Hemoactiv-mb

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT HEMOACTIV-MB (HEMOACTIV-MB)

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 its 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 of these were evaluated in comparison with a placebo control group. The study population was heterogeneous with respect to age, type of surgical procedure, and dosing. 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) during high-risk bleeding procedures, particularly in "cyanotic" patients (with significant circulatory impairment) or patients undergoing repeat surgery. The most appropriate dosing regimen identified may be as follows:

• 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 injection 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 concentration of tranexamic acid is 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 to plasma proteins 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 to 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 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 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 virtually no effect on sperm motility.

Elimination. The drug is primarily excreted in urine in unchanged form. 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 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 in connection with surgical intervention on the prostate gland or as a result of surgery or procedures 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, for example 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 coagulopathic agents (anticoagulants), except for those agents that predominantly activate the fibrinolytic system. Severe renal impairment (risk of drug accumulation). History of seizures. Intrathecal and intraventricular injectable administration, 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 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, for example when using estrogens. In addition, 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 specified 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 aortocoronary 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 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 in such cases. With continuous long-term use of tranexamic acid (injections), regular ophthalmological examinations (including visual acuity testing, color vision testing, fundoscopy, visual field testing, 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 determine 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 ureteral obstruction.

Thromboembolic complications: Before prescribing tranexamic acid, consider risk factors for thromboembolic complications. 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 only after consultation with a specialist experienced in hemostasiology and must be conducted under strict medical supervision.

Due to the increased risk of thrombosis, tranexamic acid should be prescribed with caution to 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 accompanied by acute, severe bleeding. 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 alpha-2-macroglobulin; normal plasma levels of P and P-complex; 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 spontaneously change due to the underlying disease alone. 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 reproductive 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 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.

Studies evaluating the effect on the ability to drive or operate machinery have not been conducted.

Administration and Dosage

Hemоaktiv-MB is administered intravenously (by drip 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; the rate of administration is 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 severe renal impairment, the use of tranexamic acid is contraindicated. 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

Children aged 1 year and older may be administered the drug when indicated (see section "Indications"), at a dosage of approximately 20 mg/kg/day. However, data on efficacy, safety, and dosing specifics in pediatric patients for the indicated uses are limited.

The aspects of efficacy, dosing characteristics, and safety of tranexamic acid use 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.

Administration method

Administration must strictly follow a specified regimen – slow intravenous injection (bolus) or 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 should be mixed immediately before use with one of 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 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 higher infusion rates and are characteristic of increased dosage.

Treatment of overdose is symptomatic.

Adverse reactions

The adverse reactions listed below are classified according to the MedDRA system organ class. Within each organ class, adverse reactions are listed by frequency. Within each frequency group, adverse reactions are presented in descending order of severity. Frequency is defined as follows: very common (<u>> 1/10); common (<u>> 1/100 to < 1/10); uncommon (<u>> 1/1,000 to < 1/100); not known (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 the 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 box.

Prescription status. Prescription only.

Manufacturer.

IMMAKUL LIFESCIENCES PRIVATE LIMITED

IMMACULE LIFESCIENCES PRIVATE LIMITED

Manufacturer's address and place of business.

Village Thanthewal, Ropar Road, Nalagarh, District Solan, Himachal Pradesh, IN 174101, India

Village Thanthewal, Ropar Road, Nalagarh, District Solan, Himachal Pradesh, IN 174101, India

Marketing Authorization Holder.

M.Biotech Limited

M.Biotech Limited

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