Ataksan

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

Composition:

Active substance: tranexamic acid;

1 ml of the preparation contains 50 mg or 100 mg of tranexamic acid;

Excipient: water for injections.

Pharmaceutical form. Solution for injection.

Main physicochemical properties: clear, colorless liquid.

Pharmacotherapeutic group. Blood and blood-forming organs. Antihemorrhagics. Antifibrinolytics, 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 its transformation into 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 of these patients were evaluated in comparison with a placebo control group. The study population was heterogeneous with respect to age, type of surgical intervention, and dosing regimen. Study results indicate that the use of tranexamic acid reduces blood loss and decreases the need for blood product transfusions in pediatric cardiac surgery involving cardiopulmonary bypass (CPB), particularly in high-bleeding-risk procedures, especially in "cyanotic" patients (with significant circulatory impairment) or patients undergoing reoperation. The most appropriate dosing regimen identified appears to be:

• Initial dose (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 intermittent injection into the CPB pump adapter at a dose adjusted according to the specific surgical procedure, or body weight-based dosing of 10 mg/kg, or administration into the CPB pump adapter followed by 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. Peak plasma concentration of tranexamic acid is rapidly achieved following short-term intravenous infusion, after which plasma concentrations decline in a multi-exponential manner.

Distribution. At therapeutic plasma levels, the plasma protein binding of tranexamic acid is approximately 3%; this binding is believed to be entirely attributable to binding with plasminogen. Tranexamic acid does not bind to serum albumin. The initial volume of distribution is approximately 9–12 liters.

Tranexamic acid crosses the placenta. After intravenous administration of 10 mg/kg in pregnant women, the concentration of tranexamic acid in maternal serum ranges from 10 to 53 mcg/mL, while in umbilical cord blood it ranges from 4 to 31 mcg/mL. Tranexamic acid rapidly penetrates into synovial fluid and synovial membrane tissues. After intravenous injection of 10 mg/kg in patients undergoing knee surgery, the concentration in synovial fluid was similar to that in serum. Concentrations of tranexamic acid in various other tissues and fluids are comparable to those observed in blood (in breast milk – one hundredth, in cerebrospinal fluid – one tenth, in intraocular fluid – one tenth). Tranexamic acid has been detected in semen, where it inhibits fibrinolytic activity but has virtually 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 practically 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 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 occurring following surgery on the prostate gland 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 hemorrhage 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 following consumption coagulopathy, except for excessive activation of the fibrinolytic system during acute severe bleeding.
• 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.

Drug interaction studies have not been conducted.

Concomitant (simultaneous) use of anticoagulants should be performed under strict supervision of a physician experienced in this field. Medicinal products affecting hemostasis should be used with caution in patients receiving tranexamic acid.

There is a theoretical risk of increased thrombotic potential, for example, when used concomitantly with estrogens.

In addition, the antifibrinolytic effect of the drug can be antagonized by administration of thrombolytic agents.

Special precautions for use

The specified indications and methods of administration must be strictly observed:

• Intravenous injections should be administered very slowly (maximum 1 mL per minute).
• Intramuscular administration of tranexamic acid is not permitted.

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 tranexamіc 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 should be carefully considered, including visual disturbances, blurred vision, and color vision disturbances. In such cases, treatment should be discontinued. With continuous long-term use of tranexamic acid (by injection), regular ophthalmological examinations should be performed (including assessment of visual acuity, color vision, fundus, and visual fields). If pathological ophthalmological changes occur, especially retinal disorders, the physician, after appropriate specialist consultation, should decide on the necessity and possibility of long-term tranexamic acid (injection) therapy in each individual case.

Hematuria. In cases of hematuria from the upper urinary tract, there may be a risk of urethral obstruction.

In the absence of appropriate treatment, urinary tract obstruction may lead to serious consequences such as renal failure, urinary tract infection, hydronephrosis, and anuria. Therefore, careful monitoring is recommended for patients with hematuria or at risk of hematuria from the upper urinary tract.

