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

1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POM) 284.0 mg, sodium-N- (carbonylmethoxypolyethylene glycol 2000) -1,2-distearoyl-sn-glycero-3-phosphoethanolamine -2000-DSFE) 32.0 mg, sodium citrate 32.0 mg, hydrochloric acid, concentrated qs, water for injection qs

For one vial of 1000 ME:

Lyophilizate

active substance: coagulation factor VIII 1000 ME;

Excipients: glycine 75.0 mg, lysine hydrochloride 55.0 mg, calcium chloride 2.2 mg, sucrose 500.0 mg, mannitol 400.0 mg.

Liposomal solvent 7.0 ml:

1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPH) 567.0 mg, sodium-N- (carbonylmethoxypolyethylene glycol 2000) -1,2-distearoyl-sn-glycero-3-phosphoethanolamine -2000-DSFE) 63.0 mg, sodium citrate 63.0 mg, hydrochloric acid, concentrated qs, water for injection qs

Description:

Lyophilizate: white lyophilized powder or porous mass.

Liposomal solvent: pale-white milky form of dispersion

Recovered variance:

before filtration - a pale white milk-like dispersion with possible presence of single particles, removed by filtration;

after filtering - a pale white milk-like dispersion with no visible foreign particles.

Pharmacotherapeutic group:Hemostatic agent

ATX: & nbsp

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

Pharmacodynamics:

Activated coagulation factor VIII acts as a cofactor for the coagulation factor IX, accelerating the conversion of the coagulation factor X into the activated coagulation factor Xa. The activated coagulation factor Xa promotes the conversion of prothrombin into thrombin. Thrombin, in turn, converts fibrinogen into fibrin, and thus a blood clot forms.

Hemophilia refers to X-linked X-linked hereditary blood clotting disorders due to a decrease in the coagulation activity of coagulation factor VIII (VIII: C). The disease manifests profuse bleeding in the joints, muscles or internal organs, either arising spontaneously, or as a result of trauma or surgical intervention. Substitution therapy leads to a temporary increase in plasma concentrations of coagulation factor VIII and stop bleeding.

LongAyt with a liposomal solvent shows similar coagulation factors VIII with coagulation factors VIII procoagulant (hemostatic) biological properties. The haemostatic efficacy of LongAit is longer than that of other coagulation factor preparations VIII. Pre-clinical data suggest the following mechanism of action of the drug: during the recovery, the coagulation factor VIII binds to the liposomal solvent. After the introduction of LongAite into the bloodstream, the clotting factor VIII complex with liposomes binds to von Willebrand factor and thrombocytes.

Formation of the clotting factor complex of the VIII-liposome-platelets affects blood coagulation in two different ways:

a) due to the fact that LongEt binds to platelets, the concentration of clotting factor VIII at the site of vascular injury where the platelets rush first increases even if the total concentration of clotting factor VIII in the blood is low;

b) the interaction between the LongEight preparation and the platelets accelerates the formation of the complex with coagulation factor Xa, and, thus, shortens the formation time of the blood clot even more resistant to fibrinolysis. The combination of these effects leads to an increase in the hemostatic efficacy of the coagulation factor VIII.

Human coagulation factor VIII corresponds to the natural component of the plasma and exhibits the properties of the endogenous coagulation factor VIII. The results of the acute toxicity study confirmed the absence of toxic effects on various animal species using doses several times higher than therapeutic doses.

Comprehensive preclinical studies of the liposomal solvent included in the preparation of LongAit,did not reveal any toxic effects when doses were administered, about 20 times higher than therapeutic ones, except for increasing the concentration of lipoproteins.

Pharmacokinetics:

After intravenous administration, 67% to 75% of the coagulation factor VIII remains in the bloodstream. The decrease in the activity of coagulation factor VIII in plasma has a two-phase-bi-exponential character. In the initial phase, the distribution between the intravascular bed and other body fluids occurs with a half-life of plasma from 3 to 6 hours. In the final phase, the half-life is an average of 12 hours, varying from 8 to 20 hours, which corresponds to the physiological half-life.

In vivo the reduction of coagulation factor VIII when dissolving in liposomes or water for injection does not differ.

