Coaplex - instructions for use, doses, side effects, contraindications

Active substanceFactors of blood coagulation II, VII, IX and X in combinationFactors of blood coagulation II, VII, IX and X in combination

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Coaplex

lyophilizate in / in

CESEL Behring GmbH Germany

OCTAPLEX®

lyophilizate in / in

Octapharma Pharmaceuticals Productionsgesb.H. Austria

Prothromplex 600

lyophilizate in / in

Baxter AG Austria

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

Composition:

1 bottle with lyophilizate contains:

Component	Dosages		Content in the reconstituted solution
Component	250 ME	500 ME
Active substances:
Coagulation factor II	200-480 ME	400 960 ME	20-48 IU / ml
Coagulation factor VII	100-250 ME	200-500 IU	10-25 IU / ml
Coagulation factor IX	200-310 ME	400-620 ME	20-31 IU / ml
Coagulation factor X	220-600 IU	440 1200 ME	22-60 IU / ml
Protein C	150-450 IU	300-900 ME	15-45 IU / ml
Protein S	120-380 ME	240-760 ME	12 38 IU / ml
Excipients:
Heparin sodium in terms of heparin	4-20 ME	8 40 ME	0.4 2 IU / ml
Human anthrombin III	2-15 ME	4-30 ME	0.2-1.5 IU / ml
Human albumin	20-40 mg	40-80 mg	2-4 mg / ml
Sodium chloride	30-60 mg	60-120 mg	3-6 mg / ml
Sodium citrate dihydrate in terms of sodium citrate	20-40 mg	40-80 mg	2-4 mg / ml
Sodium hydroxide or hydrochloric acid	A small amount to adjust the pH

1 bottle of solvent contains:

Water for injections

10 ml

20 ml

* The specific activity of factor IX is 2.5 IU / mg total protein.

The total protein concentration after dissolution is 6-14 mg / ml solution.

Activity of all coagulation factors of blood and proteins C and S (antigen) was tested in accordance with the current WHO standards.

Description:

Lyophilizate: white or almost white powder or amorphous mass.

Reconstituted solution: from a colorless to light yellow color, a clear or slightly opalescent liquid.

Solvent: colorless, clear liquid.

Pharmacotherapeutic group:Hemostatic agent

ATX: & nbsp

B.02.B.D.01 Factors of blood coagulation IX, II, VII and X in combination

B.02.B.D Coagulation factors

Pharmacodynamics:

Factors of blood coagulation II, VII, IX and X are synthesized in the liver with the help of vitamin K, and their combination is often called the prothrombin complex. In addition to clotting factors, Coaptex contains vitamin K-dependent inhibitors of coagulation - proteins C and S.

The blood coagulation factor VII is the precursor of the active serine protease of the coagulation factor VIIa, which triggers an external way of activating blood clotting. Complex of coagulation factor of blood VIIa with tissue thromboplastin activates blood clotting factors IX and X, resulting in the formation of activated clotting factors - IHa and Ha.With the further activation of the coagulation cascade, prothrombin (coagulation factor II) is activated, from which the prothrombin thrombin. Under the influence of thrombin, fibrinogen turns into fibrin, which forms a clot. The normal formation of thrombin also has a critical value for the function of platelets as components of primary blood clotting.

Isolated severe deficiency of the blood clotting factor VII leads to a decrease in the formation of thrombin and a tendency to bleed due to disruption of fibrin formation and disturbance of primary blood clotting. Isolated deficiency of the coagulation factor IX is an example of classical hemophilia (hemophilia B). Isolated deficiency of coagulation factors II or X is very rare, but in severe form it can be accompanied by the same tendency to bleeding, as in classical hemophilia.

Other components are coagulation inhibitors proteins C and S - also synthesized in the liver. Protein S is a co-factor that enhances the biological activity of protein C.

Activated protein C inhibits blood clotting by inactivating blood coagulation factors Va and VIIIa. Protein S as the co-factor of protein C supports the inactivation of coagulation. Protein C deficiency is accompanied by an increased risk of thrombosis.

