Tranexam^® (Tablets, Solution) Instructions for Use

ATC Code

B02AA02 (Tranexamic acid)

Active Substance

Tranexamic acid (Rec.INN registered by WHO)

Clinical-Pharmacological Group

Hemostatic agent. Fibrinolysis inhibitor – inhibitor of plasminogen to plasmin conversion

Pharmacotherapeutic Group

Hemostatic agent, fibrinolysis inhibitor

Pharmacological Action

Tranexamic acid is an antifibrinolytic agent that specifically inhibits the activation of profibrinolysin (plasminogen) and its conversion to fibrinolysin (plasmin). It has local and systemic hemostatic effects in bleeding associated with increased fibrinolysis, as well as anti-inflammatory, anti-allergic, anti-infective, and anti-tumor effects due to the suppression of the formation of kinins and other active peptides involved in allergic and inflammatory reactions.

Experimental studies have confirmed the intrinsic analgesic activity of tranexamic acid, as well as a supra-additive potentiating effect on the analgesic activity of opiates.

Tranexamic acid at a concentration of 1 mg/ml does not affect platelet aggregation in vitro; at concentrations up to 10 mg/ml of blood, it does not affect platelet count, blood clotting time, or various clotting factors in whole blood or citrated blood of a healthy person. At the same time, Tranexamic acid at both 1 mg/ml and 10 mg/ml concentrations prolongs thrombin time.

Data from preclinical studies indicate that tranexamic acid has anti-carcinogenic and anti-angiogenic properties.

Pharmacokinetics

It is distributed relatively evenly in tissues (with the exception of cerebrospinal fluid, where the concentration is 1/10 of the plasma concentration); it penetrates the placental and blood-brain barrier, into breast milk (about 1% of the concentration in maternal plasma). It is found in seminal fluid, where it reduces fibrinolytic activity but does not affect sperm migration.

The initial V_d is 9-12 L. Binding to plasma proteins (profibrinolysin) is less than 3%. In blood, about 3% is bound to protein (plasminogen).

The concentration in cerebrospinal fluid is 1/10 of the plasma concentration. Total renal clearance is equal to plasma clearance.

Antifibrinolytic concentration in various tissues persists for 17 hours, in plasma for up to 7-8 hours.

A small part is metabolized. The concentration-time curve has a triphasic shape with a T_1/2 in the terminal phase of 2 hours. Total renal clearance is equal to plasma clearance (7 L/h).

It is excreted by the kidneys (the main route is glomerular filtration) – more than 95% unchanged within the first 12 hours. Two metabolites of tranexamic acid have been identified: N-acetylated and deaminated derivatives.

Pharmacokinetics in special patient groups

In case of impaired renal function, there is a risk of accumulation of tranexamic acid.

Indications

Prevention and treatment of bleeding due to generalized or local fibrinolysis in adults and children aged 1 year and older, including

• Menorrhagia and metrorrhagia;
• Gastrointestinal bleeding;
• Bleeding after surgical interventions on the prostate gland and urinary tract;
• Bleeding during surgical interventions in the nasal cavity, mouth, and pharynx (adenoidectomy, tonsillectomy, tooth extraction);
• Bleeding during thoracic, abdominal, and other extensive surgical interventions (including cardiac surgery);
• Obstetric and gynecological bleeding (including bleeding during gynecological surgical interventions);
• Bleeding caused by the use of fibrinolytic drugs.

ICD codes

Dosage Regimen

Solution

The drug is administered intravenously (by drip or slow bolus). The rate of administration is 1 ml/min (50 mg/min). Rapid intravenous administration should be avoided.

For administration of the drug at a rate of 50 mg/min

• Undiluted tranexamic acid solution (100 mg/ml) is administered at a rate of 0.5 ml/min;
• A 1% solution (10 mg/ml) can be administered at a rate of 5 ml/min (1 g of tranexamic acid in 100 ml of infusion solution).

Tranexamic acid solution is compatible with most infusion solutions (see the “Drug Interactions” section).

Menorrhagia and metrorrhagia, gastrointestinal bleeding 500 mg (2 ampoules of 5 ml) 2-3 times/day from the onset of bleeding until it stops.

Treatment of bleeding after surgical interventions on the prostate gland and urinary tract : 1000 mg (4 ampoules of 5 ml) 3 times/day from the onset of bleeding until it stops.

Prevention and treatment of bleeding during surgical interventions in the nasal cavity, mouth, and pharynx 10-15 mg/kg body weight every 6-8 hours until bleeding stops.

Prevention and treatment of bleeding during thoracic, abdominal, and other major surgical interventions 15 mg/kg body weight every 6-8 hours until bleeding stops.

