Trombolik-cardio

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT TROMBOLIK-CARDIO (TROMBOLIK-CARDIO)

Composition:

Active substance: acetylsalicylic acid;

1 tablet contains 100 mg of acetylsalicylic acid;

Excipients: microcrystalline cellulose, corn starch, methacrylic acid copolymer dispersion, talc, triethyl citrate, polysorbate 80, sodium lauryl sulfate.

Pharmaceutical form. Enteric-coated tablets.

Main physicochemical properties: white or almost white, round-shaped tablets coated with a film, with convex upper and lower surfaces. When broken, the core surrounded by a single continuous layer is visible under a magnifying glass.

Pharmacotherapeutic group. Antithrombotic agents. Acetylsalicylic acid.

ATC code B01AC06.

Pharmacological properties.

Pharmacodynamics.

Mechanism of action. The antithrombotic effect of acetylsalicylic acid is due to inhibition of thromboxane A2 synthesis in platelets. Since even small doses of acetylsalicylic acid (ASA) are absorbed, all circulating platelets are irreversibly inhibited along the path from the gastrointestinal tract to the liver in the prehepatic mesenteric blood vessels. Meanwhile, concentrations of ASA during posthepatic circulation only slightly inhibit endothelial cyclooxygenase (responsible for prostacyclin synthesis), as it recovers more rapidly. Platelet function related to hemostasis remains largely unchanged.

Clinical efficacy.

Primary prevention. In a meta-analysis by the U.S. Preventive Services Task Force (Ann Intern Med 2002;136:161–172), based on 5 prospective clinical trials, it was demonstrated that the risk of myocardial infarction (relative risk 0.72 [95% confidence interval: 0.60–0.87]) is reduced with prophylactic treatment with acetylsalicylic acid at doses of 75–125 mg over 5–7 years in patients without prior cardiovascular events but with various risk factors (age > 50 years, arterial hypertension, diabetes mellitus, smoking, hypercholesterolemia, family history). This benefit was observed only for non-fatal cardiovascular events; no advantages were observed regarding stroke incidence or overall mortality. The risk of developing severe gastrointestinal bleeding compared to control was 0.8% vs. 0.48%, and the risk of intracranial bleeding was 0.22% vs. 0.17%. The risk of bleeding was higher in patients aged 70 years and older.

Prevention should only be initiated after adequate control of blood pressure has been established and in combination with other therapeutic measures (diet, management of diabetes, lipid metabolism correction, smoking cessation). Risk can be assessed using scales from the European Society of Cardiology (European Heart Journal, 1998, 19:1434–1503).

Secondary prevention. In a meta-analysis conducted by the Antithrombotic Trialists' Collaboration (BMJ 2002;324:71–85), the effects of acetylsalicylic acid and placebo were compared across 287 studies involving 135,000 high-risk patients. Additional comparisons of different platelet aggregation inhibitors were performed in 77,000 patients. High-risk patients were defined as those experiencing acute cardiovascular events or with a history of cardiovascular events (myocardial infarction, transient ischemic attack [TIA], unstable angina, arterial occlusive disease, post-surgical procedures such as aortocoronary bypass, percutaneous transluminal coronary angioplasty, peripheral angioplasty, and patients with arteriovenous shunts on dialysis). A reduction in the risk of serious cardiovascular events (relative reduction of 25%; p < 0.0001) and cardiovascular mortality was observed. The absolute benefit outweighed the risks of extracranial bleeding in all categories of high-risk patients.

Pharmacokinetics.

Absorption. After oral administration, acetylsalicylic acid is rapidly and completely absorbed from the gastrointestinal tract. During and after absorption, it is converted into its main active metabolite—salicylic acid. Due to the enteric coating of the tablets, release of the active substance occurs not in the stomach but in the alkaline environment of the intestine, which in turn leads to delayed absorption of acetylsalicylic acid. Because of the protection of the gastric mucosa, this dosage form is superior to conventional ASA formulations, especially during long-term therapy. Compared to Aspirin, maximum plasma concentrations of salicylates are reached 2–7 hours later.

Distribution. Salicylic acid is bound to plasma proteins by 60–90%.

Bioavailability of salicylates ranges from 80 to 100%.

Metabolism. The half-life of systemically available ASA is approximately 15 minutes. Salicylic acid, formed via hydrolysis, has a half-life of about 2–3 hours, which significantly increases after administration of high doses (> 3 g) due to saturation of the binding enzyme system.

