Gemoaktiv

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT HEMOACTIV (HEMOACTIV)

Composition:

Active substance: tranexamic acid;

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

Excipient: water for injections.

Pharmaceutical form. Injection solution.

Main physicochemical properties: clear, colorless solution.

Pharmacotherapeutic group.

Antihemorrhagic agents. Fibrinolysis inhibitors.
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 mediated by plasmin. The activity of the complex of tranexamic acid and plasmin 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 intervention, and dosing regimen. Results from studies on the use of tranexamic acid indicate reduced blood loss and decreased need for blood products 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 has been determined 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 for the specific surgical procedure or calculated according to 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. Peak plasma concentrations of tranexamic acid are rapidly achieved following short-term intravenous infusion, after which plasma concentrations decline in a multiexponential manner.

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

Tranexamic acid crosses the placenta. After intravenous administration of 10 mg/kg in pregnant women, serum concentrations range between 10–53 µg/mL, while concentrations in umbilical cord blood range between 4–31 µg/mL. Tranexamic acid rapidly penetrates into joint fluid and synovial tissue. After intravenous injection of 10 mg/kg in patients undergoing knee surgery, concentrations in joint fluid are similar to those in serum. Concentrations of tranexamic acid in various other tissues and fluids are proportional to blood levels (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 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 route of elimination. Renal clearance is practically equivalent to plasma clearance (110 to 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 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 in connection with surgical intervention on the prostate gland 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, 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 of the medicinal product.
Acute venous or arterial thrombosis. Fibrinolytic states with acute severe bleeding due to administration of anticoagulant agents, 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 carried out 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 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.

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: Cases of seizures associated with tranexamic acid treatment 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, including visual disturbances, deterioration of vision, and color vision disturbances, should be carefully monitored. Treatment should be discontinued if such symptoms occur. With continuous long-term use of tranexamic acid (injections), regular ophthalmological examinations (including assessment of visual acuity, color vision, fundoscopy, visual fields, etc.) should be scheduled. In the presence of, or if pathological ophthalmological changes develop—particularly those related to retinal disorders—the physician, after appropriate specialist consultation, 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 tranexamеic 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. 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 used cautiously in patients taking oral contraceptives.

Disseminated intravascular coagulation (DIC): Patients with DIC syndrome generally should not receive treatment with tranexamic acid. If use of tranexamic acid is considered necessary, it should be prescribed exclusively in cases of predominant activation of the fibrinolytic system associated with acute, severe bleeding. The characteristic hematological profile in such 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 implies that various elements of this profile cannot be independently altered by the underlying disease alone. In such acute cases, a single dose of 1 g of tranexamic acid is often sufficient to control bleeding. The use of tranexamic acid in patients with DIC syndrome should only be considered when appropriate hematological laboratory support and sufficient clinical experience are available.

Use during pregnancy or breastfeeding.

Women of childbearing potential should use effective contraceptive methods during treatment.

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

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 these data do not indicate a harmful effect on the fetus. Tranexamic acid may 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.

Hemоactive is administered intravenously (by drip 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; the infusion rate should be 1 ml/min.

In local fibrinolysis, the recommended starting dose is 500 mg (1 vial of 5 ml) up to 1 g (2 vials of 5 ml) of tranexamic acid administered 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 not required in patients with hepatic dysfunction.

Use in children.

Children aged 1 year and older may be treated when indicated (see section "Indications"), with a dosage of approximately 20 mg/kg/day. However, data on efficacy, safety, and dosing specifics 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 studied.

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 specified regimen – slow intravenous administration (injection/infusion).

Tranexamic acid should not be administered intramuscularly.

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

Intravenous infusion: tranexamic acid must be mixed immediately before use with the following injectable/infusion solutions:

sodium chloride 0.9%, injection solution; Ringer's injection solution;
dextrose 5% injection solution; dextrin-40 in dextrose 5% injection solution; dextrin-40 in sodium chloride 0.9% injection solution; 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 seizures (convulsions). Seizures have been shown to occur more frequently with higher infusion rates and are typically associated with increased doses.

Treatment of overdose is symptomatic.

Adverse reactions.

The adverse reactions listed below are classified according to the MedDRA system organ class (SOC). Within each organ system class, adverse reactions are ranked by frequency. Within each frequency group, reactions are listed in order of decreasing severity. Frequency has been defined as follows: very common (> 1/10); common (> 1/100 to < 1/10); uncommon (> 1/1,000 to < 1/100); unknown (cannot be estimated from available data).

Table 2

Shelf life. 2 years.

Storage conditions.

Store in the original packaging at a temperature not exceeding 25 °C.

Keep out of reach of children.

Incompatibility.

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

Packaging.

5 ml in a vial, 5 vials in a cardboard pack.

Prescription status. Prescription only.

Manufacturer.

PT. NOVELL PHARMACEUTICAL LABORATORIES

PT. NOVELL PHARMACEUTICAL LABORATORIES

Manufacturer's address.

Jl. Wanaherang No. 35 Tlajung Udik, Gunung Putri Bogor 16962, Indonesia

Jl. Wanaherang No. 35 Tlajung Udik, Gunung Putri Bogor 16962, Indonesia

Marketing authorization holder.

M.Biotech Ltd

M.Biotech Ltd

Address of the marketing authorization holder.

Gladstone House, 77-79 High Street, Egham TW20 9HY, Surrey, United Kingdom

Gladstone House, 77-79 High Street, Egham TW20 9HY, Surrey, United Kingdom