Prevention and treatment of bleeding during cardiac surgery loading dose of 15 mg/kg after induction of anesthesia before the start of surgery, then intravenous infusion at a rate of 4.5 mg/kg/h throughout the surgery; it is recommended to add tranexamic acid at a dose of 0.6 mg/kg to the cardiopulmonary bypass machine.

Treatment of obstetric and gynecological bleeding (including bleeding during gynecological surgical interventions) 15 mg/kg body weight every 6-8 hours from the onset of bleeding until it stops.

Treatment of bleeding caused by the use of fibrinolytic drugs 10 mg/kg body weight every 6-8 hours from the onset of bleeding until it stops.

If long-term (more than 48 hours) hemostatic therapy is necessary, it is recommended to use tranexamic acid preparations in tablet form.

Children over 1 year old

Experience with the use of tranexamic acid preparations in children is limited. The recommended dose of the drug for the treatment of bleeding due to local and generalized fibrinolysis is 20 mg/kg/day.

In patients with mild to moderate impaired renal excretory function, dose adjustment and frequency of administration of tranexamic acid are necessary

In patients with impaired liver function, dose adjustment is not required.

In elderly patients without renal failure, dose adjustment is not required.

Tablets

Orally, regardless of meals.

Short-term treatment of bleeding due to increased fibrinolysis: the recommended standard dose of tranexamic acid is 15-25 mg/kg body weight, on average 1000-1500 mg 2-3 times/day.

For prostatectomy and surgical interventions on the bladder: 1000 mg 6 hours before surgery, then 1000 mg 3-4 times/day until macrohematuria disappears. The use of the drug for more than 2 weeks after surgery is not recommended.

For menorrhagia the recommended dose is 1000 mg 3 times/day until menorrhagia ceases, but not more than 4 days. In case of profuse bleeding, the dose of the drug may be increased, but the total daily dose should not exceed 4000 mg. Treatment with tranexamic acid should not be started before the onset of menstrual bleeding. In clinical studies, Tranexamic acid was not used for more than three consecutive menstrual cycles.

For recurrent nosebleeds : 1000 mg 3 times/day for 7 days.

After cervical conization surgery : 1500 mg 3 times/day for 12 days after surgery.

For traumatic hyphema 1000-1500 mg 3 times/day (target dose 25 mg/kg body weight) for 7 days.

Patients with hemophilia: the drug is prescribed orally at a dose of 25 mg/kg body weight 2 hours before tooth extraction, and then 1000-1500 mg 3 times/day for 6-8 days. Coagulation factor VIII or IX preparations should be prescribed simultaneously.

For hereditary angioedema: 1000-1500 mg 2-3 times/day. If the patient can anticipate an exacerbation of the disease, the drug can be taken intermittently depending on the presence of prodromal symptoms. In other cases, the drug should be taken continuously.

Bleeding during pregnancy : 250-500 mg 3-4 times/day until complete cessation of bleeding. The average duration of the treatment course is 7 days.

Use of the drug in special patient groups

In patients with mild to moderate impaired renal excretory function, dose adjustment and frequency of administration of tranexamic acid are necessary

In patients with impaired liver function, dose adjustment is not required.

In elderly patients without renal failure, dose adjustment is not required.

Data on the efficacy and safety of tranexamic acid preparations in children are limited. In children, Tranexamic acid is prescribed at a dose of 25 mg/kg body weight 2-3 times/day.

Actions in case of a missed dose

If one dose is missed, the next dose of the drug should be taken at the scheduled time. A double dose of the drug should not be taken after missing a scheduled dose.

Adverse Reactions

The frequency of adverse drug reactions is determined according to the WHO classification: very common (≥1/10), common (≥1/100, <1/10), uncommon (≥1/1000, <1/100), rare (≥1/10000, <1/1000), very rare (<1/10000), frequency unknown (cannot be estimated from the available data).

From the digestive system common – nausea, vomiting, diarrhea (symptoms resolve when the dose is reduced).

From the skin and subcutaneous tissues rare – skin allergic reactions, including allergic dermatitis.

From the organ of vision rare – visual disturbances, including impaired color perception, retinal vessel thrombosis.

From the cardiovascular system rare – thromboembolic complications, pronounced decrease in blood pressure (usually due to excessively rapid IV administration); very rare – arterial and venous thromboses of various locations; frequency unknown – acute myocardial infarction, cerebral artery thrombosis, carotid artery thrombosis, stroke, deep vein thrombosis of the lower extremities, pulmonary embolism, renal artery thrombosis with the development of cortical necrosis and acute renal failure, occlusion of aortocoronary bypass, thrombosis of the central retinal artery and vein.

From the immune system very rare – hypersensitivity reactions, including anaphylactic shock.

From the nervous system rare – dizziness, convulsions.

