Tramix®

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT TRAMIX® (TRAMIX)

Composition:

Active substance: tranexamic acid;

1 ml of solution contains tranexamic acid, calculated as 100% substance – 100.0 mg;

Excipient: water for injections.

Pharmaceutical form. Injection solution.

Main physicochemical properties: clear, colorless liquid.

Pharmacotherapeutic group.

Antihemorrhagic agents. Fibrinolysis inhibitors. Amino acids. ATC code B02A A02.

Pharmacological properties.

Pharmacodynamics.

Tranexamic acid exerts an antihemorrhagic effect by inhibiting the fibrinolytic activity of plasmin.

Tranexamic acid forms a complex with plasminogen; tranexamic acid binds to plasminogen during its conversion to plasmin.

The activity of the tranexamic acid-plasmin complex toward fibrin is lower than that of free plasmin.

High doses of tranexamic acid have been shown to reduce complement activity.

Children from 1 year of age. Data are available on reduced blood loss and decreased need for blood products in pediatric cardiac surgery involving cardiopulmonary bypass, where there is a high risk of bleeding, particularly in cyanotic patients or those undergoing repeat surgical procedures. The following dosing regimen has been found to be most appropriate:

• initial bolus dose of 10 mg/kg administered after induction of anesthesia and before skin incision;
• continuous infusion of 10 mg/kg/h or injection into the cardiopulmonary bypass circuit priming solution at a dose corresponding to the duration of cardiopulmonary bypass or according to patient body weight at 10 mg/kg, or according to the priming volume of the cardiopulmonary bypass circuit, with the final dose of 10 mg/kg administered at the end of the cardiopulmonary bypass procedure.

Limited data suggest that continuous administration is the most favorable approach, as it maintains therapeutic plasma concentrations throughout the entire surgical period.

No specific dose-dependent pharmacokinetic studies have been conducted in children.

Pharmacokinetics.

Absorption. Maximum plasma concentration of tranexamic acid is rapidly achieved after short intravenous administration, followed by a multiexponential decline.

Distribution. Plasma protein binding of tranexamic acid is approximately 3% of the therapeutic plasma level, likely due to its binding to plasminogen. Tranexamic acid does not bind to serum albumin. The initial volume of distribution is approximately 9–12 liters.

Tranexamic acid crosses the placental barrier. After intravenous administration at a dose of 10 mg/kg to pregnant women, tranexamic acid concentrations in maternal serum ranged from 10 to 53 µg/mL and in umbilical cord blood from 4 to 31 µg/mL. Tranexamic acid rapidly penetrates into synovial fluid and synovial membrane. After intravenous administration of 10 mg/kg in patients undergoing knee surgery, concentrations in synovial fluid were similar to those observed in corresponding serum samples. Tranexamic acid concentrations in other tissues relative to blood concentrations are as follows: in breast milk – approximately 1/100, in cerebrospinal fluid – approximately 1/10, in intraocular fluid – approximately 1/10. Tranexamic acid has been detected in seminal fluid, where it inhibits fibrinolytic activity without affecting spermatozoa migration.

Elimination. Tranexamic acid is primarily excreted unchanged in urine. Renal excretion via glomerular filtration is the main elimination pathway. Renal clearance equals plasma clearance (110–116 mL/min). Approximately 90% of tranexamic acid is excreted in urine 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 populations. Plasma concentrations are increased 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 surgery on the prostate gland or as a result of surgical interventions or procedures 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, for example cardiovascular surgery;
• Control of bleeding associated with administration of a fibrinolytic medicinal product.

Contraindications.

Hypersensitivity to the active substance or to any of the excipients;

• acute venous or arterial thrombosis;

• fibrinolytic states with acute severe bleeding due to administration of coagulopathic agents (anticoagulants), except for those agents that predominantly activate the fibrinolytic system;
• severe renal insufficiency (risk of drug accumulation);
• history of seizures;
• intrathecal and intraventricular injection, intracerebral administration (risk of cerebral edema with subsequent development of seizures).

Interaction with other medicinal products and other forms of interactions.

Drug interaction studies have not been conducted. Concomitant (simultaneous) 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 who have received treatment with tranexamic acid. In these cases, there is a risk of thrombosis, for example when using estrogens. Furthermore, the antifibrinolytic effect of the drug may be antagonized by thrombolytics.

Special precautions for use.

Strict adherence to the specified indications and method of administration is required:

• Intravenous injections should be administered very slowly;
  • tranexamic acid must not be administered intramuscularly.

Seizures: Seizures associated with tranexamic acid therapy have been reported in patients. During coronary artery bypass graft (CABG) surgery, most of these cases occurred after intravenous administration of high doses of tranexamic acid. When recommended low doses of tranexamic acid are used, the incidence of postoperative seizures is the same as in patients who did not receive this medicinal product.

