenicity of Adveit^® has been studied in clinical trials involving 233 patients (children and adults) with severe hemophilia A (factor VIII level ≤1%) previously treated with factor VIII concentrates (No less than 150 days of administration in adults and children aged ≥6 years and at least 50 days of administration in children younger than 6 years). One patient after 26 days of administration of Adveit^® observed the appearance of inhibitors in low titer (2.4 Bethesda Units [WAS] based on modified Bethesda test). No inhibitors were detected after the patient's participation in the study was terminated..

Median duration of use of Advate^® in previously treated patients in all clinical studies was 97 days (sweep from 1 to 709 days of introduction). Overall frequency of occurrence of inhibitors (as high, and low titer) made 0.4% (in 1 from 233 patients).

In a completed uncontrolled clinical trial 060103, in 16 from 45 (35.6%) previously untreated patients with severe hemophilia A (factor VIII level ≤1%), who received Adveit^® for at least 25 days of application, factor VIII inhibitors developed. In 7 (15.6%) patients had a high titer of inhibitors and 9 (20%) patients – low titer of inhibitors (including one patient, in which the onset of inhibitors was classified as transient).

The risk factors for the development of inhibitors in this study were: non-Caucasian ethnicity, family history of factor VIII inhibitors and intensive therapy with high doses of Advate^® first 20 days of introduction. In 20 patients, those who did not have the listed risk factors, the appearance of inhibitors was not noted.

Data were obtained on the induction of immune tolerance (IIT) in previously untreated patients, patients, in which, when using the drug Adveit^® Factor VIII inhibitors have been identified. During the substudy within the study 060103 with patients, previously untreated, IIT treatment has been documented in 11 patients, previously untreated. In 30 patients with IIT (research 060703) a retrospective analysis of medical records was carried out. Data collection for the IIT patient registry is ongoing.

The study 060201 a comparative analysis of two regimens of long-term prophylactic treatment was carried out in 53 patients, previously treated (RLP): dosing schedule, selected on the basis of individual pharmacokinetic parameters (within range from 20 to 80 ME factor VIII on 1 kg body weight at intervals 72 ± 6 hours; n=23), and standard prophylactic dosing regimen (from 20 to 40 IU/kg every 48 ± 6 no; n=30). Purpose of dosing regimen, selected on the basis of individual pharmacokinetic parameters (and calculated by a special formula), was to maintain a minimum level of factor VIII ≥1% at 72-hour intervals between injections. The data from this study prove, that both prophylactic dosing regimens are comparable in terms of reduction in bleeding rates.

Adverse reactions, substances related, used in the production process

From 229 patients, who received treatment with Adveit^® and were examined for the presence of antibodies to Chinese hamster ovary cell proteins (SNO), in 3 patients showed a statistically significant increase in antibody titer, in 4 patients showed persistent peaks or transient rises in antibody titer, and in one patient it was noted that, and other. All these changes in antibody titers were not accompanied by clinical manifestations..

Of these 229 treated patients, who received treatment with Adveit^® and were examined for antibodies to mouse immunoglobulin G (IgG), in 10 patients showed a statistically significant increase in antibody titer, in 2 patients, stable peaks or transient rises in antibody titer were detected, and in one patient, and then, and other. Four of these patients, isolated cases of urticaria have been reported, itching, rash, a slight increase in the number of eosinophils (to all indicated patients, the drug Advate^® injected repeatedly).

Hypersensitivity

Allergic-type reactions included anaphylaxis and manifested as dizziness, paresteziej, rash, tides, swelling of the face, hives and itching.

The use of the drug in children

With the exception of inhibitor formation in previously untreated patients and catheter-related complications, no difference in frequency of adverse reactions, in patients of all ages, have not been identified in clinical studies.

Reporting Suspected Adverse Reactions

Information about suspected adverse reactions allows you to constantly monitor the benefit / risk ratio of the drug Adveit^®. Doctors, using the drug Adveit^® for the treatment of patients with hemophilia A, should report suspected adverse reactions, developed in the period after the issuance of a registration certificate for a medicinal product, to national pharmacovigilance authorities in accordance with the standard procedure.

Adveit: contraindications for use

• known hypersensitivity to the active substance or to any of the excipients, as well as to mice/hamster proteins.

Adveit: use during pregnancy and lactation

Influence of the drug Adveit^® on the reproductive function of animals has not been studied. Because, that hemophilia A is extremely rare in women, safety of the drug Adveit^® in pregnant women and in women during breastfeeding has not been established. Before prescribing Adveit^® during pregnancy and during breastfeeding, the doctor must carefully weigh the potential risk and the expected benefit for each individual patient.

Adveit: Special instructions

Hypersensitivity reactions

With the on / in the introduction of protein preparations, the development of allergic reactions is possible.. Preparation Adveit^® is a protein, and also contains trace amounts of mouse and hamster proteins.

