Evronex

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT EURONEX (EURONEX)

Composition:

Active substance: tranexamic acid;

1 ml of injection solution contains 100 mg of tranexamic acid;

Excipient: water for injections.

Pharmaceutical form. Injection solution.

Main physico-chemical characteristics: clear, colorless solution.

Pharmacotherapeutic group.

Antihemorrhagic agents, antifibrinolytic amino acids. Fibrinolysis inhibitors.
ATC code B02A A02.

Pharmacological Properties.

Pharmacodynamics.

Tranexamic acid exerts an antihemorrhagic effect by inhibiting the fibrinolytic activity of plasmin. A complex forms involving tranexamic acid and plasminogen; tranexamic acid binds to plasminogen during its conversion involving plasmin. The activity of the tranexamic acid-plasmin complex on fibrin is lower than that of plasmin alone. In vitro studies have shown that high doses of tranexamic acid reduce the activity of this complex.

Pediatric population.
Children aged 1 year and older. Data from 12 studies on efficacy in pediatric cardiac surgery involving 1073 children, of whom 631 patients received tranexamic acid, are available. Outcomes in most of these studies were assessed in comparison with a placebo control group. The study population was heterogeneous in terms of age, type of surgical intervention, and dosing. Study results indicate that tranexamic acid reduces blood loss and decreases the need for blood product transfusions in pediatric cardiac surgery involving cardiopulmonary bypass (CPB), particularly in procedures with a high risk of bleeding, especially in "cyanotic" patients (with significant circulatory impairment) or patients undergoing repeat surgery. The most appropriate dosing regimen has been determined to be as follows:

• Initial dose (loading dose): bolus infusion of 10 mg/kg, administered after induction of anesthesia and prior to skin incision;
• continuous infusion at 10 mg/kg/hour or intermittent injection into the CPB pump adapter at a dose adjusted for the specific surgical procedure, or at a body weight-based dose of 10 mg/kg, or injection into the CPB pump adapter and a final dose of 10 mg/kg at the end of the surgical procedure involving CPB.

Limited data suggest that continuous infusion is preferable, as it maintains therapeutic plasma concentrations throughout the surgery. No specific dose-response or pharmacokinetic studies have been conducted in children.

Pharmacokinetics.

Absorption. Peak plasma concentration of tranexamic acid is rapidly achieved after short-term intravenous infusion, after which plasma concentrations decline in a multiexponential manner.

Distribution. At therapeutic plasma levels, the protein binding of tranexamic acid to plasma proteins is approximately 3%; this binding is believed to be entirely due to interaction with plasminogen. Tranexamic acid does not bind to serum albumin. The initial volume of distribution is approximately 9 to 12 liters.

Tranexamic acid crosses the placenta. After intravenous administration of 10 mg/kg in pregnant women, serum concentrations of tranexamic acid range from 10–53 μg/mL, while concentrations in umbilical cord blood range from 4–31 μg/mL. Tranexamic acid rapidly penetrates into synovial fluid and synovial membrane tissues. After intravenous administration of 10 mg/kg in 17 patients undergoing knee surgery, concentrations in synovial fluid were similar to those in serum. Concentrations of tranexamic acid in several other tissues and fluids are partial relative to those observed in blood (e.g., breast milk — one hundredth, cerebrospinal fluid — one tenth, aqueous humor of the eye — one tenth). Tranexamic acid has been detected in semen, where it inhibits fibrinolytic activity but has virtually no effect on sperm migration (motility).

Elimination. The drug is primarily excreted in urine as unchanged compound. Renal excretion via glomerular filtration is the main elimination pathway. Renal clearance is practically equivalent to plasma clearance (110–116 mL/min). Approximately 90% of tranexamic acid is excreted within the first 24 hours after intravenous administration of a 10 mg/kg body weight dose. The elimination half-life of tranexamic acid is approximately 3 hours.

Special patient groups. Plasma concentrations increase in patients with renal insufficiency. No specific pharmacokinetic studies have been conducted in children.

Clinical characteristics.

Indications.

Bleeding or risk of bleeding due to enhanced fibrinolysis, either generalized or localized, in adults and children aged 1 year and older.

Specific indications include:

• Bleeding due to increased systemic or local fibrinolysis, such as:
• Menorrhagia and metrorrhagia;
• Gastrointestinal bleeding;
• Hemorrhagic disorders of the urinary tract arising from surgery on the prostate gland or due to surgical procedures or interventions on the urinary tract;
• Otolaryngological (adenoidectomy, tonsillectomy) and dental (tooth extraction) surgical procedures;
• Gynecological surgeries or complications in obstetric practice;
• Thoracic, abdominal, and other major surgical procedures, e.g., cardiovascular surgery;
• Control of hemorrhage associated with administration of a fibrinolytic medicinal product.

Contraindications.

Hypersensitivity to the active substance or to any of the excipients of the medicinal product. Acute venous or arterial thrombosis. Fibrinolytic states with acute severe bleeding due to administration of coagulopathy-inducing agents (anticoagulants), except for agents predominantly activating the fibrinolytic system. Severe renal insufficiency (risk of drug accumulation). History of seizures. Intrathecal, epidural, intraventricular, and intracerebral injection (risk of cerebral edema followed by seizures and fatal outcome).

