Xigris^® (Lyophilisate) Instructions for Use

Marketing Authorization Holder

Eli Lilly Vostok, S.A. (Switzerland)

Manufactured By

DSM Pharmaceuticals, Inc. (USA)

ATC Code

B01AD10 (Drotrecogin alfa (activated))

Active Substance

Drotrecogin alfa (activated)

Drotrecogin alfa (activated) (Rec.INN registered by WHO)

Dosage Forms

	Xigris®	Lyophilisate for preparation of solution for infusion 5 mg: vial 1 pc.
		Lyophilisate for preparation of solution for infusion 20 mg: vial 1 pc.

Dosage Form, Packaging, and Composition

Lyophilisate for preparation of solution for infusion from white to off-white color.

Excipients: sodium chloride, sodium citrate (equivalent to citrate ion), sucrose.

Glass vials (1) – cardboard packs.

Lyophilisate for preparation of solution for infusion from white to off-white color.

Excipients: sodium chloride, sodium citrate (equivalent to citrate ion), sucrose.

Glass vials (1) – cardboard packs.

Clinical-Pharmacological Group

Anticoagulant – inhibitor of factors Va and VIIIa

Pharmacotherapeutic Group

Anticoagulant

Pharmacological Action

Anticoagulant. Activated protein C exerts an antithrombotic effect by inhibiting coagulation factors Va and VIIIa. Data obtained in vitro indicate that activated protein C has an indirect profibrinolytic effect due to its ability to suppress plasminogen activator inhibitor-1 (PAI-1) and limit the production of activated thrombin-activatable fibrinolysis inhibitor. Furthermore, in vitro experimental data indicate that activated protein C has an anti-inflammatory action, due to the suppression of tumor necrosis factor synthesized by monocytes, blocking of leukocyte adhesion to selectins, and limiting the thrombin-induced inflammatory response in the endothelium of the microcirculation.

The mechanism by which drotrecogin alfa reduces mortality in patients suffering from severe sepsis is not fully understood. In patients suffering from severe sepsis, infusion of drotrecogin alfa for 48 or 96 hours led to a dose-dependent decrease in D-dimer and IL-6 levels. Compared to patients receiving placebo, patients receiving drotrecogin alfa showed a more rapid decrease in D-dimer, PAI-1, thrombin-antithrombin, prothrombin F1.2, IL-6 levels, a more rapid increase in protein C and antithrombin, and normalization of plasminogen levels. Based on the infusion duration, it was determined that the maximum pharmacodynamic effect of drotrecogin alfa on D-dimer level is observed by the end of the 96-hour infusion at a dose of 24 mcg/kg/h.

Pharmacokinetics

Absorption and Distribution

Drotrecogin alfa and endogenous human activated protein C are inactivated by endogenous plasma protease inhibitors. The concentration of activated protein C in plasma in healthy subjects and in patients suffering from severe sepsis is usually below the minimum detectable concentration level.

In patients suffering from severe sepsis, infusion of drotrecogin alfa (activated) at doses from 12 mcg/kg/h to 30 mcg/kg/h rapidly achieves C_ss, which is proportional to the infusion rate. The mean clearance of drotrecogin alfa is 40 L/h (from 27 to 52 L/h). A mean C_ss of 45 ng/ml (from 35 to 62 ng/ml) was achieved within 2 hours from the start of the infusion. In most patients, the plasma concentration of drotrecogin alfa fell below the quantitation limit of 10 ng/ml within 2 hours after stopping the infusion.

Pharmacokinetics in Special Clinical Cases

In adult patients suffering from severe sepsis, minimal differences in the plasma clearance values of drotrecogin alfa (activated) were identified depending on age, sex, severity of liver or kidney dysfunction; dose adjustment was not required.

Plasma clearance of drotrecogin alfa (activated) in patients with severe sepsis was approximately 50% higher than in healthy subjects.

In non-septic patients on hemodialysis, the mean plasma clearance of drotrecogin alfa (activated) when the drug was administered on non-dialysis days was 30±8 L/h. In non-septic patients undergoing peritoneal dialysis, the plasma clearance of drotrecogin alfa (activated) was 23±4 L/h. Such plasma clearance values were practically no different from the values observed in healthy subjects – (28±9 L/h) (n=190).

The pharmacokinetic parameters of drotrecogin alfa (activated) at a dose of 24 mcg/kg/h appear not to differ between children and adults suffering from severe sepsis.

Indications

• Sepsis accompanied by acute multiple organ failure, with a high risk of death.