Acquired deficiency of vitamin K-dependent clotting factors can develop with the use of vitamin K antagonists. If the deficit becomes severe, then the tendency to severe bleeding develops, more often in the retroperitoneal space and the brain than in the muscles and joints. Severe hepatic failure also leads to a significant decrease in the level of vitamin K-dependent clotting factors and a clinically significant tendency to bleeding. However, this phenomenon is often of a complex nature due to simultaneous small intravascular coagulation, low platelet count, deficiency of clotting inhibitors, and fibrinolysis disorders.

The introduction of the human prothrombin complex leads to an increase in the level of vitamin K-dependent clotting factors in blood plasma and can temporarily eliminate the clotting disorder in patients with deficiency of one or more of these factors.

Pharmacokinetics:

Data on pharmacokinetics and data on the level of recovery of coagulation factors in vivo were obtained by conducting a study on healthy volunteers (N = 15), and also in two studies on the elimination of a vitamin K antagonist in the treatment of acute massive bleeding or perioperative bleeding prophylaxis (N = 98, N = 43).

A study involving healthy volunteers:

Coaplex was administered to 15 healthy volunteers at a dose of 50 IU / kg. For the recovery level median in vivo (in vivo recovery - IVR) take an increase in the measured levels of plasma factors (IU / ml) that is expected after the administration of coagulation factors (IU / kg) as a dose of Coaplex. Growth IVR for clotting factors II, VII, IX, X, and proteins C and S were also taken into account. All the maximum levels of the components were achieved within 3 hours. Average increase IVR was in the range of 0.016 IU / ml for the coagulation factor IX and up to 0.028 IU / ml for protein C.

Average half-life and increment IVR are denoted as follows:

Parameter	Average half-life (range) / hours	Growth IVR (IU / mL per IU / kg body weight)
Parameter	Average half-life (range) / hours	Geometric mean	90% CI **
Factor II	60 (25-135)	0,022	(0,020-0,023)
Factor VII	4 (2-9)	0,024	(0,023-0,026)
Factor IX	17 (10-127)*	0,016	(0,014-0,018)
Factor X	31 (17-44)	0,021	(0,020-0,023)
Protein C	47 (9-122)*	0,028	(0,027-0,030)
Protein S	49 (33-83)*	0,020	(0,018-0,021)

* terminal half-life of a two-period model

**confidence interval

The study on the elimination of a vitamin K antagonist in the treatment of acute massive bleeding:

average value IVR was calculated for 98 patients who received the drug Coaplex for the treatment of bleeding concomitantly with the intake of vitamin K antagonists. The increase in the parameter IVR was in the range of 0.016 IU / ml for the coagulation factor VII and up to 0.019 IU / ml for protein C.

Study on the elimination of vitamin K antagonist in the treatment of acute massive bleeding or perioperative bleeding prophylaxis:

average value IVR was calculated for 43 patients who received Coaplex for bleeding treatment or for perioperative bleeding prophylaxis concomitantly with the intake of vitamin K antagonists.

Intravenous administration of Coaplex in a dose of 1 IU / kg increased the level of vitamin K-dependent clotting factors in plasma in the range from 0.013 IU / ml to 0.023 IU / ml.

Coagulation factors of Coaplex preparation are distributed and metabolized in the body in the same way as endogenous clotting factors II, VII, IX and X.

With intravenous administration, the drug immediately enters the systemic circulation, and bioavailability is proportional to the administered dose.

Indications:

- Treatment and perioperative prophylaxis of bleeding with the acquired deficiency of clotting factors included in the prothrombin complex, including a deficit caused by therapeutic use or overdose of vitamin K antagonists, when rapid elimination of the deficit is required.

- Treatment and perioperative prophylaxis of bleeding with congenital deficiency of any vitamin K-dependent clotting factor when the drug of the purified specific clotting factor is unavailable.

Contraindications:

- Hypersensitivity to the active ingredients or any other component included in the preparation.

- In the case of the syndrome of disseminated intravascular coagulation (DVS-syndrome), the prothrombin complex preparation can be used only after the acute phase of the disease has died down.

