Cardiseyv®

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT KARDISEYV® (CARDISAVE)

Composition:

Active substance: acetylsalicylic acid;

One tablet contains 150 mg of acetylsalicylic acid, calculated as 100% dry substance;

Excipients: magnesium hydroxide, pregelatinized starch, microcrystalline cellulose, magnesium stearate;

Film coating: Opadry II 85G18490 white (polyvinyl alcohol, polyethylene glycol, talc, titanium dioxide (E 171), lecithin).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: white or almost white, round, biconvex tablets with a score line, coated with a film coating.

Pharmacotherapeutic group. Antithrombotic agents. Inhibitors of platelet aggregation, excluding heparin. ATC code B01AC06.

Pharmacological Properties.

Pharmacodynamics.

Acetylsalicylic acid is an analgesic, anti-inflammatory, antipyretic, and antiplatelet agent. Its antiplatelet properties increase bleeding time.

The main pharmacological effect is inhibition of prostaglandin and thromboxane formation. The analgesic effect is an additional effect caused by inhibition of the enzyme cyclooxygenase. The anti-inflammatory effect is associated with reduced blood flow due to inhibition of PGE2 synthesis.

Acetylsalicylic acid irreversibly inhibits the synthesis of prostaglandins G/H. Its effect on platelets lasts longer than the presence of acetylsalicylic acid in the body. The effect of acetylsalicylic acid on thromboxane biosynthesis in platelets and on bleeding time persists for a prolonged period after discontinuation of treatment. The effect ceases only after new platelets appear in blood plasma.

Salicylic acid (the active metabolite of acetylsalicylic acid) has anti-inflammatory activity and also affects respiratory processes, acid-base balance, and gastric mucosa. Salicylates stimulate respiration, primarily through a direct effect on the medulla oblongata. Salicylates indirectly affect gastric mucosa by inhibiting its vasodilatory and cytoprotective prostaglandins, thereby increasing the risk of ulcer development.

Pharmacokinetics.

Absorption. After oral administration, acetylsalicylic acid is rapidly absorbed from the gastrointestinal tract. Absorption of the non-ionized form of acetylsalicylic acid occurs in the stomach and intestine. The rate of absorption is reduced by food intake and in patients experiencing migraine attacks, and increased in patients with achlorhydria or in those taking polysorbates or antacids. Maximum plasma concentration is achieved within 1–2 hours.

Distribution. Plasma protein binding of acetylsalicylic acid is 80–90%. The volume of distribution in adults is 170 ml/kg of body weight. As plasma concentration increases, protein binding sites become saturated, leading to an increased volume of distribution. Salicylates are extensively bound to plasma proteins and rapidly distributed throughout the body. Salicylates penetrate into breast milk and can cross the placental barrier.

Metabolism. Acetylsalicylic acid is hydrolyzed to its active metabolite—salicylic acid—in the gastric wall. After absorption, acetylsalicylic acid is rapidly converted into salicylic acid, although it remains the predominant form in plasma during the first 20 minutes after oral administration.

Excretion. Salicylic acid undergoes metabolism primarily in the liver. Thus, the steady-state plasma concentration of salicylate increases disproportionately relative to the orally administered dose. At a dose of 325 mg of acetylsalicylic acid, elimination follows first-order kinetics. The elimination half-life is 2–3 hours. At high doses of acetylsalicylic acid, the elimination half-life increases to 15–30 hours. Salicylic acid is also excreted unchanged in urine. The amount of salicylic acid excreted depends on the dose and urine pH. Approximately 30% of the dose is excreted in urine when urine is alkaline, compared to only 2% when urine is acidic. Renal excretion occurs via glomerular filtration, active tubular secretion, and passive tubular reabsorption.

Clinical characteristics.

Indications.

Acute and chronic ischemic heart disease.

Contraindications.

