Coaplex (Lyophilisate) Instructions for Use

ATC Code

B02BD01 (Blood coagulation factors IX, II, VII and X in combination)

Clinical-Pharmacological Group

Blood clotting factors (II, VII, IX, X) preparation

Pharmacotherapeutic Group

Hemostatic agent

Pharmacological Action

A prothrombin complex preparation.

Blood coagulation factors 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. Proteins C and S are vitamin K-dependent coagulation inhibitors.

Coagulation Factor VII is a precursor of the active serine protease blood coagulation factor VIIa, which triggers the extrinsic pathway of blood coagulation activation. The complex of blood coagulation factor VIIa with tissue thromboplastin activates blood coagulation factors IX and X, resulting in the formation of activated blood coagulation factors – IXa and Xa. Upon further activation of the coagulation cascade, prothrombin (blood coagulation factor II) is activated, from which thrombin is formed. Under the influence of thrombin, fibrinogen is converted into fibrin, which forms a clot. Normal thrombin formation is also critical for platelet functions as components of primary hemostasis.

Isolated severe deficiency of blood coagulation factor VII leads to reduced thrombin formation and a tendency to bleed due to impaired fibrin formation and impaired primary hemostasis.

Isolated deficiency of blood coagulation factor IX is an example of classical hemophilia (hemophilia B).

Isolated deficiency of blood coagulation factors II or X is very rare, but in severe form can be accompanied by the same tendency to bleed as in classical hemophilia.

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

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

Acquired deficiency of vitamin K-dependent coagulation factors can develop with the use of vitamin K antagonists. If the deficiency becomes severe, a tendency to severe bleeding develops, more often in the retroperitoneal space and brain than in muscles and joints. Severe liver failure also leads to a significant decrease in the level of vitamin K-dependent coagulation factors and a clinically significant tendency to bleed. However, this phenomenon is often complex due to simultaneously occurring minor intravascular coagulation, low platelet count, deficiency of coagulation inhibitors, and impaired fibrinolysis.

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

Pharmacokinetics

Pharmacokinetic data and data on the in vivo recovery level of coagulation factors were obtained from a study involving healthy volunteers, as well as from two studies on the withdrawal of vitamin K antagonist in the treatment of acute massive bleeding or perioperative bleeding prophylaxis.

When administered intravenously, the components immediately enter the systemic circulation, and bioavailability is proportional to the administered dose.

After administration of a dose of 50 IU/kg, maximum concentrations of all components were reached within 3 hours. The average increase in in vivo recovery (IVR) level ranged from 0.016 IU/ml for blood coagulation factor IX to 0.028 IU/ml for protein C.

Administration of the drug at a dose of 1 IU/kg led to an increase in the level of vitamin K-dependent blood coagulation factors in plasma within the range of 0.013 IU/ml to 0.023 IU/ml.

Coagulation factors after administration of this drug are distributed and metabolized in the body in the same way as endogenous coagulation factors II, VII, IX, and X.

Indications

Treatment and perioperative prophylaxis of bleeding in acquired deficiency of blood coagulation factors included in the prothrombin complex, including deficiency caused by therapeutic use or overdose of vitamin K antagonists, when rapid elimination of the deficiency is required; treatment and perioperative prophylaxis of bleeding in congenital deficiency of any vitamin K-dependent blood coagulation factor, when a preparation of a purified specific coagulation factor is not available.

ICD codes

Dosage Regimen

Lyophilisate

Treatment should be initiated under the supervision of a physician experienced in the treatment of coagulation disorders. The dose and duration of treatment depend on the indication for use, the severity of the disease, the location and extent of bleeding, and the clinical condition of the patient.

The dose and frequency of administration should be calculated individually for each patient. The interval between doses should be chosen taking into account the different half-lives in the blood of the coagulation factors included in the prothrombin complex.

The dose for each patient can only be determined based on regular measurement of the activity of the relevant coagulation factors in the blood plasma or by overall assessment of prothrombin complex activity (INR, Quick test) in combination with continuous monitoring of the patient’s clinical condition.

Adverse Reactions

Vascular disorders common – thromboembolic reactions (including fatal outcome).

Blood and lymphatic system disorders unknown – DIC syndrome.