ICD codes

Dosage Regimen

Xigris^® should be administered intravenously at a rate of 24 mcg/kg/h, and the duration of infusion should be 96 hours.

After interruption of the infusion, administration of Xigris^® should be resumed at a rate of 24 mcg/kg/h. Increasing the dose or bolus administration of Xigris^® is not recommended.

Rules for preparation and administration of the drug

Appropriate aseptic technique should be used when preparing Xigris^® for intravenous administration.

The required dose should be calculated and the required number of Xigris^® vials should be numbered. Each vial of Xigris^® contains 5 mg or 20 mg of the drug. The vials contain an excess of Xigris^® to provide the amount stated on the label.

The contents of the 5 mg vial should be diluted in 2.5 ml of Sterile Water for Injections, and the contents of the 20 mg vial should be diluted in 10 ml of Sterile Water for Injections. The concentration of the drug in the resulting solution will be approximately 2 mg/ml. Sterile Water for Injections should be added slowly to the vial contents without inverting or shaking the vial, then each vial should be gently swirled until the lyophilisate contained in it is completely dissolved.

The resulting Xigris^® solution must be further diluted with sterile 0.9% sodium chloride solution for intravenous administration. The appropriate amount of Xigris^® solution should be slowly withdrawn from the vial and added to the infusion bag container containing 0.9% sterile sodium chloride solution. When adding Xigris^®, the stream of solution should be directed against the wall of the infusion bag container to minimize agitation of the solution. The container should then be gently inverted to homogenize the solution. The infusion bag container should not be transported using mechanical delivery systems.

Because Xigris^® does not contain antibacterial preservatives, the solution for intravenous administration should be prepared immediately after diluting Xigris^® in the vial(s). If vials with diluted Xigris^® are not used immediately, they can be stored at room temperature from 15°C (59°F) to 30°C (86°F). However, these vials must be used within the next 3 hours. Intravenous administration must be completed within 12 hours of preparing the intravenous solution.

Before use, the solution should be visually inspected for the presence of visible suspended particles and changes in solution color.

When using an infusion pump for intravenous administration, the Xigris^® solution is usually diluted in 0.9% sodium chloride solution to a concentration of 100 mcg/ml to 200 mcg/ml.

When using a syringe pump for drug administration, the Xigris^® solution is usually diluted with sterile 0.9% sodium chloride solution for injections to a concentration of 100 mcg/ml to 1000 mcg/ml. In cases where Xigris^® is administered at low concentrations (less than 200 mcg/ml) at a low rate (less than 5 ml/h), the infusion rate for the first 15 minutes should be about 5 ml/h.

Xigris^® should be administered through a separate intravenous port or through a dedicated lumen of a multi-lumen central catheter. Only 0.9% sodium chloride solution, Ringer’s solution for injection, dextrose, or a mixture of dextrose and saline can be administered through this same port.

The Xigris^® solution should be protected from high temperatures and/or direct sunlight. No incompatibility has been identified between the Xigris^® solution and glass infusion bags, or infusion bags and syringes made of polyvinyl chloride, polyethylene, or polyolefin.

Adverse Reactions

From the hematopoietic system most frequently – bleeding (3.5%), most often developing during the infusion. Serious bleeding (any intracranial, life-threatening bleeding, or bleeding requiring transfusion of ≥3 units of packed red blood cells per day for 2 days) occurred with a frequency of 2.4%.

Patients receiving Xigris^® for the treatment of severe sepsis experience many reactions that may be a consequence of severe sepsis and may or may not be related to treatment with Xigris^®. In clinical studies, no other adverse reactions due to treatment with Xigris^®, other than bleeding, were identified.

Contraindications

• Ongoing internal bleeding;
• Recently experienced (within the previous 3 months) hemorrhagic stroke;
• Recently performed (within the previous 2 months) intracranial or spinal surgery, or severe head trauma;
• Trauma accompanied by a high risk of developing life-threatening bleeding;
• Presence of an epidural catheter;
• Intracranial tumors/masses or signs of brain herniation;
• Identified hypersensitivity to drotrecogin alfa (activated) or other substances constituting the drug.

Use in Pregnancy and Lactation

There are no data on the possible damaging effect of Xigris^® on the fetus when the drug is administered to pregnant women or on the effect of the drug on reproductive function. Xigris^® should be prescribed during pregnancy only if there are clear indications.