CardiSav® is contraindicated in the following conditions/diseases:

• Known or suspected hypersensitivity to acetylsalicylic acid, other salicylates, non-steroidal anti-inflammatory drugs (NSAIDs), or to any component of the drug.
• Predisposition to bleeding (vitamin K deficiency, thrombocytopenia, hemophilia).
• Active peptic ulcers.
• Severe renal failure (glomerular filtration rate < 0.2 mL/s (10 mL/min)).
• Severe hepatic failure.
• Severe heart failure.
• Third trimester of pregnancy (see section «Use during pregnancy or breastfeeding»).

Interaction with other medicinal products and other types of interactions.

Contraindications for concomitant use.

Metotrexate. Concomitant use of acetylsalicylic acid and methotrexate at doses of 15 mg/week or higher increases the hematological toxicity of methotrexate (due to reduced renal clearance of methotrexate caused by anti-inflammatory agents and displacement of methotrexate from plasma protein binding by salicylates).

ACE inhibitors. Angiotensin-converting enzyme (ACE) inhibitors in combination with high doses of acetylsalicylic acid may reduce glomerular filtration due to inhibition of the vasodilatory effect of prostaglandins and may reduce antihypertensive efficacy.

Acetazolamide. Increased acetazolamide concentrations may occur, potentially leading to salicylate transfer from plasma into tissues and resulting in acetazolamide toxicity (fatigue, lethargy, somnolence, confusion, hyperchloremic metabolic acidosis) and salicylate toxicity (vomiting, tachycardia, hyperpnea, confusion).

Probenecid, sulfinpyrazone. When probenecid is used concomitantly with high-dose salicylates (>500 mg), mutual inhibition of metabolism may occur, potentially reducing uric acid excretion.

Combinations requiring caution.

Clopidogrel, ticlopidine. Combined use of clopidogrel and acetylsalicylic acid has a synergistic effect. Such combination therapy should be used with caution due to increased risk of bleeding.

Anticoagulants (warfarin, phenprocoumon). Possible reduction in thrombin production, resulting in an indirect effect on decreased platelet activity (vitamin K antagonist), thereby increasing the risk of bleeding.

Abciximab, tirofiban, eptifibatide. Possible inhibition of platelet glycoprotein IIb/IIIa receptors, leading to increased risk of bleeding.

Heparin. Possible reduction in thrombin production, resulting in an indirect effect on decreased platelet activity, thereby increasing the risk of bleeding.

If two or more of the above-mentioned agents are used concomitantly with acetylsalicylic acid, this may result in a synergistic effect enhancing platelet activity inhibition and, consequently, exacerbating hemorrhagic diathesis.

NSAIDs and COX-2 inhibitors (celecoxib). Concomitant use increases the risk of gastrointestinal disorders, which may lead to gastrointestinal bleeding.

Ibuprofen. Concurrent use of ibuprofen inhibits the irreversible platelet aggregation induced by acetylsalicylic acid. Treatment with ibuprofen in patients with increased cardiovascular risk may reduce the cardioprotective effect of acetylsalicylic acid.

Patients taking acetylsalicylic acid once daily for cardiovascular disease prevention who occasionally take ibuprofen should take acetylsalicylic acid at least 2 hours before ibuprofen.

Furosemide. Possible inhibition of proximal tubular elimination of furosemide, leading to reduced diuretic effect.

Quinidine. Possible additive effect on platelets, leading to prolonged bleeding time.

Spironolactone. Possible altered renin effect, leading to reduced spironolactone efficacy.

Selective serotonin reuptake inhibitors (SSRIs). Concomitant use increases the risk of gastrointestinal disorders, which may lead to gastrointestinal bleeding.

Valproate. When used concomitantly with valproate, acetylsalicylic acid displaces valproate from plasma protein binding, increasing its toxicity (central nervous system (CNS) depression, gastrointestinal disturbances).