When using the drug Advate^® Allergic-type hypersensitivity reactions have been reported, including anaphylaxis. Patients should be informed of the early signs of immediate hypersensitivity reactions., such as hives, itch, generalized blistering rash, angioedema, hypotension (accompanied by dizziness and fainting), shock and acute respiratory distress (chest tightness, wheezing). Patients should be advised if these symptoms occur to immediately stop using the drug and contact your doctor.. In case of shock, generally accepted anti-shock measures should be taken..

Formation of factor VIII inhibitors

The emergence of neutralizing antibodies to factor VIII (inhibitors) is a known complication in the treatment of patients with hemophilia A, which is clinically manifested by a decrease in the procoagulant activity of the factor VIII drug. Inhibitors are class G immunoglobulins. The titer of inhibitors is measured in Bethesda Units. (WAS) per ml of plasma using the modified Bethesda method.

With the appearance of factor VIII inhibitors, patients may experience an insufficient clinical response to Advate.^®. In this case, it is recommended to contact a specialized hemophilia treatment center.. The risk of developing inhibitors correlates with the duration of use of the factor VIII drug (the risk is highest during the first 20 days of introduction), as well as genetic and environmental factors. Rarely, inhibitors may appear after the first 100 days of introduction.

There have been cases of re-formation of inhibitors (in low titer) in previously treated patients, with a history of inhibitors, (treated for more than 100 days of introduction) after switching a patient from one factor VIII drug to another. Therefore, after switching from treatment with one factor VIII drug to another, constant monitoring should be carried out. (as a clinical, as well as laboratory) for patients, treated with a factor VIII drug, for early detection of inhibitors.

Generally, for patients, treated with clotting factor VIII drugs, should be carefully monitored for the occurrence of inhibitors through appropriate clinical observation and laboratory testing. If the expected level of factor VIII plasma activity is not achieved, or if an adequate dose fails to control bleeding, an appropriate assay should be performed to detect factor VIII inhibitors. Treatment may not be effective in patients with high levels of factor VIII inhibitors, consideration should be given to the use of alternative therapies. These patients should be treated by a physician., experienced in the treatment of hemophilia in the presence of factor VIII inhibitors.

Preventive therapy with Adveit^® with individualized dose selection

To maintain baseline factor VIII levels ≥1% at dose interval, constituting 72 no, single dose of Advate^® can be individually selected by a doctor, taking into account the values ​​of individual pharmacokinetic parameters. In a clinical study, it was shown, that the prophylactic dosing regimen 20-40 IU/kg every 48±6 h has a similar clinical efficacy to the regimen 20-80 ME / kg with an interval of 72 ± 6 h, with a significant reduction in bleeding rates with prophylactic treatment compared to on-demand treatment.

The standard prophylaxis regimen with the administration of the drug every other day and the regimen of individual prophylactic treatment with dose selection depending on pharmacokinetic parameters and with the administration of the drug every third day have comparable efficacy..

Catheter-associated complications during treatment

If a central venous access device is required, then there is a risk of developing catheter-associated complications, such as local infection, bacteraemia, thrombosis at the site of the catheter.

Info, regarding excipients

After reconstitution, the drug solution contains 0.45 mmol sodium (10 mg) per vial. This should be taken into account when appointing drug patients, located on a diet with restriction of sodium.

Use in Pediatrics

The special warnings and precautions listed apply to children., to the same extent, as adult.

Special instructions for storage and use

To eliminate the possibility of microbiological contamination, the drug should be administered immediately after preparation of the solution. However, it has been proven, that the prepared solution of Adveit^® chemically and physically stable over time 3 h at 25°C.

Within the expiration date, the drug can be stored at room temperature (above 25 ° C) within no more 6 months. The start date and end date of storage of the drug at room temperature should be recorded on the package of the drug.. After storage at room temperature, do not place the drug for further storage in the refrigerator..

Recommended with each administration of Adveit^® record the name of the drug and the batch number in the medical records to be able to establish a link between the patient and the batch of the drug.

Effects on ability to drive vehicles and mechanisms

Preparation Adveit^® does not affect the ability to drive vehicles and the ability to work with mechanisms.

Adveit: overdose

No cases of overdose of recombinant blood coagulation factor VIII preparations have been reported.. Overdose symptoms unknown.

Adveit: drug interaction

Interaction studies of Adveit® with other medicinal products have not been conducted..

Adveit: storage conditions of Adveit®

The drug should be stored in a cardboard box to protect from light., out of reach of children at a temperature of from 2 ° to 8 ° C.; Do not freeze.

Adveit: shelf life of Adveit®

Shelf life – 2 year. Do not use beyond the expiration date.

Adveit: implementation conditions

The drug is released under the prescription.