Prothrombin complex

Brand Baxter

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Available since: 2019-09-19

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Clinical Pharmacology

Blood coagulation factors II, VII, IX and X together form a prothrombin complex. The synthesis of these factors depends on vitamin K and is carried out in the liver. Factor VII is a zymogen of the active serine-protease factor VIIa, through which the endogenous coagulation pathway is initiated.

The complex tissue factor - factor VIIa activates coagulation factors X and IX, resulting in the formation of factors Xa and IXa. With further activation of the coagulation cascade, prothrombin (factor II) is activated and its transformation into thrombin. Under the action of thrombin, fibrinogen turns into fibrin, which leads to the formation of a clot. Normal thrombin synthesis is also a prerequisite for platelet involvement in primary hemostasis. Isolated severe factor VII deficiency leads to a reduction in the formation of thrombin and causes increased bleeding due to impaired fibrin formation and impaired primary hemostasis. Isolated factor IX deficiency is one of the classic types of hemophilia (hemophilia B).

Isolated insufficiency of factor II or factor X is very rare, but, in severe forms, accompanied by increased bleeding as in cases of classical hemophilia.

Acquired vitamin K deficiency-dependent coagulation factors of the prothrombin complex are encountered during treatment with vitamin K antagonists. With a pronounced deficiency, the tendency to bleeding increases, with retroperitoneal and cerebral bleeding rather than bleeding into muscles and joints. Severe hepatic impairment also leads to a marked decrease in the levels of the prothrombin complex and clinically pronounced symptoms of increased bleeding, which, however, is complex in most cases due to simultaneously flowing mild intravascular coagulation, low platelet levels, deficiency of clotting inhibitors and impaired fibrinolysis.

The use of the human prothrombin complex drug provides increased levels of vitamin K-dependent coagulation factors in the plasma and can temporarily eliminate coagulation disorders in patients with insufficiency of one or several of these factors.

Indications

treatment of bleeding and prevention of bleeding in surgical interventions in patients with an acquired deficiency of factors of the prothrombin complex, for example, with a deficiency caused by treatment with vitamin K antagonists or overdose of vitamin K antagonists in cases where a rapid correction of the deficiency is required;
treatment of bleeding and prevention of bleeding during surgery in patients with congenital deficiency of one of the vitamin K-dependent coagulation factors, in cases where the preparation of purified specific coagulation factor is not available.

Composition

1 vial contains coagulation factor II 600 IU, coagulation factor IX 600 IU, coagulation factor VII 500 IU, coagulation factor X 600 IU, human protein C (in the form of protein contained in plasma 300-750 mg / fl.) not less than 400 IU.

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Dosage and Administration

A single dose and frequency of administration is determined individually, taking into account the initial indicators of the coagulation system, localization and severity of bleeding, the patient's clinical condition.

When prescribing to patients with an acquired deficiency of factors of the prothrombin complex, in particular, for the treatment and prevention of bleeding in overdose of indirect anticoagulants - vitamin K antagonists, the dose calculation should be guided by the value of either Kvik prothrombin or MHO, depending on which indicator determines laboratory.

If we focus on the value of protrombin by Kvik, then we should proceed from the assumption that 1 ME of the drug per 1 kg of body weight increases the value of prothrombin by about 1%.

If we take into account the initial value of MHO, the dose calculation is carried out as follows (see table).

Baseline mho	Single dose of the drug from per 1 kg of body weight
2.0-3.9	25 IU / kg
4.0-5.9	35 IU / kg
≥ 6.0	50 IU / kg

The goal of treatment is to achieve an MHO value of 1.0-1.2; sometimes up to 1.5, depending on the clinical situation. The question of the introduction of a repeated dose of the drug should be addressed individually, taking into account the dynamics of the patient’s clinical condition, concomitant therapy and the achieved value of MHO.

When prescribing to patients with a congenital isolated deficiency of one of the factors of the prothrombin complex, a single dose is calculated individually for each patient (see formulas for calculating the required dose), and the intervals between injections are set depending on the value of T_1/2scarce factor.

Treatment should begin under the supervision of a physician with experience in treating blood clotting disorders.

Formulas for calculating the required dose

factor II: dose (ME) = body weight (kg) × desired increase in factor (%) × 0.5;
factor VII: dose (ME) = body weight (kg) × desired increase in factor (%) × 0.6;
factor IX: dose (ME) = body weight (kg) × desired increase in factor (%) × 1.2;
factor X: dose (ME) = body weight (kg) × desired increase in factor (%) × 0.6.