Systemic glucocorticoids (excluding hydrocortisone used for replacement therapy in Addison's disease) reduce salicylate blood levels and increase the risk of overdose after discontinuation of treatment.

Antidiabetic agents. Concomitant use of acetylsalicylic acid and antidiabetic agents increases the risk of hypoglycemia.

Antacids. Possible increase in renal clearance and reduced renal reabsorption (due to increased urine pH), leading to reduced efficacy of acetylsalicylic acid.

Varicella vaccine. Concomitant use increases the risk of Reye's syndrome.

Ginkgo biloba. Concomitant use with Ginkgo biloba inhibits platelet aggregation, increasing the risk of bleeding.

Digoxin. When used concomitantly with digoxin, digoxin plasma concentration increases due to reduced renal excretion.

Alcohol promotes damage to the gastrointestinal mucosa and prolongs bleeding time due to synergism between acetylsalicylic acid and alcohol.

Metamizole. Concomitant use of acetylsalicylic acid and metamizole may reduce clinically significant platelet aggregation. Therefore, combination products containing acetylsalicylic acid and metamizole should be used with caution in patients taking low-dose aspirin for cardioprotection.

Special precautions for use.

To prevent the risk of adverse reactions, prolonged use of the medicinal product Cardisev® in combination with other NSAIDs is not recommended.

Prolonged use of the product in elderly patients for the treatment of pain, inflammation, fever, or rheumatic diseases is not recommended due to the risk of gastrointestinal bleeding. Because of the risk of gastrointestinal bleeding in elderly patients, low-dose acetylsalicylic acid should be used with caution for the treatment of acute or chronic ischemic heart disease, stroke, stroke prevention, and ischemic heart disease.

The medicinal product Cardisev® should be used with caution in the following situations:

• gastrointestinal mucosal disorders;
• tendency to dyspepsia;
• concomitant treatment with anticoagulants (vitamin K antagonists and heparin (see section "Interaction with other medicinal products and other forms of interaction"));
• hypersensitivity to analgesics, anti-inflammatory, or anti-rheumatic agents, as well as in the presence of allergy to other substances;
• gastrointestinal ulcers, including chronic and recurrent peptic ulcers or gastrointestinal bleeding in medical history;
• concomitant use of anticoagulants;
• impaired kidney function or cardiovascular circulation disorders (e.g., renal vascular pathology, congestive heart failure, hypovolemia, extensive surgery, sepsis, or severe bleeding), since acetylsalicylic acid may also increase the risk of impaired kidney function and acute kidney injury;
• severe glucose-6-phosphate dehydrogenase deficiency, as acetylsalicylic acid may cause hemolysis or hemolytic anemia;
• especially in the presence of factors that may increase the risk of hemolysis (high drug doses, fever, or acute infectious conditions);
• impaired liver function.

Ibuprofen may reduce the inhibitory effect of acetylsalicylic acid on platelet aggregation. If the medicinal product Cardisev® is used before starting ibuprofen as an analgesic, the patient should consult a physician.

Acetylsalicylic acid may cause bronchospasm or an asthma attack or other hypersensitivity reactions. Risk factors include a history of asthma, hay fever, nasal polyps, or chronic respiratory disease, and allergic reactions (e.g., skin reactions, itching, urticaria) to other substances in the past.

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 of increased bleeding during surgical procedures (including minor surgical interventions, such as tooth extraction).

When low doses of acetylsalicylic acid are used, excretion of uric acid may be reduced. This may trigger a gout attack in predisposed patients.

Products containing acetylsalicylic acid should not be used in children and adolescents with acute respiratory viral infections (ARVI), whether or not accompanied by elevated body temperature, without consulting a physician. In certain viral diseases, particularly influenza A, influenza B, and varicella, there is a risk of developing Reye's syndrome, which is a very rare but life-threatening condition requiring immediate medical intervention. The risk may be increased if acetylsalicylic acid is used as a concomitant medicinal product, although a causal relationship has not been established in this case. If these conditions are accompanied by persistent vomiting, this may be a manifestation of Reye's syndrome.