Immune system disorders: uncommon – hypersensitivity or allergic reactions; unknown – anaphylactic reactions in patients with antibodies to coagulation factors that are components of the combination, anaphylactic shock, formation of antibodies to one or more coagulation factors included in the prothrombin complex during replacement therapy (this is manifested by a decrease in clinical effect).

Nervous system disorders common – headache.

General disorders common – increased body temperature.

Contraindications

History of heparin-induced thrombocytopenia; hypersensitivity to the active substances.

In DIC syndrome, it can be used only after the acute phase of the disease has subsided.

Use in Pregnancy and Lactation

The safety of use in women during pregnancy and breastfeeding has not been established. Use is possible only in case of proven necessity.

Pediatric Use

The drug is contraindicated for use in children and adolescents under 18 years of age

Geriatric Use

The drug is approved for use in elderly patients

Special Precautions

Due to the risk of thromboembolic complications, the drug should be used with caution in patients with a history of coronary artery disease, myocardial infarction, liver diseases, in patients during and after surgery, in newborns, in patients with an increased risk of developing thromboembolic complications and DIC syndrome or simultaneous deficiency of coagulation inhibitors. In these cases, the expected benefit from the use of this drug should be weighed against the possible risk of complications.

During extensive surgical interventions, precise control of the effectiveness of replacement therapy is necessary by analyzing individual coagulation factors and/or overall assessment of prothrombin complex activity.

If it is necessary to use this drug, consultation with a specialist experienced in the treatment of coagulation disorders is recommended.

In patients with acquired deficiency of vitamin K-dependent coagulation factors (e.g., caused by the use of vitamin K antagonists), use only when rapid correction of prothrombin complex activity is necessary, for example, in massive bleeding or emergency surgical interventions. In other cases, it is usually sufficient to reduce the dose of the vitamin K antagonist and/or prescribe vitamin K.

Patients receiving a vitamin K antagonist may have increased blood coagulability as an underlying disease, and the administration of the prothrombin complex may enhance this condition.

Discontinuation of treatment with vitamin K antagonists is associated with the risk of thromboembolic reactions related to the underlying disease. Therefore, it is necessary to carefully consider resuming anticoagulant treatment as early as possible.

In congenital deficiency of any vitamin K-dependent coagulation factor, a preparation of that specific factor should be used whenever possible.

When using human prothrombin complex in patients with congenital or acquired deficiency of coagulation factors, there is a risk of thrombosis or development of DIC syndrome, especially with repeated administration of the drug. This risk may be increased in the treatment of isolated coagulation factor VII deficiency, because other vitamin K-dependent coagulation factors, which have a longer T_1/2, can accumulate to levels significantly exceeding normal. When using human prothrombin complex, the patient should be carefully monitored for the appearance of symptoms of DIC syndrome or thrombosis.

Patients with DIC syndrome may in some cases require replenishment of the coagulation factors included in the prothrombin complex. Such treatment, however, can only be carried out 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 (HIT-2) is possible. Characteristic signs of HIT are a drop in platelet count by > 50% and/or the development of new or unexplained thromboembolic complications during the use of heparin. Usually, such phenomena appear 4-14 days after the start of heparin use, but can also develop within 10 hours (in patients who received heparin in the previous 100 days).

When using drugs containing Blood coagulation factor IX, isolated cases of nephrotic syndrome have been reported after an attempt to induce immune tolerance to blood coagulation factor IX in patients with inhibitor form of hemophilia B and a history of allergic reaction.

It should be considered that when using drugs obtained from human blood or plasma, the possibility of transmission of infectious agents cannot be completely excluded. This provision also applies to unknown or recently discovered viruses and other infectious agents. The measures taken are considered effective for enveloped viruses 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 regularly or repeatedly receiving prothrombin complex preparations manufactured from human plasma should consider the possibility of vaccination against hepatitis A and B.

Use in pediatrics

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

Drug Interactions

Human prothrombin complex preparation neutralizes the effect of vitamin K antagonists, but interaction with other drugs is unknown.

When performing a heparin-sensitive coagulation analysis in patients receiving high doses of human prothrombin complex, the presence of heparin in the drug used should be taken into account.

Should not be mixed with other drugs and solvents.

Storage Conditions

Store at 2°C (36°F) to 25°C (77°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.