In the case of massive surgery, careful monitoring of the level of the deficient clotting factor and / or the rate of protrombin in Kvik and correction of therapy with Protrompleks 600 depending on the dynamics of these indicators is necessary.

Note. The dose of a specific factor is expressed in ME, which are determined in accordance with the current WHO standard for each factor. The activity of the coagulation factor in plasma is expressed either as a percentage (relative to normal plasma) or in IU (in accordance with the international standard for a particular coagulation factor). 1 ME of coagulation factor activity is equivalent to the amount in 1 ml of normal human plasma.

Adverse reactions

When using concentrates of prothrombin complex factors, there is a risk of thromboembolism, disseminated intravascular coagulation and hypersensitivity reactions, including anaphylactic reactions and anaphylactic shock.

When conducting replacement therapy with a concentrate of factors of the prothrombin complex, it is possible to produce circulating antibodies that inhibit one or more coagulation factors. The appearance of inhibitors manifests itself in the form of an insufficient clinical response.

The adverse reactions observed during the post-marketing use of Protrompleks 600 are grouped by organ systems and described in terms of MedDRA (Medical Dictionary of Regulatory Activities).

On the part of the circulatory and lymphatic systems: disseminated intravascular coagulation; development of inhibitors of one or more blood coagulation factors (factors II, VII, IX, X).
The immune system: anaphylactic shock, anaphylactic reactions, hypersensitivity reactions.
Of the nervous system: stroke, headache.
Since the cardiovascular system: heart failure, myocardial infarction, tachycardia; arterial thrombosis, venous thrombosis, arterial hypotension, "flush" of blood to the skin of the face.
On the part of the skin and subcutaneous tissues: urticaria, erythematous rash, pruritus.
On the part of the respiratory system, chest, mediastinum: pulmonary thromboembolism, shortness of breath, wheezing.
On the part of the kidneys: nephrotic syndrome.
On the part of the digestive system: vomiting, nausea.
Common disorders: fever.
Adverse reactions inherent in this pharmacological class of agents
On the part of the skin and subcutaneous tissues: angioedema, paresthesias.
Local reactions: reactions at the injection site.
On the part of the nervous system: drowsiness.
From the psyche: anxiety.

Contraindications

Because of the danger of thromboembolic complications, the drug should be used withextra care in patients with a history of coronary artery disease (including myocardial infarction), liver disease, as well as in patients in the postoperative period, in newborns and in patients with a high risk of developing thromboembolic complications or DIC. In these cases, it is necessary to correlate the expected benefits of using the drug Protrompleks 600 with the risk of developing these complications.

Drug interactions

Preparations of the prothrombin complex neutralize the effects of vitamin K antagonists.

Studies on the interaction with other drugs have not been conducted.

Pharmaceutical incompatibility

Protrompleks 600 can not be mixed with other drugs or solvents, except for the attached sterile water for injection.

Efficacy and tolerability of the drug can be weakened when mixed with other drugs. It is recommended that the venous catheter be washed with an isotonic solution of sodium chloride before and after applying Protromplex 600.

Pregnancy and Lactation

The safety of the use of human prothrombin complex drugs in pregnant women and during lactation has not been determined.

Animal studies are not suitable for assessing safety in relation to pregnancy, fetal / fetal development, delivery, and postnatal development. Therefore, the prothrombin complex of a person should be used during pregnancy and lactation only if there are strict indications, if the expected effect of therapy outweighs the potential risk to the fetus.

Special instructions

In patients with an acquired deficiency of coagulation factors of the prothrombin complex (for example, due to treatment with vitamin K antagonists) Protrompleks 600 is used in cases when a rapid correction of the levels of coagulation factors is necessary, in particular for life-threatening and severe bleeding, especially retroperitoneal, cerebral, gastrointestinal intestinal, as well as the need for urgent surgical intervention. In other cases, it is usually sufficient to reduce the dose of an antagonist of vitamin K and / or use of vitamin K.

In the case of congenital isolated deficiency of one of the vitamin K-dependent factors, a monocomponent preparation of a deficient clotting factor should be used first. Patients with congenital coagulation factor deficiency should be consulted by a specialist who has experience in treating patients with this pathology.