Biotransformation of salicylic acid occurs primarily in the liver. Salicylic acid metabolites are formed by conjugation of salicylic acid with glycine and further conjugation with glucuronic acid or sulfuric acid. A small portion is oxidized to gentisic acid and converted into gentisuric acid.

Elimination. Elimination occurs almost entirely via the kidneys in the form of salicylic acid (about 10%), salicyluric acid (about 75%), and conjugates of salicyluric acid (about 10%). The elimination half-life varies from 2–3 hours after low-dose administration to 12 hours after analgesic doses.

Pharmacokinetics in special clinical situations.

Elimination in patients with hepatic impairment. Since ASA metabolism occurs primarily in the liver, slower degradation of ASA to salicylic acid (accumulation) is expected.

Elimination in patients with renal impairment. Renal impairment does not affect the rate of degradation of salicylic acid; however, concentrations of inactive metabolites of salicylic acid, primarily conjugated salicyluric acid, are increased. Salicylates cross the placenta, but are found only in small amounts in breast milk.

Preclinical data

The preclinical safety profile of acetylsalicylic acid is well documented. In animal studies, salicylates caused kidney damage without other organ involvement. Acetylsalicylic acid has been sufficiently studied for mutagenicity and carcinogenicity; no relevant evidence of mutagenic or carcinogenic properties has been found. Salicylates showed embryotoxic and teratogenic effects in animal studies (e.g., cardiac and skeletal malformations, gastroschisis).

Cases of implantation disorders, embryotoxic and fetotoxic effects, and effects on child learning ability after prenatal exposure to salicylates have been reported.

Clinical characteristics.

Indications.

• Prevention of thrombosis (prevention of reocclusion) after aortocoronary bypass surgery, percutaneous transluminal catheter angioplasty, and after arteriovenous shunting in patients undergoing dialysis.
• Prevention of cerebrovascular stroke following transient ischemic attacks (warning signs).
• Reduction of the risk of coronary thrombosis after myocardial infarction (prevention of recurrent infarction).
• Prevention of myocardial infarction in combination with other therapeutic measures in patients at very high risk of cardiovascular events (according to the benefit-risk assessment by the treating physician).
• Unstable angina.
• Prevention of arterial thrombosis following vascular surgery.
• As part of standard therapy in acute myocardial infarction.
• Prevention of vascular occlusion in arterial occlusive disease.

Contraindications.

• Hypersensitivity to acetylsalicylic acid, other salicylates, or any component of the medicinal product.
• Asthma induced by salicylates or substances with similar activity, especially NSAIDs, in medical history.
• Acute peptic ulcers.
• Hemorrhagic diathesis.
• Severe renal insufficiency.
• Severe hepatic insufficiency.
• Severe congestive heart failure.
• Combination with methotrexate at doses of 15 mg/week or higher (see section "Interaction with other medicinal products and other forms of interaction").
• Third trimester of pregnancy (see section "Use in pregnancy or lactation").

Interaction with other medicinal products and other forms of interaction.

Contraindicated combinations

• When used concomitantly with methotrexate at doses of 15 mg/week or higher, hematological toxicity of methotrexate increases (due to reduced renal clearance of methotrexate by anti-inflammatory agents and displacement of methotrexate from plasma protein binding by salicylates) (see section "Contraindications").

Combinations requiring caution

• When used concomitantly with methotrexate at doses less than 15 mg/week, hematological toxicity of methotrexate may increase (due to reduced renal clearance of methotrexate by anti-inflammatory agents and displacement of methotrexate from plasma protein binding by salicylates).
• Antidiabetic agents (e.g., insulin, sulfonylureas): possible reduction in blood glucose levels.
• Potentiation of the effects of anticoagulants/thrombolytic agents, barbiturates, lithium, sulfonamides, and triiodothyronine.
• Pharmacodynamic interactions may occur between selective serotonin reuptake inhibitors (SSRIs) and acetylsalicylic acid: increased risk of bleeding due to synergistic effects.
• Increased plasma concentration of digoxin due to reduced renal excretion.
• Increased plasma levels of phenytoin and valproate. When used concomitantly with valproic acid, acetylsalicylic acid displaces it from plasma protein binding, reducing its metabolism. As a result, plasma valproate levels increase, leading to a higher incidence of adverse reactions and signs of intoxication such as tremor, nystagmus, ataxia, and personality changes.
• Enhanced effects and adverse reactions of all non-steroidal anti-rheumatic agents.
• Concomitant use with NSAIDs such as ibuprofen or naproxen may attenuate the irreversible platelet inhibition by acetylsalicylic acid. The clinical significance of this interaction is unknown. Treatment with NSAIDs such as ibuprofen or naproxen in patients at risk of cardiovascular disease may reduce the cardioprotective effect of acetylsalicylic acid (see section "Special precautions").
• Metamizole may inhibit the effect of acetylsalicylic acid on platelet aggregation when used concomitantly; therefore, this combination should be used with caution in patients taking low-dose acetylsalicylic acid for cardioprotection.
• Antihypertensive agents (ACE inhibitors and β-blockers): patients receiving both this product and the aforementioned medicinal products should have their blood pressure monitored closely, with dose adjustments as necessary.
• Diuretics in combination with high doses of acetylsalicylic acid: reduced diuretic efficacy.
• Reduced efficacy of uricosuric agents (e.g., probenecid, sulfinpyrazone).
• Systemic glucocorticosteroids: increased risk of gastrointestinal ulcers and bleeding. Decreased blood levels of salicylates during corticosteroid therapy; risk of salicylate overdose after discontinuation of glucocorticosteroid therapy.
• Alcohol: increased risk of gastrointestinal ulcers and bleeding, prolonged bleeding time.

