Tranexam

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT TRANEKSAM (TRANEKSAM)

Composition:

Active substance: tranexamic acid;

1 ml of solution contains 50 mg of tranexamic acid;

Excipient: water for injections.

Pharmaceutical form. Injection solution.

Main physicochemical properties: transparent or nearly transparent, colorless or slightly light-brownish solution.

Pharmacotherapeutic group. Antihemorrhagic agents. Antifibrinolytics. Amino acids. Tranexamic acid.

ATC code B02A A02.

Pharmacological Properties.

Pharmacodynamics.

An antifibrinolytic agent. Tranexamic acid specifically inhibits the activation of plasminogen (profibrinolysin) and its conversion into plasmin (fibrinolysin). It exerts local and systemic hemostatic effects in bleeding associated with increased fibrinolysis (thrombocyte disorders, menorrhagia). Additionally, by suppressing the formation of kinins and other active peptides involved in allergic and inflammatory reactions, tranexamic acid demonstrates anti-inflammatory, antiallergic, anti-infective, and antitumor effects. Experimental evidence has confirmed intrinsic analgesic activity of tranexamic acid, as well as its ability to enhance the analgesic effect of opioids.

Pediatric population (children aged 1 year and older)

Twelve studies on the efficacy of tranexamic acid in pediatric cardiac surgery involving 1073 children, of whom 631 received tranexamic acid, have been described in the scientific literature. Most patients were evaluated in comparison with a placebo control group. The studied population was heterogeneous with respect to age, type of surgical intervention, and dosing regimens. 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) during high-risk bleeding procedures, particularly in "cyanotic" patients (with significant circulatory impairment) and patients undergoing reoperation. The most appropriate dosing regimen has been established as follows:

• Initial administration (loading dose): bolus infusion of 10 mg/kg administered after induction of anesthesia and before skin incision;

• Continuous administration via infusion at 10 mg/kg/h or injection into the CPB pump adapter at a dose adjusted for the specific surgical procedure or calculated according to patient body weight at 10 mg/kg, or administration into the CPB pump adapter followed by a final injection of 10 mg/kg at the end of the surgical procedure involving CPB.

Some data suggest that continuous infusion may be more favorable, as it maintains therapeutic plasma concentrations throughout the surgery. No specific dose-response or pharmacokinetic studies have been conducted in children.

Pharmacokinetics.

Absorption.

Maximum plasma concentration of tranexamic acid is rapidly achieved after short-term intravenous infusion, after which plasma concentrations decline in a multi-exponential manner.

Distribution.

Distributed relatively uniformly in tissues (except cerebrospinal fluid, where concentration is about 1/10 of plasma levels); crosses the blood-brain and placental barriers, and is excreted into breast milk (approximately 1% of maternal plasma concentration). Detected in seminal fluid, where it reduces fibrinolytic activity without affecting spermatozoa migration. Initial volume of distribution is 9–12 L. Less than 3% binds to plasma proteins (plasminogen).

Antifibrinolytic concentrations in various tissues are maintained for up to 17 hours, in plasma for up to 7–8 hours. A minor portion undergoes metabolism. The concentration-time curve is triphasic, with a terminal half-life of 2 hours. Total renal clearance equals plasma clearance (7 L/h).

Excreted by the kidneys (primarily via glomerular filtration)—approximately 95% unchanged within the first 12 hours.

Two metabolites of tranexamic acid have been identified (N-acetylated and deaminated). In patients with impaired renal function, there is a risk of accumulation of tranexamic acid.

Special patient groups.

Plasma concentration increases in patients with renal impairment. No specific pharmacokinetic studies have been conducted in children.

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 arising from surgical intervention 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 (uterine bleeding, cervical conization);
• 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 listed in the excipients section; subarachnoid hemorrhage; severe renal insufficiency (risk of accumulation); coagulopathy due to disseminated intravascular coagulation (DIC syndrome) without significant fibrinolytic activation; acute arterial or venous thrombosis; history of seizures; fibrinolytic states following coagulopathy due to exhaustion, except in cases of excessive activation of the fibrinolytic system during acute severe bleeding; intrathecal and intraventricular applications (risk of cerebral edema and seizures); color vision disturbances; macroscopic hematuria; high risk of thrombosis, thrombophlebitis, myocardial infarction.

Interaction with other medicinal products and other types of interactions.

Pharmaceutically incompatible with blood products, solutions containing penicillin, hypertensive agents (norepinephrine, desoxynorepinephrine hydrochloride), tetracyclines, dipyridamole, diazepam. Incompatible with urokinase, except when used as an antidote following overdose of the latter.