- The presence in the anamnesis of thrombocytopenia, induced by the use of heparin.

Carefully:

Because of the risk of thromboembolic complications, Coaplex should be used with caution inpatients with a history of coronary heart disease, myocardial infarction, liver disease, in patients during and after operations, in newborns, in patients with an increased risk of developing thromboembolic complications and disseminated intravascular coagulation (DVS) or concomitantly deficient inhibition of coagulation. In these cases, the expected benefit from using Coaptex should be correlated with the possible risk of complications.

Pregnancy and lactation:

The safety of Coaptex in women during pregnancy and breastfeeding has not been established. Animal studies do not apply to assess the safety of the drug in women during pregnancy, embryo or fetus development, childbirth and postnatal development.

Therefore, the drug Coaplex can be used during pregnancy and during breastfeeding only if there is an obvious need.

Dosing and Administration:

Below are only general recommendations.

Treatment should be started under the supervision of a doctor who has experience in the treatment of blood clotting disorders.

The dose and duration of treatment depend on the indication for use, the severity of the disease, the localization and extent of bleeding, and the clinical condition of the patient.

Dose and multiplicity of drug administration should be calculated individually for each patient. The interval between doses should be chosen taking into account different half-lives in the blood of clotting factors included in the prothrombin complex (see subsection "Pharmacokinetics"). The dose for each patient can be determined only on the basis of a regular measurement of the activity of the corresponding coagulation factors in the blood plasma or by a general evaluation of the activity of the prothrombin complex (International Normalized Ratio (INR), Kwick test) in combination with continuous monitoring of the clinical state of the patient.

With extensive surgical interventions, precise control of the effectiveness of replacement therapy is necessary by analyzing individual coagulation factors and / or a general evaluation of the activity of the prothrombin complex.

- Treatment and perioperative prophylaxis of bleeding during treatment with antagonists of vitamin K

The dose depends on the INR prior to treatment and on the required INR.To more accurately calculate the required dose, the INR value before the start of treatment should be measured as close as possible to the time of administration of the drug. The table below shows approximate doses (in ml reconstituted drug solution / kg body weight and in ME coagulation factor IX/ kg of body weight) necessary for the normalization of INR (for example, up to ≤ 1.3) for different initial INR values.

INR before treatment	2,0-3,9	4,0-6,0	>6,0
Approximate dose in ml / kg of body weight	1	1,4	2
The approximate dose in ME coagulation factor IX / kg body weight	25	35	50

The dose is based on the body weight not exceeding 100 kg. For patients with a body weight of more than 100 kg, the maximum single dose (ME coagulation factor IX) should not exceed 2500 ME for INR 2.0-3.9; 3500 ME for INR 4.0-6.0 and 5000 ME for INR >6,0.

Correction of vitamin K-induced antagonists of clotting is achieved at the latest 30 minutes after the injection. However, the effect of simultaneously administered vitamin K is usually achieved in 4-6 hours. Therefore, with the simultaneous use of vitamin K, it is usually not necessary to reintroduce the human prothrombin complex.

These recommendations are based on clinical trials involving a small number of patients.The degree of recovery of blood clotting and the duration of the effect may fluctuate, so during the treatment it is necessary to monitor INR.

- Bleeding and perioperative prophylaxis with congenital deficiency of any vitamin K-dependent clotting factors, when the preparation of the purified deficient blood clotting factor is unavailable

Calculation of the required dose of the prothrombin complex is based on the results of clinical studies:

- 1 ME coagulation factor IX / kg body weight on average increases the activity of this factor in blood plasma by 1.3% (0.013 IU / ml) of the normal index;

- 1 ME factor of blood clotting VII / kg of body weight increases the activity of this factor in blood plasma by 1.7% (0.017 IU / ml) from the normal value;

- 1 ME Coagulation factor II / kg body weight increases the activity of this factor in blood plasma by 1.9% (0.019 IU / ml) from the normal value;

- 1 ME the blood coagulation factor X / kg of body weight increases the activity of this factor in blood plasma by 1.9% (0.019 IU / ml) from the normal value.