Prolongation of the plasma elimination half-life of penicillin.

Special precautions for use.

Trombolyk-Cardio should be used with caution in the following situations:

• Impaired renal function or impaired cardiovascular circulation (e.g. renal vascular disease, congestive heart failure, hypovolemia, extensive surgery, sepsis, or severe bleeding), as acetylsalicylic acid may also increase the risk of renal dysfunction and acute renal failure;
• Impaired liver function;
• Concomitant use of NSAIDs such as ibuprofen or naproxen, as NSAIDs may reduce the inhibitory effect of acetylsalicylic acid on platelet aggregation. If Trombolyk-Cardio is used, the patient should consult a physician before starting NSAIDs for pain relief (see section "Interaction with other medicinal products and other forms of interaction");
• Presence of symptoms of chronic gastric or duodenal dyspepsia or their recurrence;
• Presence of bronchial asthma or general tendency to hypersensitivity, as acetylsalicylic acid may cause bronchospasm, an asthma attack, or other hypersensitivity reactions. Risk factors include a history of asthma, hay fever, nasal polyps, or chronic respiratory disease: allergic reactions (e.g. rash, itching, or urticaria) to other substances in the past;
• Nasal polyps;
• Severe glucose-6-phosphate dehydrogenase deficiency, as acetylsalicylic acid may cause hemolysis or hemolytic anemia. Factors that may increase the risk of hemolysis include high drug doses, fever, or acute infection;
• Concomitant use of anticoagulants;
• Due to the inhibitory effect of acetylsalicylic acid on platelet aggregation, which persists for several days after administration, the use of products containing acetylsalicylic acid may increase the likelihood or severity of bleeding during surgical procedures (including minor surgical interventions, such as tooth extraction).

When used in low doses, ASA reduces uric acid excretion. In patients who normally have reduced uric acid excretion, this may lead to the development of gout.

The use of acetylsalicylic acid in children and adolescents with fever and/or viral infections is possible only upon a physician's prescription as second-line therapy (due to the risk of Reye's syndrome, a life-threatening encephalopathy whose main symptoms include severe vomiting, loss of consciousness, and liver dysfunction).

In certain viral infections, particularly influenza A, influenza B, and varicella, there is a risk of developing Reye's syndrome, a very rare but life-threatening condition requiring immediate medical intervention. The risk may be increased if acetylsalicylic acid is used concomitantly, although a causal relationship has not been proven. If these conditions are accompanied by persistent vomiting, this may be a manifestation of Reye's syndrome;

• Gastrointestinal ulcers, including chronic and recurrent ulcer disease or gastrointestinal bleeding in the past;
• Hypersensitivity to analgesics, anti-inflammatory, or anti-rheumatic agents, as well as allergy to other substances.

Use during pregnancy or breastfeeding.

Pregnancy.

Suppression of prostaglandin synthesis may negatively affect pregnancy and/or embryonic/fetal development. Epidemiological data indicate an increased risk of miscarriage and cardiac malformations and gastroschisis following the use of prostaglandin synthesis inhibitors in early pregnancy. The risk increases with higher doses and longer duration of therapy.

Epidemiological data do not confirm an association between acetylsalicylic acid use and an increased risk of miscarriage. Epidemiological data on miscarriage are inconsistent, but an increased risk of gastroschisis cannot be excluded with acetylsalicylic acid use. Results from a prospective study on the effect of the drug in early pregnancy (1–4 months) involving approximately 14,800 mother-child pairs do not indicate any association with an increased risk of malformations.

