Tranexamic acid

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT TRANEXAMIC ACID (TRANEXAMIC ACID)

Composition:

Active substance: tranexamic acid;

1 ml of solution contains tranexamic acid calculated as 100% anhydrous substance – 100 mg;

Excipient: water for injections.

Pharmaceutical form. Injection solution.

Main physicochemical characteristics: clear colorless or light brown liquid.

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 is formed involving tranexamic acid and plasminogen; tranexamic acid binds to plasminogen during 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.

Children

In children aged 1 year and older. A literature review identified 12 studies on efficacy in pediatric cardiac surgery, involving 1073 children, of whom 631 received tranexamic acid. Most of these were placebo-controlled. The study population was heterogeneous in terms of age, types of surgery, and dosing regimens. Study results indicate that tranexamic acid reduces blood loss and decreases the need for blood products in pediatric cardiac surgery involving cardiopulmonary bypass (CPB), where there is a high risk of bleeding, particularly in cyanotic patients or those undergoing repeat surgery. The most commonly used dosing regimen is as follows:

• Initial dose (loading dose) – bolus infusion of 10 mg/kg, administered after induction of anesthesia and before skin incision;
• Continuous infusion at 10 mg/kg/hour, or injection into the CPB pump at a dose adapted to the CPB procedure, or according to patient body weight at 10 mg/kg, or according to the CPB pump volume; the final injection of 10 mg/kg is administered at the end of CPB.

Although only a small number of patients have been studied, limited data suggest that continuous infusion is preferable, as it maintains therapeutic plasma concentrations throughout the surgery.

No specific studies on dose effect or pharmacokinetics of tranexamic acid have been conducted in children.

Pharmacokinetics.

After intravenous administration of a 1 g dose, the plasma concentration–time curve shows a triexponential decline, with an elimination half-life of approximately 2 hours for the terminal phase. The initial volume of distribution is approximately 9 to 12 liters. Renal excretion is the main elimination pathway, occurring via glomerular filtration. Total renal clearance equals total plasma clearance (110–116 mL/min), and more than 95% of the dose is excreted unchanged in urine. Elimination of tranexamic acid reaches approximately 90% within 24 hours after intravenous administration of 10 mg/kg body weight.

Antifibrinolytic concentrations of tranexamic acid are maintained in various tissues for approximately 17 hours, and in blood serum – up to 7–8 hours.

Tranexamic acid crosses the placenta. After intravenous administration of 10 mg/kg to pregnant women, the concentration in umbilical cord blood is approximately 30 mg/L, which is as high as in maternal blood. Tranexamic acid rapidly diffuses into synovial fluid and synovial membrane. Concentrations in synovial fluid are similar to those in serum. The biological half-life of tranexamic acid in synovial fluid is approximately 3 hours.

Concentrations of tranexamic acid in several other tissues are lower than in blood. The concentration in breast milk is approximately 1/100 of the maximum serum concentration. The concentration of tranexamic acid in cerebrospinal fluid is approximately 1/10 of the plasma concentration. The drug penetrates into the aqueous humor of the eye, where its concentration is approximately 1/10 of the plasma concentration.

Clinical characteristics.

Indications.

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

Specific indications include:

− bleeding caused by increased systemic or local fibrinolysis, such as:

• menorrhagia and metrorrhagia;
• gastrointestinal bleeding;
• hemorrhagic disorders of the urinary tract occurring following surgical intervention on the prostate gland or as a result of surgical procedures or interventions on the urinary tract;

− otorhinolaryngological (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 tranexamic acid or to any excipient.
• Acute venous or arterial thrombosis.
• Fibrinolytic states following consumption coagulopathy, except in cases with predominant activation of the fibrinolytic system associated with acute severe bleeding.
• Severe renal insufficiency (risk of accumulation).
• History of seizures.
• Intrathecal and intraventricular administration, intracerebral use (risk of cerebral edema and seizures).

Interaction with other medicinal products and other forms of interaction.

Studies on interactions between tranexamic acid and other medicinal products have not been conducted. Concomitant treatment with anticoagulants should be carried out under strict supervision of a physician experienced in this field. Medicinal products affecting hemostasis should be prescribed with caution to patients receiving tranexamic acid. There is a theoretical risk of increased thrombotic potential, for example, when estrogens are used. In addition, the antifibrinolytic effect of the drug can be antagonized by thrombolytic agents.

Special precautions for use.

Strict adherence to the indications and methods of use specified above is required:

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

Seizures. Cases of seizures associated with tranexamic acid treatment have been reported. Most such cases during coronary artery bypass graft (CABG) surgery were reported after high-dose intravenous (i.v.) injection of tranexamic acid. When the recommended lower doses of tranexamic acid are used, the incidence of postoperative seizures is the same as in patients who did not receive treatment.

Visual disturbances. Possible visual disorders, including blurred vision, impaired visual acuity, and color vision disturbances, should be considered, and if necessary, treatment should be discontinued. Regular ophthalmological examinations (eye examination including visual acuity, color vision, fundoscopy, and visual fields) are recommended during continuous long-term use of tranexamic acid. In the presence of pathological ophthalmological findings, particularly retinal disorders, the physician, after consultation with a specialist, should decide on a case-by-case basis whether continued long-term use of tranexamic acid is necessary.

