Transtope

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

Composition:

Active substance: tranexamic acid;

1 ml of injection solution contains 100 mg of tranexamic acid;

Excipient: water for injections.

Pharmaceutical form. Solution for injection.

Main physicochemical properties: clear, colorless solution.

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 is formed involving tranexamic acid and plasminogen; tranexamic acid binds to plasminogen during conversion mediated by 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.

Paediatric population:

In children over one year of age: A literature review identified 12 studies on efficacy in paediatric cardiac surgery involving 1073 children, of whom 631 patients received tranexamic acid. Most compared with a placebo control group. The study population was heterogeneous in terms of age, type of surgical intervention, and dosing. Study results indicate that tranexamic acid reduces blood loss and the need for blood products in paediatric cardiac surgery involving cardiopulmonary bypass (CPB, cardiopulmonary bypass), particularly in procedures with a high risk of bleeding, especially in "cyanotic" (with significant circulatory impairment) patients or patients undergoing reoperation. The most appropriate dosing regimen identified may be as follows:

• Initial dose (loading dose) – bolus infusion of 10 mg/kg administered after induction of anaesthesia and before skin incision;
• continuous infusion at 10 mg/kg/hour or intermittent injection into the CPB pump adapter at a dose adjusted for the duration of the surgical procedure, or at a body weight-based dose of 10 mg/kg, or into the CPB pump adapter, and a final injection of 10 mg/kg at the end of the surgical procedure involving CPB.

Limited data suggest that continuous infusion is preferable, as it maintains therapeutic plasma concentrations throughout the surgery. No specific dose-response or pharmacokinetic studies have been conducted in children.

Pharmacokinetics.

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

Distribution. The extent of plasma protein binding of tranexamic acid at therapeutic levels 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 litres.

Tranexamic acid crosses the placenta. After intravenous administration of 10 mg/kg in pregnant women, serum concentrations of tranexamic acid range from 10 to 53 µg/mL, while concentrations in umbilical cord blood range from 4 to 31 µg/mL. Tranexamic acid rapidly penetrates into synovial fluid and synovial membrane tissues. After intravenous administration of 10 mg/kg in patients undergoing knee surgery, concentrations in synovial fluid were similar to those in serum. Concentrations of tranexamic acid in other tissues and fluids are partial relative to blood levels (e.g., breast milk – one hundredth, cerebrospinal fluid – one tenth, aqueous humour of the eye – one tenth). Tranexamic acid has been detected in semen, where it inhibits fibrinolytic activity but has virtually no effect on sperm migration (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 practically equivalent to plasma clearance (110 to 116 mL/min). Approximately 90% of tranexamic acid is eliminated 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 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 over one year of age.

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 following surgical intervention on the prostate 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;
• Thoracic, abdominal, and other major surgical procedures, for example, cardiovascular surgery;
• Control of hemorrhage associated with administration of a fibrinolytic medicinal agent.

Contraindications.

Hypersensitivity to the active substance or to any of the excipients of the medicinal product. 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 interaction.

Currently, no drug interaction studies have 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 may be a theoretical risk of increased thrombogenic potential, for example, when using estrogens. In addition, 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 must be administered very slowly.
  • Tranexamic acid must not be administered intramuscularly.

Seizures: Seizures associated with tranexamic acid treatment have been reported in patients. During aortocoronary bypass surgery (ACBS), 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 not receiving this medicinal product.

Visual disturbances: Possible ophthalmological complications, including visual disturbances, deterioration of vision, and color vision disturbances, should be carefully monitored. 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. In the presence of, or if pathological ophthalmological changes develop—particularly those related to retinal disorders—after appropriate specialist consultation, the physician must individually decide on the necessity and feasibility of long-term tranexamic acid (injection) 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 using tranexamic acid. Tranexamic acid (injection solution) should be administered only in cases of direct life-threatening indications in patients with a history of thromboembolic disorders or in patients with a family history indicating an increased risk of thromboembolic complications (patients at high risk of thrombophilia). In such cases, treatment should be initiated only after consultation with a specialist experienced in hemostasis 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 should generally not receive treatment with tranexamic acid. If the use of tranexamic acid is necessary, it should be prescribed exclusively for patients with predominantly activated fibrinolytic system and acute severe bleeding. The characteristic hematological profile in these conditions typically 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 assumes that the underlying disease state does not independently alter these hematological parameters. 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 childbearing potential should use effective contraceptive measures 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.

Limited clinical data are available on the use of tranexamic acid in various hemorrhagic conditions during the second and third trimesters of pregnancy, with no identifiable harmful effects on the fetus. Tranexamic acid should be used during pregnancy only if the expected therapeutic benefit outweighs the potential risk.

Tranexamic acid is excreted in 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 on the ability to drive or operate machinery are lacking.

Method of administration and dosage.

Transstop is administered intravenously (by infusion or bolus injection).

Adults.

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

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

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

Table 1

Dosing in patients with hepatic impairment. Dose adjustment is generally not required in patients with hepatic dysfunction.

Use in children.

Children aged one year and older may be treated according to current approved therapeutic indications as described in the section "Indications", at a dosage of approximately 20 mg/kg/day. However, when used in children according to these recommendations, data on efficacy, safety, and dosing are limited.

The efficacy, dosing characteristics, and safety of tranexamic acid in children undergoing 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 must strictly follow a limited regimen – slow intravenous injection (injection/infusion).

Tranexamic acid should not be administered intramuscularly.

Administration method

Intravenous injection: tranexamic acid should be administered by slow bolus injection over at least 5 minutes.

Intravenous infusion: tranexamic acid should be mixed directly with the following injectable/infusion solutions:

sodium chloride 0.9%, injection solution; Ringer's injection solution;

dextrose, injection solution, 5%; dextrin-40 in dextrose injection solution (5%) and dextrin-40 in sodium chloride 0.9% injection solution; amino acid solution.

Children.

The maximum single dose should not exceed 10 mg/kg body weight. The maximum daily dose is 20 mg/kg body weight.

Overdose.

Cases of overdose have not been reported.

Signs and symptoms may include dizziness, headache, hypotension, and seizures (convulsions). Seizures have been shown to occur more frequently with higher infusion rates and are characteristic when the dose is increased.

Treatment of overdose should consist of symptomatic therapy.

Adverse reactions

The adverse reactions listed below are systematized according to the MedDRA classification (primary system organ classes). Within each system organ class, adverse reactions are ordered by frequency. Within each frequency grouping, adverse reactions are presented in order of decreasing severity. Frequencies were defined as follows: very common (> 1/10); common (> 1/100 to < 1/10); uncommon (> 1/1,000 to < 1/100); not known (cannot be estimated from available data).

Table 2

Shelf life. 2 years.

Storage conditions. Store in a place inaccessible to children, at a temperature not exceeding 30 °C.

Incompatibility.

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

Packaging. 5 ml of injection solution in a vial, 6 vials in a cardboard box.

Prescription status. Prescription only.

Manufacturer.

Eugia Pharma Specialities Limited, Unit-III

Manufacturer's address and place of business.

Plot No’s: 4, 34 to 48, EPIP, TSIIC, IDA, Pashamylaram Village, Patancheru Mandal, Sanga Reddy District, Telangana state, 502307, India.

Marketing Authorization Holder.

Aurobindo Pharma Ltd, India.