Contraindications

• Hypersensitivity to tranexamic acid or other components of the drug;
• Severe chronic renal failure (GFR less than 30 mg/ml/1.73 m²) due to the risk of accumulation;
• Current or history of venous or arterial thrombosis (including deep vein thrombosis of the leg, pulmonary embolism, intracranial vessel thrombosis) when simultaneous therapy with anticoagulants is not possible;
• Fibrinolysis due to consumption coagulopathy (hypocoagulation stage of DIC syndrome);
• History of seizures;
• Acquired color vision impairment;
• Subarachnoid hemorrhage (due to the risk of developing cerebral edema, cerebral ischemia, and infarction);
• Treatment of menorrhagia in patients under 16 years of age (no experience of use);
• Age under 1 year (no experience of use).

With caution tranexamic acid should be used in the following situations

• Hematuria caused by renal parenchymal diseases, and bleeding from the upper urinary tract (risk of secondary mechanical obstruction of the urinary tract by a blood clot with the development of anuria);
• Patients at high risk of thrombosis (history of thromboembolic events or family history of thromboembolic diseases, verified diagnosis of thrombophilia);
• Female patients taking combined oral contraceptives (due to an increased risk of venous thromboembolic complications and arterial thromboses);
• Simultaneous use of blood coagulation factor II, VII, IX and X preparations in combination [prothrombin complex] or anti-inhibitor coagulant complex;
• Patients receiving anticoagulant therapy (experience of use is limited);
• DIC syndrome;
• Presence of blood in cavities, for example, in the pleural cavity, joint cavities, and urinary tract.

Use in Pregnancy and Lactation

In preclinical studies, Tranexamic acid did not have a teratogenic effect. Adequate and strictly controlled studies of the efficacy and safety of tranexamic acid preparations in pregnant women have not been conducted. Tranexamic acid crosses the placental barrier and can be present in umbilical cord blood at a concentration close to the maternal concentration.

Since studies of reproductive function in animals do not always predict human responses, tranexamic acid should be used during pregnancy only if absolutely necessary.

Tranexamic acid passes into breast milk (the concentration of the drug in milk is about 1% of the concentration in maternal blood plasma). The development of an antifibrinolytic effect in the infant is unlikely. Nevertheless, caution should be exercised when using tranexamic acid in nursing mothers.

Use in Hepatic Impairment

In patients with impaired liver function, dose adjustment is not required.

Use in Renal Impairment

The use of the drug is contraindicated in severe chronic renal failure (GFR less than 30 mg/ml/1.73 m²) due to the risk of accumulation.

In patients with mild to moderate impaired renal excretory function, dose adjustment is necessary.

Pediatric Use

The use of the drug is contraindicated in patients under 1 year of age and for the treatment of menorrhagia in patients under 16 years of age (no experience of use).

Geriatric Use

In elderly patients without renal failure, dose adjustment is not required.

Special Precautions

Tranexam^® acid should not be administered intramuscularly.

Cases of seizures associated with the use of tranexamic acid have been described. In patients who underwent coronary artery bypass surgery, seizures, in most cases, developed with the use of tranexamic acid in high doses. When the drug was used in recommended doses, the frequency of seizures after surgery was the same as in patients who did not receive tranexamic acid.

When using tranexamic acid, visual disturbances, including impaired color perception, may develop. Before starting and during treatment with tranexamic acid preparations, consultations with an ophthalmologist are necessary (determination of visual acuity, color vision, fundus condition). If visual disturbances occur during treatment with tranexamic acid, the drug should be discontinued.

Tranexamic acid preparations should be used with caution in hematuria caused by renal parenchymal diseases, since intravascular fibrin deposition is often observed under these conditions, which may worsen kidney damage. Furthermore, in cases of massive bleeding of any etiology from the upper urinary tract, antifibrinolytic therapy increases the risk of blood clot formation in the renal pelvis and/or ureter and, accordingly, secondary mechanical obstruction of the urinary tract and the development of anuria.

Before starting the use of tranexamic acid, possible risk factors for the development of thromboembolic events should be taken into account. Although conducted clinical studies have not revealed a significant increase in the frequency of thrombosis, the risk of thrombotic complications cannot be completely excluded. Cases of venous and arterial thrombosis and thromboembolism have been described in patients receiving tranexamic acid. Furthermore, cases of central retinal artery occlusion and central retinal vein occlusion have been reported. Several patients developed intracranial thrombosis during treatment with tranexamic acid.

Accordingly, in patients with a high risk of thrombosis (history of thromboembolic complications, family history of thromboembolism, verified diagnosis of thrombophilia), tranexamic acid should be used only in cases of extreme necessity and under strict medical supervision. Before using tranexamic acid, an examination aimed at identifying risk factors for thromboembolic complications should be performed.