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

Thromboembolic effects. Risk factors for thromboembolic disease should be considered before administering tranexamic acid. Tranexamic acid should be prescribed to patients with a history of thromboembolic disorders or to patients with a high familial incidence of thromboembolic events (patients at high risk of thrombophilia) only if there are strong medical indications, after consultation with a physician experienced in the field of hemostasis, and under strict medical supervision (see section "Contraindications"). Tranexamic acid should be prescribed with caution to patients receiving oral contraceptives due to the increased risk of thrombosis (see section "Special precautions for use").

Disseminated intravascular coagulation (DIC). Tranexamic acid is generally not recommended for patients with DIC. If tranexamic acid is administered, it should be restricted to patients with predominant activation of the fibrinolytic system accompanied by acute severe bleeding. The typical hematological profile includes: shortened euglobulin clot lysis time; prolonged prothrombin time; decreased plasma levels of fibrinogen, factors V and VIII, plasminogen, fibrinolysin, and α-2-macroglobulin; normal levels of P and P complex in blood plasma (i.e., factors II [prothrombin], VIII, and X); elevated plasma levels of fibrinogen degradation products; and normal platelet count. The above assumes that the underlying disease itself does not alter the various components of this profile. In such acute cases, a single dose of 1 g of tranexamic acid is often sufficient to stop bleeding. The use of tranexamic acid in DIC syndrome should be considered only if appropriate hematological laboratory facilities and expertise are available.

Use during pregnancy or breastfeeding.

Women of childbearing potential should use effective contraceptive methods during treatment.

Pregnancy. Data on the use of tranexamic acid in pregnant women are lacking or limited. Although animal studies do not indicate teratogenic effects, the use of tranexamic acid is not recommended during the first trimester of pregnancy.

Limited clinical data on the use of tranexamic acid for various bleeding conditions during the second and third trimesters have not shown harmful effects on the fetus. Tranexamic acid should be used during pregnancy only if the expected benefit outweighs the potential risk.

Breastfeeding. Tranexamic acid passes into breast milk. Therefore, breastfeeding is not recommended.

Ability to affect 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.

The use of the medicinal product is strictly limited to slow intravenous administration (injection or infusion).

Adults. Unless otherwise prescribed, the recommended doses are as follows:

1. Standard treatment for local fibrinolysis:

from 0.5 g (1 vial of 5 ml) to 1 g (2 vials of 5 ml) of tranexamic acid by slow intravenous injection or infusion (= 1 ml/min) 2–3 times daily.

2. Standard treatment for general fibrinolysis:

1 g (2 vials of 5 ml) of tranexamic acid by slow intravenous injection or infusion (= 1 ml/min) every 6–8 hours, equivalent to 15 mg/kg body weight (BW).

Renal impairment. In severe renal insufficiency, which poses a risk of accumulation, the use of tranexamic acid is contraindicated. For patients with mild to moderate renal impairment, the dose of tranexamic acid should be reduced according to serum creatinine levels:

Hepatic impairment. Dose adjustment is not required in patients with hepatic impairment.

Elderly patients. Dose reduction is not required if there are no signs of renal insufficiency.

Method of administration

Administration is strictly limited to slow intravenous injection or infusion at a maximum rate of 1 ml per minute.

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

Heparin may be added to the medicinal product.

Diluted solutions should be used immediately after dilution.

Tranexamic acid should not be administered intramuscularly.

Children.

For children aged 1 year and older, when used according to approved indications, the dose is 20 mg/kg/day. However, data on efficacy, safety, and dosing for these indications are limited.

The efficacy, safety, and dosing of tranexamic acid in children undergoing cardiac surgery have not been fully established. Limited available data are provided in the "Pharmacodynamics" section.

Overdose.

Cases of overdose have not been observed. Signs and symptoms may include dizziness, headache, hypotension, and seizures. Seizures generally occur more frequently with increased doses.

In case of overdose, provide supportive therapy.

Adverse reactions.

Adverse reactions reported in clinical trials and post-marketing experience are listed below by organ system class.

Adverse reactions are presented according to the MedDRA system organ class. Within each organ system class, adverse reactions are ordered by frequency. Within each frequency group, adverse reactions are presented in decreasing order of severity.

Reporting of suspected adverse reactions

Reporting of adverse reactions after drug registration is of great importance. It allows monitoring of the benefit-risk balance of this medicinal product. Medical and pharmaceutical professionals, as well as patients or their legal representatives, should report all cases of suspected adverse reactions and lack of drug efficacy through 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 °C. Keep out of reach of children.

Incompatibility.

This medicinal product should not be added to blood for transfusion or to injectable penicillin solutions.

Packaging. 5 ml in an ampoule, 5 ampoules in a blister, 1 or 2 or 10 blisters in a carton.

Prescription status. Prescription only.

Manufacturer. Private joint-stock company "Lekhim-Kharkiv".

Manufacturer's address and place of business.

36 Severin Pototskoho Street, Kharkiv, Kharkiv region, 61115, Ukraine.