Indications:

Prevention and treatment of bleeding in hereditary (haemophilia A) or acquired coagulation factor deficiency VIII.

Contraindications:Hypersensitivity to any component of the drug.

Carefully:

Use in children

The safety and efficacy of LongAyt in children have not been studied.

Pregnancy and lactation:

Hemophilia A refers to X-linked chromosome diseases and occurs almost exclusively in men. In connection with this, there were no controlled studies of LongAit in pregnant women. Data on the reproductive toxicity of LongAit and its intake in animal milk are also not obtained.

The safety of LongAit for pregnant women is not established, therefore LongAit is not recommended for use during pregnancy and lactation, except when the potential benefit to the mother is significantly greater than the possible risk to the fetus and the baby.

Dosing and Administration:

Only for intravenous administration! Treatment with LongAit should be performed under the supervision of a physician with sufficient experience in the treatment of hemophilia A.

Prevention of bleeding

For prolonged prevention of bleeding in patients with severe haemophilia A, the drug is usually administered every 7 days at a dose of approximately 35 IU / kg body weight. An individual approach to the determination of the dose of the drug and the frequency of its administration is possible.

Treatment of bleeding

The necessary dose and duration of replacement therapy with a coagulation factor VIII concentrate depends onthe severity of the deficiency of coagulation factor VIII, the localization and severity of bleeding, and the general condition of the patient.

The amount of coagulation factor VIII introduced is expressed in international units (ME), which represent the international standard (WHO) for coagulation factor concentrates VIII. The activity of coagulation factor VIII in plasma is expressed as percent (relative to normal human plasma) or in ME (relative to the international standard of coagulation factor VIII in plasma).

1 ME the activity of coagulation factor VIII is equivalent to (corresponds to) the activity of coagulation factor VIII contained in 1 ml of normal human plasma.

To calculate the required dose of coagulation factor VIII, an empirical approach is used: when 1 ME coagulation factor VIII: C per kg body weight, the activity of coagulation factor VIII in plasma is increased by 1.5-2.0% of normal activity (1.5-2.0 IU / dl).

The required dose is determined by the following formula:

Necessary number of units = body weight (kg) x desired percentage of increase in clotting factor activity VIII: C (% or IU / dl) x 0.5.

The amount of preparation of coagulation factor VIII and the frequency of its administration should always be determined on the basis of the clinical efficacy of the drug in this patient.

In the cases of the hemorrhagic complications listed below, the activity of coagulation factor VIII should not fall below the indicated limits of plasma activity (in% or IU / dL) for the relevant period.

Table 1. Determination of the dose and frequency of the coagulation factor VIII preparation, depending on the type of hemorrhagic complication

Type of bleeding	The need for a factor preparation coagulation VIII (% or IU / dl)	Duration of administration (hours) / Duration of treatment (days)
Minor bleeding Started hemarthrosis, bleeding in the muscles or in the mucous membrane of the oral cavity	2040	Every 12-24 hours. At least 1 day, until the bleeding stops (the saline syndrome is stopped) or there is healing
Significant bleeding Extensive hemarthrosis, bleeding into the muscle or bruising	3060	Repeated administration every 12-24 hours for 3-4 days or longer until relief of pain or recovery of function
Life-threatening bleeding Gastrointestinal bleeding, intra-abdominal, intracranial or pleural bleeding	60-100	Repeated administration every 8-24 hours before resolution of symptoms
Surgical interventions
Minor interventions, including tooth extraction	60	Every 24 hours, at least 1 day, until healing.
Extensive Interventions		LongAyt has not been studied with extensive surgical interventions, so in these situations the drug should not be used

In certain situations, the amount of coagulation factor VIII may be required more than indicated in the table, especially at the first administration.

The total dose of LongAit for 1 week should not exceed 150 IU / kg of body weight, and the maximum daily dose should not be above 100 IU / kg of body weight.

The drug LongAit is available as a lyophilizate, which is reconstituted with a liposomal solvent just prior to administration. The solvent may slightly opalescent. Do not use a solvent in which visible foreign particles are detected.