The dose of the clotting factor is expressed in international units (ME), which are correlated with the current WHO standards for each factor.The activity of this or that clotting factor in plasma is expressed either as a percentage (relative to normal plasma) or in ME (relative to the international standard of this factor).

One international unit (ME) of clotting factor activity corresponds to the content of this factor in 1 ml of normal human blood plasma.

For example, the calculation of the required dose of coagulation factor X is based on the data that 1 ME Coagulation Factor X / kg body weight increases the activity of this factor in the plasma by 0.019 IU / ml.

The required dose is calculated by the following formula:

Required amount ME = body weight (kg) x the desired coefficient of increase in the activity of the coagulation factor X (IU / ml) x 53,

where 53 (ml / kg) is the inverse of the expected recovery.

The calculation is based on data from patients receiving vitamin K antagonists. A calculation based on the data of healthy volunteers gives a lower value of the required dose.

If the recovery value of a particular patient is known, then it should be used in the calculation.

Special patient groups

Children

The safety and efficacy of the use of Coaptex in children and adolescents in controlled clinical trials were not evaluated.

Elderly patients

Dosage and method of administration for elderly patients (> 65 years) are consistent with general recommendations.

Mode of application

The preparation Coaplex should be dissolved, as described in the subsection "Preparation of reconstituted solution". The resulting solution should be administered intravenously at a rate of no more than 3 IU / kg / min, maximum 210 IU / min, i.e. about 8 ml / min.

General instructions

1. The reconstituted solution should be a clear or slightly opalescent liquid from a colorless to light yellow color. After filtration and before administration, it is recommended to inspect the reconstituted preparation for the presence of particles and discoloration. Do not use a cloudy solution or solution containing the precipitate after filtration.

2. The preparation of the reconstituted solution of the preparation and the set in the syringe is carried out under aseptic conditions.

3. The unused preparation or solution of the preparation, as well as its packaging, should be disposed of in accordance with local requirements.

Preparation of the reconstituted solution

Heat the solvent to room temperature. It should be ensured that the caps from the vials with the solvent and the preparation are removed,the plugs are treated with an antiseptic solution and dried prior to opening the device for adding a solvent with a built-in filter *.

1. Remove the cap from the packaging of the solvent addition device with the built-in filter. Not Remove the device for adding the solvent with the built-in filter from the blister pack!

2 Place vial with solvent on an even, clean surface, without opening it. Take the device for adding the solvent with the built-in filter together with the blister packing and, firmly holding the bottle, with the sharp rod of the blue part of the device, pierce the stopper of the vial with the solvent, pressing vertically downwards.

3. Gently holding the edge of the blister pack, remove the blister pack in the direction vertically up from a device for adding a solvent. Make sure that you have removed only the blister pack, not the device itself.

4. Place vial of drug on a hard, level surface and turn over the solvent bottle together with the solvent addition device attached to it. Then with a sharp rod transparent parts of the device for the addition of a solvent, puncture the stopper of the vial with the drug, pressing vertically down. The solvent will automatically move into the vial with the drug.

5. With one hand, grasp the device for adding the solvent from the side of the vial with the preparation, the other from the side of the vial with the solvent and gently unfold the device in two parts, turning counter-clockwise. The solvent bottle with the blue part of the device for adding the solvent should be discarded.

6. Carefully twist the vial with the drug and attached to it a transparent part of the device for adding the solvent until the drug is completely dissolved. Do not shake the bottle.

7. Draw air into an empty sterile syringe and, while holding the bottle in the upright position, attach the syringe to the Luer tip on the solvent add-on device with the built-in filter by turning the syringe clockwise. Enter the air into the vial with the drug.

Fence and administration of the drug

8. By pressing the plunger of the syringe, flip the bottle together with the syringe. Slowly pulling the plunger of the syringe, put into it a reconstituted solution.

9.After the reconstituted solution is recruited into the syringe, grasp the syringe barrel (holding the syringe with the piston down) and detach the transparent part of the device for adding the solvent with the built-in filter from the syringe by turning the device to add the solvent counterclockwise.