During the first and second trimesters of pregnancy, products containing acetylsalicylic acid should not be prescribed without clear clinical necessity. For women who may be pregnant and for pregnant women in the first and second trimesters, the dose of products containing acetylsalicylic acid should be as low as possible and the duration of treatment as short as possible.

Animal studies have shown that the use of prostaglandin inhibitors leads to increased pre- and post-implantation losses and embryo/fetal death. In addition, a higher frequency of severe developmental abnormalities, including cardiovascular defects, has been observed in animals treated with prostaglandin inhibitors during organogenesis.

According to previous experience, the risk is low when the drug is used at therapeutic doses.

All prostaglandin synthesis inhibitors may:

• Affect the fetus as follows:
  • Cardio-pulmonary toxicity (with premature closure of the ductus arteriosus and pulmonary hypertension);
  • Impaired renal function with possible subsequent development of renal failure with oligohydramnios;
• Affect the woman and the fetus as follows:
  • Prolonged bleeding time, anti-aggregatory effect, which may occur even with very low doses;
  • Inhibition of uterine contractions and bleeding in the pregnant woman and prolonged duration of labor.

Therefore, acetylsalicylic acid is contraindicated during the third trimester of pregnancy.

Breastfeeding. Salicylates pass into breast milk. Concentrations in breast milk are equivalent to or even higher than plasma concentrations in the mother.

In cases of unavoidable use during lactation, breastfeeding should be discontinued if high doses (> 300 mg/day) are regularly used.

Ability to affect reaction speed when driving or operating machinery.

No effect on the ability to drive or operate machinery has been reported.

Method of administration and dosage.

Unless otherwise prescribed by a physician, the following dosages are recommended:

Cardiovascular indications without aortocoronary bypass or percutaneous transluminal catheter angioplasty: 1 × 100 mg/day.

Prevention of thrombosis after aortocoronary bypass or percutaneous transluminal catheter angioplasty: 100–300 mg/day.

Prevention of cerebrovascular stroke after transient ischemic attacks (TIA): 3 × 100 mg/day or 1 × 300 mg/day.

It is recommended to take the tablet with a small amount of liquid at least 30 minutes before meals. Drink ½–1 glass of water. To prevent the release of the active substance before reaching the alkaline environment of the intestine, tablets should not be crushed, split, or chewed.

Acute myocardial infarction: In the case of acute myocardial infarction, 200–300 mg of acetylsalicylic acid should be administered intravenously or orally in a form with rapid release of acetylsalicylic acid (not enteric-coated). Enteric-coated acetylsalicylic acid tablets should be crushed or chewed before administration to achieve faster absorption. After this, 100 mg of Trombolyk-Cardio should be taken daily.

Children.

According to the indications (see section "Indications"), Trombolyk-Cardio should not be used in children (under 18 years) due to the lack of data on efficacy and safety in this patient group.

The use of acetylsalicylic acid in children under 16 years of age may cause severe adverse effects (including Reye's syndrome, one of the signs of which is persistent vomiting). Please refer to the information provided in the section "Special precautions for use."

Overdose.

Severe intoxication may be life-threatening. Newborns are more sensitive than adults. Symptoms of severe poisoning may develop acutely or slowly, e.g., within 12–24 hours after administration. After oral administration of ASA doses up to 150 mg/kg body weight, moderate intoxication may occur, and at doses > 300 mg/kg body weight, severe intoxication.

Absorption of acetylsalicylic acid may be delayed due to delayed gastric emptying, formation of concretions in the stomach, or when the drug is taken in enteric-coated tablet form.

The severity of the condition cannot be assessed solely based on salicylate concentration in plasma. Arterial blood gas analysis (ABGA) must be carefully monitored, as therapy is based not on blood salicylate levels but on clinical symptoms and ABGA.

Warning.

Local signs of irritation, which usually predominate in ASA overdose, such as nausea, vomiting, and stomach pain, may be absent because this pharmaceutical form of ASA has an enteric coating and absorption occurs only in the small intestine.

Symptoms.

Headache, nausea, hypoglycemia or hyperglycemia, skin rash, dizziness, tinnitus, visual and hearing disturbances, tremor, confusion, hyperthermia, increased sweating, hyperventilation, respiratory alkalosis with metabolic compensation leading to metabolic acidosis, electrolyte imbalance, dehydration, seizures, coma, respiratory distress syndrome, cardiac arrhythmia.

Symptoms of chronic salicylate poisoning are nonspecific (e.g., tinnitus, headache, irritability, increased sweating, hyperventilation) and may therefore go unnoticed.