Restoration of the drug should be carried out in aseptic conditions. Do not use vials immediately after removal from the refrigerator.

- The vial with lyophilizate and the vial with liposomal solvent should be kept until room temperature is reached.

- Remove the plastic caps from the vials.

- Disinfect the surface of the stoppers with the supplied napkins.

- Remove the protective film from the adapter.

- The bottle with the solvent is installed vertically, attach the blue side of the adapter to the vial and press the adapter all the way. The adapter must be securely connected to the vial.

- Remove the protective cover from the other side of the adapter.

- The adapter connected to the flask is turned over, using a transparent part of the adapter, pierce the stopper of the vial with lyophilizate and secure the adapter to the stop.

- While holding all three elements together, wait until all the solvent has evaporated into the vial of the lyophilisate under the action of a vacuum. During the transfer it is necessary that the solvent evenly wet the entire surface of the lyophilizate. The solvent must be completely transferred to the vial with lyophilizate.

- Gently stir the contents of the vial with rotational movements for at least 5 minutes until the lyophilisate is completely dissolved, avoiding the formation of foam during dissolution.

- The lyophilisate usually dissolves within 5 minutes and must completely dissolve within no more than 10 minutes.

- The solution should be a pale-white milky form with possible presence of single particles,removed by filtration.

- Remove the empty solvent vial and the blue adapter cap by turning it counter-clockwise.

- Attach the syringe and select the contents of the vial slowly and slowly pulling the plunger of the syringe.

- It is necessary to select the contents of the vial completely.

- Carefully unplug the filled syringe.

- The solution should be a pale white milk type with no visible foreign particles.

Insert the needle into the vein and fix the system for intravenous administration with a patch. Connect the filled syringe to the intravenous system and make sure that the blood does not enter the syringe.

The first 3 infusions should be carried out at a rate not exceeding 1 ml per minute. Subsequently, the drug is administered for 5-10 minutes, while the rate of administration should not exceed 4 ml per minute.

If you need to introduce another dose of the drug, use a new syringe with a solution prepared according to the instructions above.

If you have entered the entire required dose of the drug, remove the needle from the vein and firmly press the puncture site with a swab that is held on the patient's elongated arm for about 2 minutes.Then put a pressure bandage on this site of the arm.

Side effects:

In rare cases, hypersensitivity reactions may occur, or allergic reactions (angioedema, burning sensation at the injection site, chills, "tides" of blood to the skin, paresthesia, decreased blood pressure, drowsiness, nausea, vomiting, restlessness, tachycardia, sensation of shortness of breath, wheezing breathing, fever).

It is extremely rare to develop a severe allergic reaction - anaphylactic shock. It is recommended to use conventional methods of treatment of hypersensitivity reactions.

Treatment of patients with hemophilia A coagulation factor VIII preparation may be complicated by the appearance of the inhibitor, the major clinical manifestation of which is the reduction of the therapeutic effect of the drug. In such cases it is recommended to seek the advice of a specialized center for the treatment of hemophilia.

Intravenous drug LongEyt accompanied by a dose-dependent, moderate and reversible increase in lipoprotein level, which persists approximately 72 hours and normal 7 days after infusion.

Overdose:

There were no reported cases of overdose with a drug containing the human coagulation factor VIII.

Interaction:

Patients who, as a means for inhalation anesthesia, are prescribed a lipophilic drug isoflurane in combination with LongAit, should be carefully observed in the postoperative period in connection with the possibility of increasing the awakening period after anesthesia.

Clinically significant interaction of LongEit with other drugs was not noted.

Special instructions:

LongAyt can not be mixed in one syringe with other medicines. For the administration of the drug, only the attached system for intravenous administration should be used, because the loss of therapeutic effectiveness can be caused by the adsorption of coagulation factor VIII on the inner surface of some infusion systems.

LongAyt does not contain vWF, so it is not intended to treat patients with Willebrand's disease.