Visual disturbances: Possible ophthalmological complications should be carefully monitored, including visual disturbances, blurred vision, and color vision disorders. In such cases, treatment should be discontinued. With continuous prolonged use of tranexamic acid (injections), regular ophthalmological examinations (including visual acuity, color vision, fundoscopy, visual field testing, etc.) should be scheduled. In the presence of, or if pathological ophthalmological changes develop—particularly those related to retinal disorders—after appropriate specialist consultation, the physician must individually assess the necessity and feasibility of long-term tranexamic acid (injections) therapy in each specific case.

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

Thromboembolic complications: Risk factors for thromboembolic complications should be evaluated before prescribing tranexamic acid. Tranexamic acid (injection solution) should be administered to patients with a history of thromboembolic disorders or to those with a family history indicating a risk of thromboembolic complications (patients at high risk of thrombophilia) only when there are clear, life-threatening indications. In such cases, treatment should be initiated after consultation with a specialist experienced in hemostasiology and must be conducted under strict medical supervision.

Due to the increased risk of thrombosis, tranexamic acid should be administered cautiously to patients taking oral contraceptives.

Disseminated intravascular coagulation (DIC): Patients with DIC syndrome generally should not receive treatment with tranexamic acid. If the use of tranexamic acid is necessary, it should be prescribed only in cases of predominant activation of the fibrinolytic system accompanied by 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 indicates that the underlying disease does not affect various components in 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 patients with DIC should only be considered when appropriate hematological laboratory support and clinical experience are available.

Use during pregnancy or breastfeeding.

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

There is insufficient clinical data on the use of tranexamic acid in pregnant women.
As a precautionary measure, the use of tranexamic acid during the first trimester of pregnancy is not recommended.

There are only limited clinical data on the use of tranexamic acid in various hemorrhagic conditions during the second and third trimesters of pregnancy, and based on these data, no harmful effects on the fetus can be identified. Tranexamic acid may be used during pregnancy only if the expected therapeutic benefit outweighs the potential risk.

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.

Studies evaluating the effect of tranexamic acid on the ability to drive or operate machinery are not available.

Method of administration and dosage.

Tramix® should be administered intravenously only (by infusion or bolus injection).

In generalized fibrinolysis: administer at a dose of 1 g (2 vials of 5 ml) or 15 mg/kg body weight every 6–8 hours by slow intravenous injection (administration rate – 1 ml/min).

In local fibrinolysis: the recommended dose is 0.5 g (1 vial of 5 ml) to 1 g (2 vials of 5 ml) 2–3 times daily by slow intravenous injection (administration rate – 1 ml/min).

Renal impairment.

In case of renal insufficiency, there is a risk of accumulation; therefore, the use of tranexamic acid is contraindicated in patients with severe renal impairment.

For patients with mild to moderate renal impairment, dosage should be adjusted according to serum creatinine levels.

Hepatic impairment.

Dose adjustment is not required in patients with liver disease.

Elderly patients do not require dose adjustment in the absence of renal impairment.

Tramix® can be mixed with electrolyte solutions, amino acid solutions, and glucose solution.

Heparin may be added to the injection solution.

The solution should be prepared immediately before administration. Any unused solution should be discarded.

Children.

For children aged 1 year and older, the recommended dose is 20 mg/kg/day. Data on efficacy, dosing, and safety are limited.

The efficacy, dosing, and safety of tranexamic acid in children undergoing cardiac surgery have not been fully established.

Overdose.

Cases of overdose have not been reported.

Symptoms of overdose may include dizziness, headache, hypotension, and seizures (convulsions). The incidence of seizures increases with higher doses.

Treatment of overdose is symptomatic.

Side effects.

The adverse reactions listed below are systematized according to the MedDRA classification (primary system organ classes). Within each organ system class, adverse reactions are listed in order of frequency. Within each frequency group, reactions are presented in decreasing order of occurrence. Frequency was defined as follows: very common (> 1/10); common (> 1/100 to < 1/10); uncommon (> 1/1000 to < 1/100); not known (cannot be estimated from available data).

Skin and subcutaneous tissue disorders.

Uncommon: allergic dermatitis.

Gastrointestinal disorders.

Common: diarrhea, vomiting, nausea.

Nervous system disorders.

Not known: seizures, particularly in cases of incorrect use.

Eye disorders.

Not known: visual disturbances, including disturbances of color vision.

Blood and lymphatic system disorders.

Not known: malaise due to hypotension, with or without loss of consciousness (usually following too rapid intravenous injection; exceptionally after oral administration).

Arterial or venous thromboembolism at any site.

Immune system disorders.

Not known: hypersensitivity reactions, including anaphylactic-type reactions.

Shelf life. 2 years.

Storage conditions.

Store in original packaging at a temperature not exceeding 25 °C. Do not freeze!

Keep out of reach of children.

Incompatibility.

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

Packaging.

5 ml in a vial, 5 vials in a blister pack; 1 blister pack in a carton;

5 ml in a vial, 5 vials in a blister pack; 2 blister packs in a carton.

Prescription category. Prescription only.

Manufacturer. JSC "Halychpharm".

Manufacturer's address and location of its business activity.

6/8 Opryshkivska St., Lviv, 79024, Ukraine.