Sanger

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

Composition:

Active ingredient: tranexamic acid;

1 ml of solution contains 100 mg of tranexamic acid;

Excipient: water for injections.

Pharmaceutical form. Solution for injection.

Main physicochemical properties: clear colorless or slightly yellowish liquid.

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 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. \textit{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, of whom 631 received tranexamic acid, have been described in the scientific literature. 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. Study results indicate that the use of tranexamic acid reduces blood loss and decreases the 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 identified appears to be:

• Initial dose (loading dose) – bolus infusion of 10 mg/kg administered after induction of anesthesia and prior to skin incision;
• continuous infusion at 10 mg/kg/h or intermittent injection into the cardiopulmonary bypass pump adapter at a dose adjusted for the specific surgical procedure or calculated according to patient body weight – 10 mg/kg, or injection into the cardiopulmonary bypass pump adapter and a final dose 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 a therapeutic plasma concentration 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 levels decline in a multi-exponential manner.

Distribution. At therapeutic plasma levels, the protein binding of tranexamic acid to plasma proteins 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 placental barrier. After intravenous administration of 10 mg/kg in pregnant women, the concentration of tranexamic acid in maternal serum ranges from 10–53 μg/mL, while in umbilical cord blood it ranges 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 serum. Concentrations of tranexamic acid in 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 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 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 occurring following surgical intervention on the prostate or as a result of 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. Color vision disorders. Acute venous or arterial thrombosis. Fibrinolytic states due to consumption coagulopathy, except in conditions with excessive activation of the fibrinolytic system during acute severe bleeding. Severe renal impairment (risk of drug accumulation). History of seizures. Subarachnoid hemorrhage. 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 such 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 of tranexamic acid should be administered very slowly (maximum 1 mL per minute);
• 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 comparable to that in patients who did not receive this medicinal product.

Visual disturbances: Possible ophthalmological complications should be carefully monitored, including visual disturbances, decreased visual acuity, and impaired color vision. Treatment should be discontinued in such cases. With continuous long-term use of tranexamic acid (injections), regular ophthalmological examinations should be scheduled (including assessment of visual acuity, color vision, fundus, and visual fields). In patients with pre-existing or newly developed pathological ophthalmological changes, particularly those related to retinal disorders, the physician, after appropriate specialist consultation, should individually determine the necessity and possibility 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 patients 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 hemostasis and must be conducted under strict medical supervision.

Due to the increased risk of thrombosis, tranexamic acid should be used cautiously in patients receiving oral contraceptives.

Disseminated intravascular coagulation (DIC) syndrome: Patients with DIC syndrome generally should not receive treatment with tranexamic acid. If the 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 hematological profile in these conditions is characterized by the following: 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; normal platelet count. The above-mentioned profile implies that various elements of this profile cannot be altered by the underlying disease alone. 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 syndrome should only be considered when appropriate hematological laboratory facilities and clinical experience are available.

Use during pregnancy or breastfeeding

Women of childbearing potential 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 allow identification of 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 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

No studies evaluating the effect on the ability to drive or operate machinery have been conducted.

Method of administration and dosage.

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

Adults

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

For systemic fibrinolysis, tranexamic acid should be administered intravenously slowly at a dose of 1 g or 15 mg/kg body weight every 6–8 hours; the rate of administration should be 1 ml/min.

Dosing in patients with renal impairment

In cases of renal insufficiency leading to a risk of accumulation, 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 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, safety, and dosing specifics in children for the indicated uses 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 in the absence of renal impairment.

Route of administration

Administration must strictly follow the specified regimen – slow intravenous injection/infusion.

Sangery (Sangeryu) can be mixed with most infusion solutions, such as electrolyte solutions, carbohydrate solutions, amino acid solutions, and dextran solutions.

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

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 increased doses.

Treatment of overdose is symptomatic.

Adverse reactions

Below is a list of adverse reactions classified according to the MedDRA system organ class (SOC). Within each organ system class, adverse reactions are listed by frequency. Within each frequency group, reactions are presented in descending order of severity. Frequencies are defined as follows: very common (<u>> 1/10); common (<u>> 1/100 to < 1/10); uncommon (<u>> 1/1000 to < 1/100); unknown (cannot be estimated from available data).

Table 2

Shelf life. 2 years.

Storage conditions.

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

Keep out of the reach of children.

Incompatibility.

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

Packaging.

5 ml or 10 ml in glass ampoules, 5 ampoules in a contour cellular pack, 1 contour cellular pack with the instruction for medical use in a carton.

Prescription status. By prescription only.

Manufacturer.

LLC "Yuria-Pharm".

Manufacturer's address and place of business.

108, Kozbirska St., Cherkasy, Cherkasy region, 18030, Ukraine. Tel.: (044) 281-01-01.