The presence of blood in body cavities, for example, in the pleural cavity, joint cavities, and urinary tract (including the renal pelvises and bladder) can lead to the formation of an “insoluble clot” due to extravascular blood coagulation, which may be resistant to physiological fibrinolysis.

Women with irregular menstrual bleeding should not be prescribed tranexamic acid until the cause of dysmenorrhea is established. If the volume of menstrual bleeding does not adequately decrease during treatment with tranexamic acid, the possibility of alternative treatment should be considered.

The efficacy and safety of tranexamic acid preparations for the treatment of menorrhagia in patients under 16 years of age have not been established.

Tranexamic acid should be used with caution in women simultaneously taking combined oral contraceptives due to an increased risk of thrombosis.

The use of tranexamic acid in patients with DIC syndrome is contraindicated in most cases. Tranexamic acid may be prescribed to such patients only if the patient has symptoms of predominant activation of the fibrinolytic system with acute severe bleeding. In such acute cases, a single administration of tranexamic acid at a dose of 1 g is often sufficient to stop the bleeding. Prescription of tranexamic acid in DIC syndrome should be done only in the presence of appropriate laboratory data and after evaluation of these data by a specialist.

Due to the lack of adequate clinical studies, the simultaneous use of tranexamic acid with anticoagulants should be carried out under careful supervision by a specialist experienced in the treatment of coagulation disorders.

Effect on the Ability to Drive Vehicles and Operate Machinery

The ability of tranexamic acid to affect the speed of psychomotor reactions and the ability to drive vehicles or other mechanical means has not been studied. Tranexamic acid may cause dizziness and visual disturbances, and, accordingly, may affect the ability to engage in potentially hazardous activities requiring increased concentration and speed of psychomotor reactions.

Overdose

There is limited data on overdose cases. One case of overdose (oral intake of 37 g of tranexamic acid) is reported.

Symptoms dizziness, headache, nausea, vomiting, diarrhea, orthostatic symptoms (including dizziness when moving from a horizontal to a vertical position), orthostatic arterial hypotension. In predisposed patients, the risk of thrombosis is increased.

Treatment an antidote is unknown. If an overdose of tranexamic acid is suspected, hospitalization is necessary. When providing assistance, vomiting should be induced, followed by gastric lavage. Activated charcoal reduces the absorption of tranexamic acid when taken orally within the first 1-2 hours after overdose. If the patient is unconscious or has impaired swallowing, activated charcoal can be administered through a nasogastric tube. Oral or parenteral administration of a large amount of fluid to enhance renal excretion, forced diuresis, and control of urine output are recommended. In some cases, the use of anticoagulants may be justified.

Drug Interactions

Special clinical studies on the interaction of tranexamic acid with other medicinal products have not been conducted.

Tranexamic acid counteracts the development of the pharmacological effect of fibrinolytic (thrombolytic) drugs.

Combined oral contraceptives increase the risk of venous thromboembolic complications and arterial thromboses (in particular, ischemic stroke and myocardial infarction). Experience with the use of tranexamic acid in women taking combined oral contraceptives is lacking. Since Tranexamic acid has an antifibrinolytic effect, simultaneous use with combined oral contraceptives may lead to an additional increase in the risk of thrombotic complications.

Simultaneous use of tranexamic acid with blood coagulation factor II, VII, IX, and X preparations in combination [prothrombin complex] or anti-inhibitor coagulant complex increases the risk of thrombosis.

An increase in the risk of thrombotic complications (in particular, myocardial infarction) is possible with the simultaneous use of tranexamic acid with hydrochlorothiazide, desmopressin, ampicillin-sulbactam, ranitidine, and nitroglycerin.

When used concomitantly with hemostatic drugs, activation of thrombus formation is possible.

Simultaneous administration of tranexamic acid with anticoagulants should be carried out under strict medical supervision (experience of use is limited).

Pharmaceutical drug interactions

The tranexamic acid solution is compatible with most infusion solutions (0.9% sodium chloride solution, Ringer’s solution, 5% dextrose solution, amino acid solutions, dextrans).

The tranexamic acid solution is compatible with unfractionated heparin.

The tranexamic acid solution is pharmaceutically incompatible with urokinase, norepinephrine, dipyridamole, diazepam.

The tranexamic acid solution should not be mixed with antibiotic solutions (penicillins, tetracyclines) and blood products.

Storage Conditions

The drug should be stored out of the reach of children at a temperature not exceeding 25°C (77°F).

Shelf Life

The shelf life of the solution for intravenous administration 50 mg is 5 years; the solution for intravenous administration 100 mg is 3 years. Do not use after the expiration date stated on the packaging.

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.