Index of drugs

Treatment of adult patients with severe sepsis (septicemia) with multi-organ failure, as an additional treatment for standard therapy. The use of the preparation should be considered mainly in situations when the treatment can be started within 24 hours after the onset of organ failure.

1 vial contains 5 mg of drotrecogin alfa (activated). The product contains sodium (approximately 17 mg in one vial).

The preparation is a recombinant form of naturally occurring activated protein C, from which it differs only by the presence of oligosaccharides in the carbohydrate part of the molecule. Activated protein C is a very important blood coagulation regulator: it limits the formation of thrombin by inactivating factors Va and VIIIa. Activated protein C is a modulator of systemic response to infection with anticoagulant and profibrynolytic activity. The anticoagulant effect of the drug is due to the limitation of thrombin formation and the alignment of sepsis-induced coagulopathy. The product restores endogenous fibrinolytic potential and limits the inflammatory response of the body as a result of the decrease in interleukin-6 concentration. The drug prolongs the activated partial thromboplastin time (APTT) and the minimum prothrombin time (PT); during treatment, there is a decrease in the concentration of coagulation activation products, increase in protein C concentration and normalization of plasminogen concentration with a decrease in the concentration of plasminogen-1 activator inhibitor. Drotrecogin alfa (activated), like the endogenous activated C protein, is inactivated by endogenous plasma protease inhibitors, however, the mechanism for removing the drug from plasma is unknown. In healthy persons, a concentration exceeding 90% of steady-state plasma concentrations is reached within 2 hours of the start of drug administration. The concentration of the drug in the blood is proportional to the speed of its administration. After the end of drug administration, the decrease in blood concentration is two-phase: the initial phase (fast) lasts for 13 minutes, and the second phase (slow) -1.6 hours.

Hypersensitivity to drotrecogin alfa (activated) or the remaining ingredients of the preparation or beef thrombin. Active internal bleeding. Patients with intracranial changes, cancer or features of intussusception. Concurrent therapy with Heparin ≥15 IU / kg / h. Hemorrhagic diathesis, except coagulopathy associated with sepsis. Chronic severe liver disease. Thrombocytopenia <30,000 x 10⁶/ l, even if the number of platelets increases after transfusion. Patients with an increased risk of bleeding, eg within 12 hours after each major surgery requiring general or spinal anesthesia, after an operation with symptoms of active bleeding when planned or not possible during the infusion of the drug; with severe head injury, requiring a history of hospitalization, after intracranial or spinal surgery, hemorrhagic stroke in the last 3 months or whenever there has been a malformation of arterial or venous vessels in the brain, aneurysm or massive brain injury; in patients with the presence of a catheter in the epidural space or its planned placement during the infusion; with congenital hemorrhagic diathesis in an interview; with gastrointestinal bleeding in the last 6 weeks requiring medical intervention (unless an appropriate surgical procedure has been performed); in patients after an injury with an increased risk of bleeding. Children under 18 years.

The preparation has not been approved for the treatment of patients with single organ dysfunction and should not be used in this particular subset of patients, especially if surgery has been performed recently (within 30 days). Due to the increased risk of bleeding during the administration of the drug, in the following situations, the preparation can only be used if the anticipated benefits of treatment outweigh its risks: recent (in the last 3 days) thrombolytic treatment; recent (in the last 7 days) use of oral anticoagulants, Acetylsalicylic acid or other platelet inhibitors; recent (up to 3 months) ischemic stroke; any other situations of increased risk of significant bleeding. In the case of planned medical procedures with an increased risk of bleeding, the administration of drotrecogin alfa (activated) should be discontinued 2 h before the beginning of the procedure. Drug administration can be resumed after 12 hours after the end of the procedure, provided that an adequate level of haemostasis has been achieved.The incidence of severe bleeding after administration was higher among patients who underwent surgery over the last 30 days than patients undergoing no treatment. Resumption of drug administration may occur immediately after completing less invasive, uncomplicated procedures if proper haemostasis has been achieved. If subsequent measurements of coagulation parameters indicate an uncontrolled or worsening coagulopathy, which can significantly increase the risk of bleeding, the benefits of continuing the medicine should be considered in relation to the patient's risk of bleeding. It is not possible to completely rule out the possibility of allergic reactions to the components of the drug in certain predisposed patients. If an allergic or anaphylactic reaction occurs, immediately discontinue the treatment and initiate appropriate treatment. Caution should be exercised if the medicine is given to the patient a second time. The product contains sodium - this should be taken into account in patients on a controlled sodium diet. The pharmacokinetics of drotrecogin alfa have not been studied
(activated) in patients with severe sepsis and concurrent renal disease and chronic liver disease. In patients with severe sepsis, the plasma clearance of drotrecogin alfa (activated) is significantly reduced in renal failure and hepatic dysfunction; however, this does not involve the need to change the dosage of the drug.

Potential risk of unknown use of the drug (no relevant studies) - the drug should not be used during pregnancy unless clearly necessary. The woman receiving the preparation should not breastfeed.

The drug increases the risk of bleeding. The incidence of major bleeding during the infusion was higher among patients who had undergone surgery in the last 30 days than in non-treated patients (3.3% versus 2% and 5%, respectively, compared to 3.1 %). The incidence of major bleeding events over the 28-day study period was 3.5% for drotrecogin alfa (activated) patients and 2% for placebo patients, respectively. The incidence of bleeding in o.u.n. during the 28-day duration of the study was 0.2%, respectively, in patients treated with drotrecogin alfa (activated) and 0.1% in patients who received placebo. The overall risk of bleeding may increase in patients with severe coagulopathy and severe thrombocytopenia. In Phase 1 studies, adverse reactions occurring at a frequency of ≥5% included headache (30.9%), ecchymosis (23%) and pain at the injection site (5.8%). The incidence of antibodies against human activated C-protein or neutralizing antibodies in adult patients with severe sepsis is low.

The drug should be used by doctors who have experience in the treatment of severe sepsis. Treatment should be started within 48 hours and preferably within 24 hours after the onset of the first symptoms of organ dysfunction due to sepsis.
Adults: 24 μg / kg / h (based on current body weight) in a continuous intravenous infusion over 96 hours. It is recommended to administer the medication through an infusion pump in order to correctly control the infusion rate. In case of temporary interruption of the infusion, the drug should be resumed at a dose of 24 μg / kg / h and continue until the recommended total time of administration, ie 96 hours. No dosage adjustment is required due to age, sex, liver function (measured transaminase activity), renal function, obesity or concurrent prophylactic use of heparin.