* Device for adding a solvent with a built-in filter ("Mix-2Vial20/20 ") is intended for single use only, do not use the device in the event of damage to the package, or after the expiry date indicated on the paper part of the blister package as follows:" EXP. year-month "

Care should be taken so that blood does not enter the syringe with the drug, since there is a risk that blood can coagulate in the syringe and clots of fibrin, thus, will be administered to the patient.

The reconstituted drug solution should be administered using a separate injection / infusion system by intravenous slow injection.

The reconstituted solution remains chemically and physically stable for 24 hours at room temperature (not above 25 ° C). However, since the preparation of Coaplex does not contain preservatives, from the microbiological point of view the reconstituted solution of the drug should be used immediately.

The reconstituted solution of the drug should not be diluted.

Side effects:

The undesirable reactions presented below are listed in accordance with the damage to organs and organ systems and frequency of occurrence.

Frequency of occurrence is based on clinical trial data and is determined as follows: Often (≥ 1/10), often (≥ 1/100 and <1/10), infrequently (≥ 1/1 000 and <1/100\ rarely (≥ 1/10 000 and <1/1 000), rarely (<1/10 000, including individual cases) or unknown (can not be determined on the basis of available data).

Frequency categories were formed on the basis of clinical studies of the drug, post-registration observation and scientific literature data.

Frequency of occurrence of undesirable reactions:

Vascular disorders:
Often:	thromboembolic reactions.
Violations from the blood and lymphatic system:
Unknown:	disseminated intravascular coagulation (ICE) (see the "Caution" section).
Immune system disorders:
Infrequently:	hypersensitivity or allergic reactions.
Unknown:	anaphylactic reactions, including anaphylactic shock (cm.section "Special instructions").
Unknown:	Anaphylactic reactions in patients with antibodies to coagulation factors, which are part of the preparation Coaplex.
Unknown:	the formation of antibodies to one or more coagulation factors entering the prothrombin complex, with replacement therapy. This is manifested by a decrease in the clinical effect. In such cases it is recommended to consult a specialist center for the treatment of hemophilia.
Impaired nervous system:
Often:	headache
General disorders and disorders at the site of administration:
Often:	fever.

* Including cases with fatal outcome

Medical workers are encouraged to report any undesirable reactions to an authorized organization in the territory of the Russian Federation (see the subsection "For Further Information").

Overdose:

In order to avoid an overdose during treatment, it is necessary to regularly monitor blood coagulability, since the administration of large doses of the prothrombin complex (overdose) in some cases was accompanied by myocardial infarction, disseminated intravascular coagulation, venous thrombosis and pulmonary embolism.In case of an overdose, the risk of developing thromboembolic complications and disseminated intravascular coagulation is increased in patients from the high-risk group of these complications.

Interaction:

Coaplex should not be mixed with other drugs and solvents.

The drug prothrombin complex of a person neutralizes the action of vitamin K antagonists, but interaction with other drugs is unknown.

When carrying out a blood coagulability test sensitive to heparin, patients who receive high doses of the human prothrombin complex should take into account the presence of heparin in the drug used.

Special instructions:

Consult a specialist with experience of treating coagulation disorders.

In patients with a deficiency of vitamin K-dependent clotting factors (for example, caused by the use of vitamin K antagonists), the Coaplex preparation should be used only if rapid correction of prothrombin complex activity is necessary, for example, with massive bleeding or emergency surgical interventions.In other cases, it is usually enough to reduce the dose of a vitamin K antagonist and / or prescribe vitamin K.

Patients receiving a vitamin K antagonist may have increased blood clotting as a major disease, and the administration of a prothrombin complex can enhance this condition.

Suspension of treatment with vitamin K antagonists is associated with a risk of thromboembolic reactions associated with the underlying disease. In this regard, the possible renewal of anticoagulant treatment should be carefully considered.

With a congenital deficiency of any vitamin K-dependent clotting factor, the drug of this particular factor should be used whenever possible.

Data on the use of Coaptex in cases of perinatal bleeding caused by vitamin K deficiency in newborns.