There are no data on the possibility of Xigris^® excretion in breast milk or systemic absorption after the drug enters the gastrointestinal tract. Since many drugs are excreted in breast milk, and due to the likelihood of adverse reactions in the breastfed infant, a decision should be made to discontinue breastfeeding or discontinue the drug, taking into account the importance of continuing treatment with this drug for the mother.

Use in Hepatic Impairment

Xigris^® should be prescribed with particular caution (due to an increased risk of bleeding) in severe chronic liver disease.

Pediatric Use

The safety and efficacy of Xigris^® in newborns (gestational age 38 weeks) and in children and adolescents under 18 years of age have not been studied. Data on the efficacy of Xigris^® in adult patients with severe sepsis and a high risk of death cannot be extrapolated to children with severe sepsis.

Special Precautions

Xigris^® should be prescribed with particular caution (due to an increased risk of bleeding) during concomitant treatment with heparin (≥15 units/kg/h); with a platelet count <30,000 x 10⁶ /L (even if the platelet count increased after transfusion); with prothrombin time-INR >3.0; after (within 6 weeks) recently experienced gastrointestinal bleeding; if thrombolytic therapy was performed within 3 days before prescribing Xigris^®; when taking oral anticoagulants or glycoprotein IIb/IIIa receptor inhibitors within the previous 7 days, acetylsalicylic acid in a dose >650 mg/day or other antiplatelet agents; with a history (within the previous 3 months) of ischemic stroke; in the presence of intracranial vascular malformations or aneurysms, hemorrhagic diathesis; in severe chronic liver disease; in any other conditions where there is a high risk of bleeding or where stopping bleeding may be difficult due to its location.

The most frequent of the serious adverse effects noted during treatment with Xigris^® is bleeding. Every patient for whom Xigris^® is intended to be prescribed should be thoroughly examined, and the expected treatment effect should be weighed against the possible risk of using the drug.

If clinically significant bleeding occurs, the infusion of Xigris^® should be stopped immediately. Other drugs affecting the coagulation system should be used with particular caution. Once adequate hemostasis parameters are achieved, the question of continuing the use of Xigris^® may be considered.

Treatment with Xigris^® should be discontinued 2 hours before surgery or other procedures associated with an increased risk of bleeding. Once adequate hemostasis parameters are achieved, administration of Xigris^® may be started 12 hours after major invasive procedures and surgeries or resumed immediately after uncomplicated less invasive interventions.

Most patients with severe sepsis have coagulopathy, which is usually associated with an increase in activated partial thromboplastin time (aPTT) and prothrombin time (PT). Xigris^® may increase aPTT to varying degrees. Therefore, the aPTT value cannot be used to assess the severity of coagulopathy during the infusion of Xigris^®. Xigris^® has a minimal effect on PT values, so the PT value can be used to assess the severity of coagulopathy in this category of patients.

As with the use of other protein drugs, there is a possibility of potential immunogenicity when using Xigris^®. The frequency of antibody formation in patients receiving Xigris^® has not been reliably determined because the sensitivity of the assay methods is not high enough to detect all cases of antibody production.

Xigris^® has not been re-administered to patients suffering from severe sepsis.

No differences in efficacy and safety of the drug were identified in elderly patients compared to younger patients.

Use in pediatrics

The safety and efficacy of Xigris^® in newborns (gestational age 38 weeks) and in children and adolescents under 18 years of age have not been studied. Data on the efficacy of Xigris^® in adult patients with severe sepsis and a high risk of death cannot be extrapolated to children with severe sepsis.

In pediatric practice, the safety and efficacy of Xigris^® in patients suffering from severe sepsis have not been evaluated, therefore dosing recommendations are not available.

Overdose

Symptoms in most cases (patients received a dose 60 times the recommended dose), no adverse reactions were noted. In other cases, known side effects of the drug and complications associated with sepsis were observed.

Treatment immediate discontinuation of the drug infusion and establishment of careful monitoring for possible bleeding. Antidotes are unknown.

Drug Interactions

In patients suffering from severe sepsis, the interaction of Xigris^® with other drugs has not been studied.

Caution should be exercised when using Xigris^® in combination with other drugs that affect hemostasis. Concomitant use of low-dose heparin for prophylactic purposes did not affect the safety of Xigris^®.

Storage Conditions

The drug should be stored out of the reach of children, in a refrigerator at a temperature from 2°C (35.6°F) to 8°C (46.4°F); do not freeze.

Shelf Life

Shelf life – 3 years.

Store in a light-protected place in the cardboard packaging until use.

Dispensing Status

The drug is dispensed by prescription.

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.