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 equivalent to 100 % anhydrous substance – 50 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 forms involving tranexamic acid and plasminogen; tranexamic acid binds to plasminogen during conversion involving plasmin. The activity of the complex of tranexamic acid and plasmin 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 trials. The study population was heterogeneous in terms of age, types of surgery, and dosing regimens. Results from studies on the use of tranexamic acid indicate reduced blood loss and decreased need for blood products in pediatric cardiac surgery involving cardiopulmonary bypass (CPB), where there is a high risk of bleeding, especially in cyanotic patients or those undergoing repeat surgery. The most commonly used dosing regimen is:

• 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 administration into the CPB pump at a dose adapted to the CPB procedure, or according to patient body weight at a dose of 10 mg/kg, or according to the CPB pump volume, with the final 10 mg/kg dose 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 relationship or pharmacokinetics of tranexamic acid have been conducted in children.

Pharmacokinetics.

After intravenous administration of a 1 g dose, the plasma concentration-time curve is characterized by 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. Excretion of tranexamic acid amounts to 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 of the substance 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 surgery on the prostate gland or as a result of surgical interventions or procedures 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 accompanied by 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 must be performed 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, e.g., when estrogens are used. In addition, the antifibrinolytic effect of the drug can be antagonized by fibrinolytic (thrombolytic) agents.

Special precautions for use.

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

• Intravenous injections or infusions should be administered very slowly (maximum 1 mL per minute).
• Intramuscular administration of tranexamic acid is not permitted.

Seizures. Cases of seizures associated with tranexamic acid treatment have been reported. During coronary artery bypass graft (CABG) surgery, most such cases were reported after intravenous (i.v.) injection of high-dose tranexamic acid. When 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 case of pathological ophthalmological findings, particularly retinal disorders, the physician should, after consultation with a specialist, 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 ureteral obstruction.

Thromboembolic effects. Risk factors for thromboembolic disorders should be considered before administering tranexamic acid. Tranexamic acid should be prescribed to patients with a history of thromboembolic disorders or to those with a family history of increased thromboembolic events (patients at high risk of thrombophilia) only if there is a strong medical indication, after consultation with a physician experienced in hemostasis, and under strict medical supervision (see section "Contraindications"). Tranexamic acid should be prescribed with caution to patients taking oral contraceptives due to an increased risk of thrombosis.

Disseminated intravascular coagulation (DIC). Tranexamic acid is generally not recommended for patients with DIC. If tranexamic acid is prescribed, it should be limited to those with predominant activation of the fibrinolytic system accompanied by acute, severe bleeding. Characteristically, the hematological profile is approximately as follows: shortened euglobulin clot lysis time; prolonged prothrombin time; decreased plasma levels of fibrinogen, factors V and VIII, plasminogen, fibrinolysin, and α-2-macroglobulin; normal plasma levels of P and P complex, i.e., factors II (prothrombin), VIII, and X; increased plasma levels of fibrinogen degradation products; 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 reproductive age should use effective contraceptive methods during treatment.

Pregnancy. Data on the use of tranexamic acid in pregnant women are absent 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 in various bleeding conditions during the second and third trimesters have not revealed any 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 following doses are recommended:

1. Standard treatment of local fibrinolysis:

from 0.5 g (2 vials of 5 ml) to 1 g (4 vials of 5 ml) of tranexamic acid by slow intravenous injection or infusion (= 1 ml/min), 2–3 times daily.

2. Standard treatment of general fibrinolysis:

1 g (4 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 leading to 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 necessary if there are no signs of renal insufficiency.

Method of administration. Administration is strictly limited to slow intravenous injection or infusion at a rate of no more than 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 must not be administered by intramuscular injection.

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. Available limited data are presented in the "Pharmacodynamics" section.

Overdose.

Cases of overdose have not been observed. Signs and symptoms may include dizziness, headache, hypotension, and convulsions. Convulsions usually occur more frequently with increased doses. In case of overdose, supportive therapy should be administered.

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 class, adverse reactions are listed by frequency. Within each frequency group, adverse reactions are presented in order of decreasing severity.

Reporting of suspected adverse reactions

Reporting of adverse reactions after registration of the medicinal product is of great importance. It allows monitoring of the benefit-risk balance of the use of this medicinal product. Medical and pharmaceutical personnel, as well as patients or their legal representatives, should report all cases of suspected adverse reactions and lack of efficacy of the medicinal product via the Automated Information System for Pharmacovigilance 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 solutions of penicillin.

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

Prescription status. Prescription only.

Manufacturer. Private Joint-Stock Company "Lekhym-Kharkiv".

Manufacturer's address and place of business.

36 Severina Pototskoho Street, Kharkiv, Kharkiv Oblast, 61115, Ukraine.