The drug Coaplex contains up to 343 mg of sodium (about 15 mmol) in 100 ml. This should be taken into account in the treatment of patients receiving a diet low in sodium.

With the development of an allergy or anaphylactic reaction, the administration of Coaplex should be stopped immediately (that is, stopping the injection) and appropriate therapy should be started.Treatment depends on the type and severity of the undesirable phenomenon. It is necessary to follow the current standards of shock treatment.

When using a prothrombin complex of a man in patients with a congenital or acquired deficiency of clotting factors, there is a risk of thrombosis or development of the DIC syndrome, especially with repeated administration of the drug. This risk may be increased in the treatment of an isolated deficiency of clotting factor VII, since other vitamin K-dependent clotting factors having a longer half-life can accumulate to levels well above normal. When using the human prothrombin complex, the patient should carefully monitor the appearance of signs or symptoms of the ICE or thrombosis syndrome in the patient.

Patients with DIC syndrome may in some cases require replenishment of clotting factors included in the prothrombin complex. Such treatment, however, can be carried out only after the acute phase has been stopped (for example, by treating the underlying disease or normalizing the level of antithrombin III).

When using drugs containing heparin, the development of heparin-induced thrombocytopenia type 2 (GT-2) is possible.Characteristic features of HG are a decrease in platelet count by> 50% and / or development of new or unexplained thromboembolic complications with heparin. Typically, these phenomena appear 4-14 days after the onset of heparin, but may develop for 10 hours (in patients who received heparin in the previous 100 days).

When using drugs containing coagulation factor IX, single cases of development of a nephrotic syndrome after an attempt to conduct an induction of immune tolerance to the coagulation factor IX in patients with an inhibitory form of hemophilia B and an allergic reaction in the anamnesis have been reported.

Viral safety

Standard measures to prevent the transmission of infections resulting from the use of drugs derived from human blood or plasma include selection of donors, screening of individual donations and plasma pools for the presence of specific infection markers and the inclusion of effective production steps aimed at inactivating and / or removing viruses . Despite this, with the use of drugs derived from human blood or plasma, the possibility of transmitting infectious agents can not be completely ruled out.This provision also applies to unknown or newly discovered viruses and other infectious agents. The measures taken are considered effective for viruses that have a membrane, such as human immunodeficiency virus, hepatitis B and C viruses, as well as for non-enveloped viruses such as hepatitis A virus and parvovirus B19.

Patients who regularly or repeatedly receive prothrombin complex preparations produced from human plasma should consider the possibility of vaccination against hepatitis A and B.

With each administration of Coaplex, it is strongly recommended to register the name and serial number of the drug to be administered to maintain communication between the patient and the drug series.

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

Studies of the effect of the drug on the ability to drive and move vehicles have not been carried out.

Form release / dosage:

Lyophilizate for the preparation of a solution for intravenous administration, 250 ME and 500 ME.

Packaging:

250 each ME or 500 ME preparation in a vial of colorless transparent glass (type II, Eur.F.), sealed with a rubber stopper, coated with an aluminum cap with a plastic disc,complete with a solvent (water for injection) of 10 ml (for a dosage of 250 ME) or 20 ml (for a dosage of 500 ME) in a vial of colorless transparent glass (type I, Hearth.F), sealed with a rubber stopper and rinsed with an aluminum cap with a plastic disc.

A device for adding a solvent with a built-in 15 μm filter ("Mix-2Vial™ 20/20 ") is packed in the blister polyethylene terephthalate / paper laminated with polyethylene.

1 bottle with lyophilizate, 1 vial with solvent and 1 device for adding a solvent with a built-in filter with instructions for use in a cardboard pack.

Storage conditions:

Store at a temperature of no higher than 25 ° C, in a place protected from light. Do not freeze.

Keep out of the reach of children.

Shelf life:

3 years.

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

Terms of leave from pharmacies:On prescription

Registration number:LP-003500

Date of registration:14.03.2016

Expiration Date:14.03.2021

The owner of the registration certificate:CESEL Behring GmbHCESEL Behring GmbH Germany

Manufacturer: & nbsp