Thromboembolic complications. Risk factors for thromboembolic complications should be evaluated before prescribing tranexamic acid. Patients with a history of thromboembolic disorders or those with a family history of frequent thromboembolic events (patients at high risk of thrombophilia) should receive tranexamic acid (injection solution) only when there are direct life-threatening indications. In such cases, treatment should be initiated only after consultation with a specialist experienced in hemostasis and 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 tranexamic acid. If tranexamic acid use is necessary, it should be prescribed only in the presence of predominant activation of the fibrinolytic system associated with acute severe bleeding.

Typical 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; increased plasma levels of fibrinogen degradation products; normal platelet count. The above assumes that the underlying disease itself does not alter the various components of this profile. In such acute cases, a single dose of 1 g of tranexamic acid is sufficient to stop bleeding. The possibility of using tranexamic acid in patients with DIC syndrome should be considered only if appropriate hematological laboratory facilities and clinical expertise are available.

Use during pregnancy or breastfeeding.

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

Pregnancy. There is insufficient clinical data on the use of tranexamic acid in pregnant women.

Use of tranexamic acid during the first trimester of pregnancy is not recommended.

Limited clinical data on the use of tranexamic acid in various hemorrhagic conditions during the second and third trimesters have not shown harmful effects on the fetus.

Tranexamic acid may be used during pregnancy only if the expected therapeutic benefit to the pregnant woman outweighs the potential risk to the fetus.

Breastfeeding. Tranexamic acid passes into breast milk. Therefore, breastfeeding is not recommended.

Fertility. 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.

The method of administration of Atrakson is strictly limited to slow intravenous injection (injection/infusion).

Adults.

For local fibrinolysis, the recommended dose is 500 mg to 1 g administered intravenously slowly (approximately 1 mL/min) 2–3 times daily.

For generalized fibrinolysis, tranexamic acid should be administered intravenously slowly at a dose of 1 g or 15 mg/kg body weight every 6–8 hours, at an infusion rate of 1 mL/min.

Dosing in patients with renal impairment. Tranexamic acid is contraindicated in patients with severe renal insufficiency. 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 not required in patients with impaired liver function.

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 and safety regarding dosing specifics when used in children for the indicated conditions are limited.

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

Use in elderly patients. Dose adjustment is generally not required unless there are signs of renal impairment.

For intravenous infusion, Atthracin may be mixed with most infusion solutions, such as electrolyte solutions, carbohydrate solutions, amino acid solutions, and dextran solutions. Heparin may be added to Atthracin.

The diluted mixture should be used immediately after preparation.

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.

There have been no reports of overdose cases.

Symptoms of overdose may include dizziness, headache, arterial hypotension, and seizures (convulsions). Seizures have also been shown to occur more frequently with increasing doses.

Treatment of overdose is symptomatic.

Adverse Reactions

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 listed in descending order of occurrence. Frequency is defined as follows: very common (> 1/10); common (> 1/100 to < 1/10); uncommon (> 1/1000 to < 1/100); unknown (cannot be estimated from available data).

Gastrointestinal tract.

Common: diarrhea, vomiting, nausea.

Skin and subcutaneous tissue.

Uncommon: allergic dermatitis.

Vascular disorders.

Unknown: malaise with arterial hypotension, with or without loss of consciousness (usually after too rapid intravenous injection, exceptionally after oral administration).

Arterial or venous thrombosis at any site.

Nervous system.

Unknown: seizures, particularly in cases of incorrect use.

Eye disorders.

Unknown: visual disturbances, including impaired color perception.

Immune system.

Unknown: hypersensitivity reactions, including anaphylactic reactions.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after marketing authorization is important. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals and patients, as well as patients’ legal representatives, should report any suspected adverse reactions and lack of efficacy via the Automated Pharmacovigilance Information System at: https://aisf.dec.gov.ua.

Shelf life

Ataksan, injection solution, 100 mg/mL – 3 years.

Ataksan, injection solution, 50 mg/mL – 2 years.

Storage conditions

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

Incompatibilities

Intravenous tranexamic acid must not be added to blood intended for transfusion or to solutions containing penicillin.

Packaging

5 mL of solution in an ampoule. 5 ampoules per cassette. 1 cassette with the package leaflet in a cardboard box.

Prescription status

Prescription only.

Manufacturer

Public Joint-Stock Company "Scientific-Production Center "Borshchagovskiy Chemical and Pharmaceutical Plant".

Manufacturer's address and location of operations

17 Miru Street, Kyiv, 03134, Ukraine.