There is a risk of increased thrombus formation when used concomitantly with estrogens. Do not use together with thrombolytics. Tranexamic acid is incompatible with metaraminol bitartrate.

High-potency prothrombin complex concentrates and antifibrinolytic agents, antithrombin coagulation complexes should not be administered simultaneously with tranexamic acid. The combination of chlorpromazine and tranexamic acid should be avoided in patients with subarachnoid hemorrhage; this may lead to cerebral vasospasm and cerebral ischemia, and possibly to reduced cerebral blood flow; the pharmacological properties of both drugs may contribute to the development of vasospasm and cerebral ischemia in these patients.

Special precautions for use.

Do not administer intramuscularly!

Intravenous injections should be administered very slowly (maximum 1 mL per minute).

Risk factors for thromboembolic disorders should be evaluated prior to administration. Patients with thromboembolic disease may be at increased risk of venous or arterial thrombosis. Cases of venous and arterial thrombosis or thromboembolism have been reported in patients receiving tranexamic acid.

Seizures have been reported during the use of tranexamic acid. Most of these cases occurred after intravenous administration of high doses of tranexamic acid during coronary artery bypass graft (CABG) surgery. When recommended low doses of tranexamic acid are used, the incidence of postoperative seizures is similar to that in patients not receiving tranexamic acid.

Visual disturbances, including blurred vision and color vision disturbances, may occur. If these symptoms appear, treatment should be discontinued. In addition, cases of central retinal artery occlusion and central retinal vein thrombosis have been reported. After consultation with an ophthalmologist, the physician should determine the necessity of prolonged use of the injection solution in patients with ophthalmological pathological conditions, especially retinal disorders.

Do not prescribe to patients taking oral contraceptives or estrogens due to increased risk of thrombosis.

Tranexamic acid should not be administered concomitantly with Factor IX complex or antithrombin-coagulation complexes, as this may increase the risk of thrombosis formation.

Patients with disseminated intravascular coagulation (DIC) requiring treatment with tranexamic acid must be under the supervision of a physician experienced in managing such conditions.

The use of tranexamic acid should be restricted to patients with predominant activation of the fibrinolytic system in cases of acute severe bleeding.

It has been established that the characteristic hematological profile in these conditions includes: reduced 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; elevated plasma levels of fibrinogen degradation products; and normal platelet count. The above suggests that, in the presence of an underlying disease, various elements of this profile may not change independently. 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 DIC should be considered only when appropriate hematological laboratory support and clinical experience are available.

Tranexamic acid has been detected in semen at fibrinolytic concentrations, but it does not affect sperm motility. Clinical studies have not revealed any effect on fertility.

Use with caution in thrombohemorrhagic complications (in combination with heparin and indirect anticoagulants), thrombosis (deep vein thrombophlebitis, thromboembolic syndrome, myocardial infarction) or risk of their development, color vision disturbances, hematuria from the upper urinary tract (possible obstruction by a blood clot), and renal impairment (risk of accumulation).

An ophthalmological examination assessing visual acuity, color vision, and fundus condition should be performed before and during treatment.

Use during pregnancy or breastfeeding.

Women of reproductive age should use effective contraception during treatment.

Clinical data on the use of tranexamic acid in pregnant women are limited or absent. Administration of tranexamic acid during the first trimester of pregnancy is not recommended, although animal studies do not indicate teratogenic effects. Limited clinical data are available on the use of tranexamic acid in various clinical hemorrhagic conditions during the second and third trimesters of pregnancy, in which no harmful effects on the fetus have been identified. Tranexamic acid should be used during pregnancy only if the expected benefit to the mother outweighs the potential risk to the fetus.

Tranexamic acid passes into breast milk; therefore, breastfeeding is not recommended.

There are no clinical data on the effect of tranexamic acid on fertility.

Ability to affect reaction speed when driving or operating machinery.

During the use of Tranexam in usual doses, dizziness and arterial hypotension, as well as impaired color vision and visual clarity, may occur. Therefore, during treatment, patients should refrain from driving or operating machinery.

Administration and Dosage.

Intravenous (infusion, bolus).

The dosage regimen is individual and depends on the clinical situation.

Adults.

For local fibrinolysis, it is recommended to administer the drug starting from 500 mg (2 vials of 5 ml) up to 1 g (4 vials of 5 ml) intravenously, slowly (administration rate 1 ml/min) 2–3 times daily.