When treating with LongAit, as with intravenous administration of other protein preparations, the development of hypersensitivity reactions is possible.This preparation contains traces of human proteins other than clotting factor VIII. Patients should be alerted to early symptoms of hypersensitivity reactions, including urticaria, generalized rash, hampered or hoarse breathing, lowering blood pressure, and anaphylactic reactions. When the first symptoms of a hypersensitivity reaction appear, LongAit should be stopped immediately and the patient should seek specialized medical care.

In extremely rare cases, the development of pseudoallergic reactions against the background of the introduction of liposomes is possible. Characteristic symptoms of this condition include: back pain, lower blood pressure, a feeling of heat in the face and mouth, which usually appear in the first few minutes of the drug. Stopping the drug is usually accompanied by the disappearance of the above symptoms and does not require special treatment. Reduction in the rate of administration of the drug allows continuing treatment in most patients without resuming the above symptoms.In order to reduce the risk of developing pseudoallergic reactions, it is recommended that the first 3 infusions be administered at a rate not exceeding 1 ml per minute.

In the case of shock, standard anti-shock therapy should be used. Despite the use of all available modern methods of preventing infection of drugs prepared from human plasma, the possibility of contamination of the drug with blood-borne agents can not be completely ruled out.

The drug is effectively protected from enveloped viruses: HIV, hepatitis B and C, as well as non-enveloped viruses - hepatitis A.

There is no full guarantee of protection against parvovirus B19, which is most dangerous for pregnant women (infection of the fetus), for people with immunodeficiency and for patients with hemolytic anemia.

It is strongly recommended that each time the drug is administered, the number and series of bottles should be recorded in order to maintain the relationship between the patient and the drug used.

The formation of neutralizing antibodies, coagulation factor VIII inhibitors is a known complication in the treatment of hemophilia A. The inhibitory activity to coagulation Factor VIII: C exhibits exclusively immunoglobulins of class G, the number of which is expressed in modified Bethesda units (BY) per 1 ml of plasma. The risk of the appearance of an inhibitor correlates with the duration of exposure with an anti-hemophilic coagulation factor VIII. Most often, inhibitory activity is determined during the first 20 treatment sessions. It is extremely rare that an inhibitor may appear after the first 100 injections of a clotting factor preparation VIII.

Patients who receive treatment with the coagulation factor VIII drug should undergo a regular examination (clinical and laboratory) for the timely detection of inhibitory antibodies.

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

The effect of LongAit on the ability to drive vehicles and the use of mechanisms has not been identified.

Form release / dosage:Lyophilizate for preparation of dispersion for intravenous prolonged release, complete with liposomal solvent, 500 ME and 1000 ME.

Packaging:

500 or 1000 ME of coagulation factor VIII in a vial of transparent colorless glass of type I (Hebrew F) with a capacity of 30 ml, sealed with a gray siliconized halobutyl rubber stopper, sealed on top by an aluminum cap with a detachable white plastic lid.

3.5 ml (for a dosage of 500 IU) or 7.0 ml (for a dosage of 1000 IU) of a liposomal solvent in a clear glass colorless glass type I bottle (Hef.) With a capacity of 10 ml, sealed with a gray bromobutyl rubber stopper, sealed with an aluminum cap with a detachable plastic lid of white color.

1 bottle with lyophilizate and 1 bottle with liposomal solvent in a pack of cardboard.

The composition of the kit required for a single intravenous administration includes:

1. 1 vial with lyophilizate and 1 vial with liposomal solvent in a pack of cardboard.

2. 1 syringe (without needle) with a capacity of 5 ml (for a dosage of 500 ME) or 1 syringe (without a needle) with a capacity of 10 ml (for a dosage of 1000 ME) in individual packaging.

3. 1 system of minivans "Terumo®", consisting of a 25G x 19 mm butterfly needle and a 300 mm infusion tube, in individual packing.

4. 1 bottle adapter "MIX2VIAL®", equipped with a filter with a pore size of 25 microns, in an individual package.

5. 2 wipes soaked in 70% isopropanol, each in individual packaging.

Storage conditions:

At a temperature of 2 to 8 ° C.

Do not freeze.

Keep out of the reach of children.

Shelf life:

3 years.

Do not use after the expiration date printed on the package.

Terms of leave from pharmacies:On prescription

Registration number:LSR-002694/10