Interaction with other medicinal products and other forms of interaction.

Drug interaction studies have not been conducted to date. Concomitant use of anticoagulants should be performed under strict supervision of a physician experienced in this area of therapy. Medicinal products affecting hemostasis should be used with caution in patients receiving treatment with tranexamic acid. Concurrent use with hormonal contraceptives may increase thrombotic potential. Furthermore, the antifibrinolytic effect of the medicinal product may be antagonized by thrombolytics.

Special precautions for use.

Strictly adhere to the specified indications and method of administration:

• Intravenous injections must be administered very slowly (maximum 1 mL per minute).
  • Tranexamic acid should not be administered intramuscularly.

Risk of medication errors due to incorrect route of administration

The medicinal product Evronex is intended for intravenous use only. Intrathecal, epidural, intraventricular, and intracerebral administration of Evronex is contraindicated (see section "Contraindications"). Serious adverse reactions, including fatal cases, have been reported when tranexamic acid was inadvertently administered intrathecally. These events included severe back, buttock, and lower limb pain, myoclonus, generalized seizures, and cardiac arrhythmias. Extreme caution must be exercised to ensure the correct route of administration of Evronex. Healthcare professionals should be aware of the potential risk of confusing Evronex with other injectable medicinal products, which may lead to inadvertent intrathecal administration. This particularly applies to injectable products administered intrathecally, which may be used during the same procedure as tranexamic acid.

Syringes containing tranexamic acid must be clearly labeled indicating intravenous administration only.

Seizures. Cases of seizures associated with tranexamic acid treatment have been reported in patients. During coronary artery bypass graft (CABG) surgery, most of these cases occurred after intravenous (i.v.) administration of high-dose tranexamic acid. When recommended low doses of tranexamic acid are used, the incidence of postoperative seizures in patients is the same as in patients not receiving this medicinal product.

Visual disturbances. The possibility of ophthalmological complications, including visual disturbances, worsening of vision, and color vision impairment, should be considered. Treatment should be discontinued in such cases. Regular ophthalmological examinations (including visual acuity, color vision, fundus examination, visual field testing, etc.) should be scheduled during continuous long-term use of tranexamic acid (injections). In cases of existing or newly developed ophthalmological abnormalities, particularly retinal disorders, after appropriate specialist consultation, the physician must individually assess the necessity and feasibility of long-term use of tranexamic acid (injections) in each specific case.

Hematuria. In cases of hematuria involving the upper urinary tract, there is a risk of urethral obstruction.

If obstruction of the urinary tract is left untreated, it may lead to serious consequences such as renal failure, urinary tract infection, hydronephrosis, and anuria. Therefore, careful monitoring of patients with hematuria or at risk of hematuria involving the upper urinary tract is recommended.

Thromboembolic complications. Risk factors for thromboembolic complications should be evaluated before administering tranexamic acid. Tranexamic acid (injection solution) should be administered only in cases of direct life-threatening indications to patients with a history of thromboembolic disorders or to patients with a family history indicating an increased risk of thromboembolic complications (patients at high risk of thrombophilia). Treatment should be initiated only after consultation with a specialist experienced in hemostasis and conducted under strict medical supervision.

Due to the increased risk of thrombosis, tranexamic acid should be prescribed with caution to patients receiving oral contraceptives.

Disseminated intravascular coagulation (DIC). Patients with DIC syndrome should generally not receive tranexamic acid treatment. If tranexamic acid use is necessary, it should be administered only in cases of predominant activation of the fibrinolytic system associated with acute severe bleeding. The characteristic hematological profile in these conditions includes: shortened euglobulin clot lysis time; prolonged prothrombin time; decreased plasma levels of fibrinogen, factors V and VIII, plasminogen, fibrinolysin, and alpha-2-macroglobulin; normal plasma levels of P and P-complex (i.e., factors II [prothrombin], VIII, and X); elevated plasma levels of fibrinogen degradation products; and normal platelet count. The above profile suggests that the underlying disease state itself may not alter these various elements. In such acute cases, a single dose of 1 g of tranexamic acid is often sufficient to stop bleeding. The possibility of using tranexamic acid in patients with DIC should only be considered when appropriate hematological laboratory facilities and clinical experience are available.

Use during pregnancy or breastfeeding.

Women of reproductive age

Women of reproductive age should use effective contraceptive methods during treatment.

Pregnancy

Available data from published studies, case series, and reports of tranexamic acid use in pregnant women during the second and third trimesters and during delivery do not allow determination of whether there is a drug-related risk of miscarriage or adverse outcomes for the mother or fetus.

There have been reports of fetal structural abnormalities leading to neonatal death after maternal use of tranexamic acid during conception or in the first trimester of pregnancy; however, due to other concurrent risk factors, the risk of serious congenital malformations associated with tranexamic acid use during pregnancy has not been established.

Animal studies do not indicate a direct or indirect harmful effect regarding reproductive toxicity.