For generalized fibrinolysis, administer tranexamic acid intravenously, slowly, at a dose of 1 g (4 vials of 5 ml) or 15 mg/kg body weight every 6–8 hours, at an administration rate of 1 ml/min.

During prostatectomy or bladder surgery, administer 1 g intraoperatively, followed by 1 g every 8 hours for 3 days, then switch to oral tablet form until macrohematuria resolves.

If there is a high risk of bleeding, in systemic inflammatory response, it is recommended to administer the drug at a dose of 10–11 mg/kg within 20–30 minutes before the procedure.

For patients with coagulopathy prior to tooth extraction, administer the drug at a dose of 10 mg/kg body weight; after tooth extraction, prescribe oral tablet form.

Patients with renal impairment.

In renal dysfunction, there is a risk of tranexamic acid accumulation.

The use of tranexamic acid is contraindicated in patients with severe renal insufficiency or renal insufficiency that increases the risk of accumulation. For patients with mild to moderate renal insufficiency, the dose of tranexamic acid should be reduced depending on serum creatinine levels:

Table 1

Elderly patients.

In the absence of renal excretory function impairment, dose adjustment is not required.

Patients with hepatic impairment.

Dose adjustment is not required in patients with hepatic impairment.

Use in children.

Children aged 1 year and older may be treated when indicated (see section "Indications"); the maximum daily dose is 20 mg/kg body weight. However, data on efficacy, safety, and dosing specifics when used in children for the indicated conditions are limited.

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

Method of administration.

Administration must strictly follow a limited regimen – slow intravenous injection/infusion at a maximum rate of 1 ml per minute.

The drug can be administered with isotonic sodium chloride solution, glucose solution, 20% fructose solution, 10% invertase solution, dextrin 40 or 70, and Ringer's solution. Heparin may be added during intravenous drip infusion. The combination with heparin should be used with caution in patients with coagulation disorders.

Children.

The maximum single dose for children aged 1 year and older is 10 mg/kg body weight. The maximum daily dose is 20 mg/kg body weight.

Overdose.

Cases of overdose have not been reported.

Possible symptoms include nausea, vomiting, dizziness, headache, seizures, arterial hypotension, and orthostatic hypotension. Treatment is symptomatic; forced diuresis is indicated. Maintenance of water and electrolyte balance is required.

Adverse Reactions

The frequency of adverse reactions is defined as follows: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1000 to < 1/100); rare (≥ 1/10000 to < 1/1000); very rare (< 1/10000); frequency not known (cannot be estimated due to insufficient data).

Immune system disorders: frequency not known – allergic reactions (rash, pruritus, urticaria), allergic dermatitis, hypersensitivity reactions, including anaphylaxis.

Nervous system disorders: frequency not known – seizures, particularly in cases of incorrect use.

Gastrointestinal disorders: common – dyspeptic symptoms (anorexia, nausea, vomiting, heartburn, diarrhea, discomfort in the stomach and intestines).

Cardiac disorders: frequency not known – tachycardia, chest pain, arterial or venous embolism, hypotension with or without loss of consciousness (after rapid intravenous injection or in exceptional cases after oral administration).

Eye disorders: frequency not known – color vision disturbances, blurred vision.

Blood and lymphatic system disorders: frequency not known – thrombosis or thromboembolism (risk of development is minimal).

Renal disorders: frequency not known – acute cortical necrosis of the kidneys.

General disorders: frequency not known – seizures, dizziness, weakness, somnolence, malaise.

Skin and subcutaneous tissue disorders: uncommon – allergic dermatitis.

Reporting of suspected adverse reactions.

Reporting suspected adverse reactions after authorization of the medicinal product is important. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals and patients, as well as their legal representatives, are encouraged to report all suspected adverse reactions and lack of efficacy to the State Expert Center of the Ministry of Health of Ukraine via the following link: https://aisf.dec.gov.ua/

Shelf life. 3 years.

Storage conditions. Store at a temperature not exceeding 25 °C. Keep out of reach of children.

Incompatibilities.

Incompatible with blood products, solutions containing penicillin, hypertensive agents (norepinephrine, deoxyepinephrine hydrochloride), tetracyclines, dipyridamole, diazepam. Incompatible with urokinase, except when used as an antidote following urokinase overdose.

Packaging. 5 ml in a vial, 5 or 10 vials per pack.

Prescription status. Prescription only.

Manufacturer.

Private Joint-Stock Company "Lekhym-Kharkiv".

Manufacturer's location and address of business activity.

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