Bleeding in patients with acquired deficiency of vitamin K-dependent coagulation factors can occur with prolonged therapy or overdose of oral anticoagulants (vitamin K antagonists); in diseases of the organs of the hepatopancreatoduodenal zone (cirrhosis, hepatocellular carcinoma, obstruction of the common bile duct with a stone or stricture, drainage of the common bile duct, chronic pancreatitis); with bowel disease,leading to impaired absorption of vitamin K (short bowel syndrome due to surgery; Crohn's disease); with prolonged parenteral nutrition without the addition of vitamin K; as a result of exposure to therapy with certain drugs (cefamandol, cefoperazone, rifampicin, isoniazid, barbiturates, chemotherapeutic agents that damage the liver parenchyma); in diseases involving the development of coagulation inhibitors (lupus anticoagulant, multiple myeloma and other paraproteinemias), in acute promyelocytic leukemia, in case of massive blood loss.

Multicenter clinical studies of the drug Protrompleks 600 in children have not been conducted.

If allergic or anaphylactic reactions occur, the drug should be immediately discontinued. In the event of shock, standard anti-shock medical measures should be provided.

Standard measures to prevent infections resulting from the use of drugs derived from human blood or plasma include donor selection, screening of individual donor samples and plasma pools to identify specific markers of infection, and the use of effective inactivation / removal of viruses in the production. Despite this, when using drugs derived from human blood and plasma, transmission of the infectious agent cannot be completely excluded. This also applies to unknown or new viruses and other pathogens.

The measures taken are considered effective against enveloped viruses, such as HIV-1/2, hepatitis B and C viruses and the non-enveloped hepatitis A virus.

The technologies used for removal and inactivation may not be sufficiently effective against some shellless viruses, such as parvovirus B19, for example. Infection with parvovirus B19 can be dangerous for pregnant women (fetal infection) and immunocompromised patients, for patients with increased red blood cell disruption (for example, in hemolytic anemia).

With regular use of drugs made from human plasma, it should be envisaged to vaccinate a patient against hepatitis A and hepatitis B.

Each time a patient is prescribed Protromplex 600, the name of the drug and the series number in the patient's history or patient card should be recorded.

With repeated injections of preparations of the human prothrombin complex, incl. drug Protrompleks 600, there is a risk of thrombosis and disseminated intravascular coagulation. The risk may be higher in the treatment of isolated factor VII deficiency, since other vitamin K-dependent coagulation factors with longer T_1/2can accumulate to levels significantly higher than normal.

Patients who receive therapy with the prothrombin complex should be carefully monitored for signs of intravascular coagulation or thrombosis. Control is shown for patients with coronary artery disease, liver disease, patients who have a tendency to thrombosis, for newborns, as well as for patients in the pre- and postoperative periods. In these patients, the potential benefits of treatment should be correlated with the risk of complications.

Laboratory tests. It should be borne in mind that the drug contains heparin, which is important when performing heparin-sensitive coagulation tests, especially in the case of the use of the drug in high doses.

Since heparin can cause allergic reactions and a decrease in the number of blood cells, which affects the coagulation system, the administration of heparin-containing drugs to patients with a history of heparin-induced allergic reactions should be avoided.

The bottle with the drug Protrompleks 600 contains 80 mg of sodium. This should be taken into account when prescribing the drug to patients on a low-sodium diet.

Within the specified expiration date, patients can store the drug at room temperature (not above 25 ° C) for 6 months. The date of storage at room temperature should be marked on the package. If the preparation was stored at room temperature for 6 months, it must be either administered to the patient or disposed of. Subsequent storage in the refrigerator is unacceptable.

The recovered solution is chemically and physically stable when stored for 3 hours at a temperature of from 20 ° to 25 ° C. The reconstituted solution cannot be stored in the refrigerator. Since the product contains no preservatives, from a microbiological point of view, the prepared solution should be used immediately.

Influence on ability to drive motor transport and control mechanisms

Studies on the effect of the drug on the management of vehicles and mechanisms have not been conducted.

Overdosage

Cases of overdose preparations of prothrombin complex are not described. Based on the pharmacodynamic properties of the drug, it can be assumed that the possible manifestations of overdose will be thrombotic complications.

Studies and clinical trials of Prothrombin complex (Click to expand)