Treatment.

Due to life-threatening conditions resulting from severe intoxication, all necessary preventive measures should be taken immediately: immediate hospitalization, prevention or reduction of resorption by administering appropriate doses of activated charcoal within the first 4 hours (10 times the amount of activated charcoal relative to the mass of ASA); in case of severe intoxication—gastric lavage or endoscopic removal of tablets.

Appropriate monitoring and correction of electrolytes. Administration of glucose and sodium bicarbonate in the early stages to correct acidosis and to accelerate excretion (urine pH > 8), improvement of diuresis, cooling in case of hyperthermia, benzodiazepines for seizures.

Hemodialysis may be considered in cases of severe intoxication.

Cases of decompensation leading to fatal outcomes after intubation have been described. Therefore, if possible, intubation should be performed after initiation of alkalization, apnea time should be minimized, and support of hyperventilation should be maintained.

Detailed information can be obtained from a toxicology center.

Adverse reactions.

Within each group, adverse reactions are listed in decreasing order of severity: very common: > 1/10; common: > 1/100 to < 1/10; uncommon: > 1/1000 to < 1/100; rare: > 1/10,000 to < 1/1000; very rare: < 1/10,000.

Information on other adverse reactions has been reported spontaneously for all dosage forms of acetylsalicylic acid, including oral short-term and long-term therapy; therefore, classification by frequency categories is not possible.

In patients with severe glucose-6-phosphate dehydrogenase deficiency, hemolysis and hemolytic anemia have been observed.

Due to the antiplatelet effect, the use of ASA may increase the risk of bleeding. Bleeding events such as perioperative bleeding, hematomas, epistaxis, urogenital bleeding, and gingival bleeding have been observed.

Serious bleeding events, such as gastrointestinal bleeding and hemorrhagic stroke, have been observed rarely or very rarely, especially in patients with uncontrolled arterial hypertension and/or concomitant use of anticoagulants, which in some cases could potentially be life-threatening.

Blood and lymphatic system disorders:
Prolongation of bleeding time;
rare: thrombocytopenia, agranulocytosis, pancytopenia, leukopenia, aplastic anemia, iron-deficiency anemia.

Immune system disorders:
uncommon: asthma;
rare: hypersensitivity reactions such as erythematous/eczematous skin reactions, urticaria, rhinitis, nasal congestion, bronchospasm, angioedema, hypotension progressing to shock;
very rare: severe skin reactions including exudative multiform erythema, Stevens-Johnson syndrome, toxic epidermal necrolysis.

Metabolism and nutrition disorders:
very rare: hypoglycemia, acid-base imbalance.

Nervous system disorders:
rare: headache, dizziness, tinnitus, visual disturbances, hearing disturbances, confusion.

Gastrointestinal disorders:
very common: microbleeding (70%);
common: gastric symptoms;
uncommon: dyspepsia, nausea, vomiting, diarrhea;
rare: gastrointestinal bleeding, gastrointestinal ulcers, which in very rare cases may lead to perforation.

Hepatobiliary disorders:
rare: hepatic dysfunction;
very rare: increased transaminase levels.

Renal and urinary disorders:
rare: renal function impairment;
acute kidney injury has been reported.

Other:
very rare: Reye's syndrome (see section "Special precautions").

Bleeding may lead to acute and chronic post-hemorrhagic anemia/iron-deficiency anemia (due to so-called occult microbleeding), with corresponding laboratory findings and clinical symptoms such as asthenia, pallor of the skin, and hypoperfusion.

Gastrointestinal disturbances such as general symptoms and signs of dyspepsia, epigastric pain, and abdominal pain; in individual cases, inflammation of the gastrointestinal tract, erosive-ulcerative lesions of the gastrointestinal tract, which potentially may in rare cases lead to gastrointestinal hemorrhage and perforation, with corresponding laboratory and clinical manifestations.

Hypersensitivity reactions with corresponding laboratory and clinical manifestations include asthmatic episodes, mild to moderate skin reactions, and reactions involving the respiratory, gastrointestinal, and cardiovascular systems, including symptoms such as rash, swelling, pruritus, cardiorespiratory failure, and very rarely severe reactions including anaphylactic shock.

Shelf life.
4 years.

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

Packaging.
10 tablets of 100 mg in blisters.
2, 3, or 10 blisters per cardboard pack.

Prescription status.
Over-the-counter.

Manufacturer.
JSC "Tekhnolohiya".

Manufacturer's address and location of business activity.
8 Stara Prorina Street, Uman, Cherkasy region, 20300, Ukraine.