Tranexa

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

Composition:

Active substance: 5 ml of solution contains 500 mg of tranexamic acid;

Excipient: water for injections.

Pharmaceutical form. Solution for injection.

Main physicochemical properties: Clear, colorless solution.

Pharmacotherapeutic group.

Antihemorrhagic agents. Fibrinolysis inhibitors. Amino acids. Tranexamic acid.

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 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.

Pediatric population (children aged 1 year and older).

Twelve studies on efficacy in pediatric cardiac surgery, involving 1073 children, have been described in the scientific literature; of these, 631 patients received tranexamic acid. Most were evaluated in comparison with a placebo control group. The study population was heterogeneous with respect to age, type of surgical procedure, and dosing. Study results indicate that tranexamic acid reduces blood loss and the need for blood product transfusions in pediatric cardiac surgery involving cardiopulmonary bypass (CPB) during high-bleeding-risk procedures, particularly in "cyanotic" patients (with significant circulatory impairment) or patients undergoing repeat surgery. The most appropriate dosing regimen appears to be:

− Initial administration (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 adapter at a dose adjusted for the surgical procedure or based on patient body weight (10 mg/kg), or administration into the CPB pump adapter and a final bolus injection of 10 mg/kg at the end of the surgical procedure involving CPB.

Some data suggest that continuous infusion may be preferable, 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 multiexponential manner.

Distribution

At therapeutic plasma levels, the protein binding of tranexamic acid to plasma proteins is approximately 3%; this binding is considered to be entirely attributable to binding with plasminogen. Tranexamic acid does not bind to serum albumin. The initial volume of distribution is approximately 9 to 12 L. Tranexamic acid crosses the placenta. After intravenous injection of 10 mg/kg in pregnant women, serum concentrations of tranexamic acid range from 10–53 μg/mL, while concentrations in umbilical cord blood range from 4–31 μg/mL. Tranexamic acid rapidly penetrates into synovial fluid and synovial membrane tissues. After intravenous injection of 10 mg/kg in patients undergoing knee surgery, concentrations in synovial fluid were similar to those in blood serum. Concentrations of tranexamic acid in several other tissues and fluids are proportional to those observed in blood (in breast milk – one hundredth, in cerebrospinal fluid – one tenth, in aqueous humor of the eye – one tenth). Tranexamic acid has been detected in semen, where it inhibits fibrinolytic activity but has almost no effect on sperm motility.

Elimination

The drug is primarily excreted in urine as unchanged compound. Renal excretion via glomerular filtration is the main elimination pathway. Renal clearance is nearly equivalent to plasma clearance (110–116 mL/min). Approximately 90% of tranexamic acid is excreted 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 patient groups

Plasma concentrations increase 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 localized, 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 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 bleeding associated with administration of a fibrinolytic medicinal product.

Contraindications.

Hypersensitivity to tranexamic acid and components included in the formulation. Acute venous or arterial thrombosis. Fibrinolytic states with acute severe bleeding due to administration of coagulopathy-inducing agents (anticoagulants), except for agents predominantly activating the fibrinolytic system. Severe renal impairment (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 types of interactions.

Drug interaction studies have not been conducted. Concomitant 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 cautiously in patients who have received treatment with tranexamic acid. In such cases, there is a risk of thrombosis, e.g., when using estrogens. Furthermore, the antifibrinolytic effect of the drug may be antagonized by thrombolytics. Heparins may be added during intravenous infusion.

Special precautions for use.

Strictly adhere to the indicated indications and method of administration:

− intravenous injections should be administered very slowly;

− tranexamic acid must not be administered intramuscularly.

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

Visual disturbances. The possibility of ophthalmological complications, including visual disturbances, worsening of vision, and color vision disorders, should be considered. In such cases, treatment should be discontinued. With continuous long-term use of tranexamic acid (injections), regular ophthalmological examinations (including assessment of visual acuity, color vision, fundus, visual fields, etc.) should be scheduled. If pathological ophthalmological changes occur, particularly those related to retinal disorders, the physician, after appropriate specialist consultation, should individually decide on 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 may be 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 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. Treatment should be initiated after consultation with a specialist experienced in hemostasiology and conducted under strict medical supervision.

Due to the increased risk of thrombosis, tranexamic acid should be used with caution in 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 associated with acute severe bleeding. It has been established that 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 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 profile implies that, in the presence of the underlying disease, various components of this profile cannot independently change. 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 patients with DIC syndrome should only be considered when appropriate hematological laboratory facilities and clinical experience are available.

Use during pregnancy or breastfeeding.

Women of childbearing 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, which do not indicate harmful effects on the fetus. 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 influence the speed of reactions when driving or operating machinery.

Studies evaluating the effect on the ability to drive or operate machinery are lacking.

Administration and Dosage

The drug should be administered intravenously (by infusion or bolus injection).

Adults

In generalized fibrinolysis, tranexamic acid should be administered intravenously, slowly, at a dose of 1 g (2 vials of 5 ml) or 15 mg/kg body weight every 6–8 hours, at an infusion rate of 1 ml/min.

In local fibrinolysis, the recommended dose is 500 mg (1 vial of 5 ml) to 1 g (2 vials of 5 ml) of the drug administered intravenously, slowly (approximately 1 ml/min), 2–3 times daily.

Dosing in patients with renal impairment

In patients with renal impairment, tranexamic acid is contraindicated in cases of severe renal insufficiency. For patients with mild or moderate renal impairment, the dosage of tranexamic acid should be reduced according to serum creatinine levels:

Dosing in patients with hepatic impairment

Dose adjustment is not required in patients with hepatic impairment.

Use in children

For children aged 1 year and older, use as indicated (see section "Indications"), with a dosage of approximately 20 mg/kg/day. However, data on efficacy, safety, and specific dosing regimens 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 investigated.

Use in elderly patients

Dose adjustment is generally not required, unless there are signs of renal impairment.

Route of administration

Administration is strictly limited to slow intravenous injection (bolus) or infusion.

Tranexamic acid should not be administered intramuscularly.

Intravenous injection: Tranexamic acid must be administered by slow bolus injection over at least 5 minutes.

Intravenous infusion: Tranexamic acid should be mixed directly with the following injection/infusion solutions: sodium chloride 0.9% injection; injection solution of Ringer's; dextrose 5% injection; dextrin-40 in dextrose 5% injection; dextrin-40 in sodium chloride 0.9% injection; amino acid solution.

Children

Maximum single dose for children aged 1 year and older: 10 mg/kg body weight. Maximum daily dose: 20 mg/kg body weight.

Overdose

Cases of overdose have not been reported.

Symptoms of overdose may include dizziness, headache, hypotension, and convulsions. Convulsions have also been observed to occur more frequently with higher infusion rates and are characteristic with increased doses.

Treatment of overdose is symptomatic.

Side effects

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

Shelf life. 2 years.

Storage conditions.

Keep out of reach of children. Store at a temperature not exceeding 25 °C in the original packaging.

Incompatibility.

Transamic acid for injection must not be added to blood intended for transfusion or to injectable solutions containing penicillin group medicinal products.

Packaging.

5 ml in vials; 5 vials in a cardboard box with labeling in Ukrainian.

Prescription status. By prescription only.

Manufacturer.

Immacul Life Sciences Private Limited, India

Manufacturer's address and place of business.

Village Tantewal, Ropar Road, Nalagarh, Solan District, 174101, India.