Tranexamic acid crosses the placenta. The concentration in umbilical cord blood after intravenous injection of 10 mg/kg in pregnant women is approximately 30 mg/L, similar to that in maternal blood.

Thirteen clinical studies have described functional problems in the fetus and/or newborn, such as low Apgar scores, neonatal sepsis, and cephalohematoma, and nine clinical studies have discussed growth changes, including low birth weight and preterm delivery at 22–36 weeks of gestation in fetuses and infants exposed to tranexamic acid in utero.

When deciding on the use of tranexamic acid during pregnancy, the potential risk of tranexamic acid for the fetus and the mother's clinical need for tranexamic acid should always be considered; a precise risk-benefit assessment should form the basis for the treating physician's decision.

Breastfeeding

Published literature reports the presence of tranexamic acid in human milk. Data on the effect of tranexamic acid on the breastfed infant or on lactation are limited. The benefits of breastfeeding for the infant's development and health should be weighed against the mother's clinical need for tranexamic acid and any potential adverse effects on the breastfed infant from tranexamic acid or the mother's underlying condition. Due to limited data, a definitive assessment of tranexamic acid use during breastfeeding cannot be made.

Fertility

Clinical data on the effect of tranexamic acid on fertility are lacking. In animal studies, tranexamic acid administered at clinically relevant doses had no effect on male or female fertility.

Ability to influence reaction speed when driving or operating machinery.

Studies evaluating the effect on the ability to drive or operate machinery have not been conducted.

Method of administration and dosage.

Evronex is administered intravenously (by drip or bolus injection).

Adults.

For local fibrinolysis, the recommended dose is 500 mg (1 vial of 5 mL) to 1 g (2 vials of 5 mL) administered intravenously, slowly (approximately 1 mL/min), 2–3 times daily.

For generalized fibrinolysis, tranexamic acid should be administered intravenously, slowly, at a dose of 1 g (2 vials of 5 mL) or 15 mg/kg body weight every 6–8 hours, with an administration rate of 1 mL/min.

Dosing in patients with renal impairment. In patients with renal insufficiency, tranexamic acid is contraindicated in cases of severe renal impairment. For patients with mild or moderate renal impairment, the dosage of tranexamic acid should be reduced according to serum creatinine levels:

Table 1

Dosing in patients with hepatic impairment. Dose adjustment is generally not required in patients with impaired liver function.

Use in elderly patients. Dose adjustment is usually not necessary unless there are signs of renal insufficiency.

Administration method

Administration must strictly follow a defined regimen — slow intravenous injection (injection/infusion) at a maximum rate of 1 mL per minute.

Tranexamic acid must not be administered intramuscularly.

The medicinal product Evronex may be mixed with electrolyte solutions, amino acids, carbohydrates, and dextran solutions.

Heparin may be added to Evronex.

Evronex is intended for single use only. Unused solution or waste material should be discarded.

TRANEXAMIC ACID MUST BE ADMINISTERED INTRAVENOUSLY ONLY and must not be administered intrathecally or epidurally (see sections "Contraindications" and "Special precautions").

To reduce the risk of fatal medication errors due to incorrect route of administration of tranexamic acid, it is strongly recommended to label syringes containing tranexamic acid (see sections "Contraindications" and "Special precautions").

Children.

The maximum single dose for children aged 1 year and older is 10 mg/kg body weight. For children aged 1 year and older, use is recommended according to current approved therapeutic indications as described in the section "Indications", with a dosage of approximately 20 mg/kg/day. However, data on efficacy, safety, and dosing specifics in children according to these recommendations are limited.

The aspects of efficacy, dosing characteristics, and safety of tranexamic acid use in children who have undergone cardiac surgery have not been fully investigated.

Overdose.

Cases of overdose have not been reported. Signs and symptoms may include dizziness, headache, hypotension, and seizures. Seizures have also been observed to generally occur with higher infusion rates and increased doses.

In case of overdose, symptomatic treatment should be provided.

Adverse reactions

Below is a list of adverse reactions classified by organ systems according to MedDRA (Medical Dictionary for Regulatory Activities). Within each organ system, adverse reactions are ranked by frequency. Within each frequency group, reactions are listed in decreasing order of occurrence.

Table 2

Reporting of suspected adverse reactions

Reporting of adverse reactions after registration of a medicinal product is important. It allows continuous monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals and patients or their legal representatives should report all suspected adverse reactions and lack of efficacy of the medicinal product via the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua.

Shelf life. 2 years.

Storage conditions. Store in the original packaging at a temperature not exceeding 25 ºC. Keep out of the reach of children.

Incompatibilities. Tranexamic acid for injection must not be added to blood for transfusion or to injectable solutions containing penicillin group drugs.

Packaging. 5 ml in a vial; 5 vials in a cardboard box.

Prescription status. Prescription only.

Manufacturer.

Steril-Jen Life Sciences (P) Ltd.

Address of the manufacturer and location of its business operations.

No. 45, Mangalam Main Road, Villianur Commune, Puducherry, 605 110, India.