If the risk of increased bleeding outweighs the risk of ischemia, the possibility of temporarily discontinuing low-dose treatment with the medicinal product Cardisev® several days before a scheduled surgery should be considered.

Fertility. The use of acetylsalicylic acid may reduce fertility; therefore, the product is not recommended for women wishing to become pregnant. Discontinuation of acetylsalicylic acid should be considered for women who are unable to conceive or undergoing infertility evaluation (see section "Use during pregnancy or breastfeeding").

Use during pregnancy or breastfeeding.

Inhibition of prostaglandin synthesis may adversely affect pregnancy and/or embryonic/fetal development. Epidemiological data available indicate a risk of miscarriage and fetal malformations after use of prostaglandin synthesis inhibitors in early pregnancy. The risk increases with increasing dose and duration of therapy. According to available data, no link between acetylsalicylic acid intake and an increased risk of miscarriage has been confirmed.

Available epidemiological data on the occurrence of birth defects are inconsistent; however, an increased risk of gastroschisis cannot be ruled out with the use of acetylsalicylic acid.

Results of a prospective study on early pregnancy exposure (1–4 months) involving approximately 14,800 mother-child pairs do not indicate any association with an increased risk of malformations.

Animal studies indicate reproductive toxicity.

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 or during the first and second trimesters of pregnancy, the dose of products containing acetylsalicylic acid should be as low as possible, and the duration of treatment should be as short as possible.

During the third trimester of pregnancy, all prostaglandin synthesis inhibitors may affect the fetus as follows:

• cardiopulmonary toxicity (with premature closure of the ductus arteriosus and pulmonary hypertension);
• impaired kidney function with possible subsequent development of renal failure associated with oligohydramnios.

In women and newborns at the end of pregnancy, prostaglandin synthesis inhibitors may have the following effects:

• possible prolongation of bleeding time, anti-aggregatory effect, which may occur even after very low doses;
• inhibition of uterine contractions, which may lead to delayed or prolonged labor.

Due to these effects, acetylsalicylic acid is contraindicated during the third trimester of pregnancy.

Salicylates and their metabolites pass into breast milk in small amounts.

Since no harmful effects of the drug on the infant have been observed after administration to women during lactation, breastfeeding interruption is generally not required. However, with regular use or use of high doses, breastfeeding should be discontinued at an early stage.

Fertility.

Acetylsalicylic acid should not be used in women who are trying to conceive, as prostaglandin synthesis inhibitors reduce fertility.

If acetylsalicylic acid use is necessary, the duration of treatment should be as short as possible, and the dose should be as low as possible. The effect on fertility is reversible.

Ability to influence reaction speed when driving or operating machinery.

The medicinal product Cardisev® has no effect or negligible effect on reaction speed when driving or operating machinery.

Method of Administration and Dosage

The drug is intended for oral administration.

The recommended dose for adults is 150 mg (1 tablet) per day.

Tablets should be swallowed whole, with water if necessary. For faster absorption, the tablet may be chewed or dissolved in water.

Hepatic impairment. Cardiseiv® is contraindicated in patients with severe hepatic dysfunction. Dose adjustment may be required in patients with impaired liver function.

Renal impairment. Cardiseiv® should not be used for the treatment of patients with severe renal insufficiency (glomerular filtration rate < 0.2 ml/sec (10 ml/min)). Dose adjustment may be necessary in patients with impaired renal function.

Children.

According to indications (see section "Method of Administration and Dosage"), Cardiseiv® should not be administered to children.

The use of acetylsalicylic acid in children under 15 years of age may cause serious adverse effects (including Reye's syndrome, one of the signs of which is persistent vomiting). For detailed information, see section "Special Warnings and Precautions for Use".

Overdose.

Toxicity.

Poisonous dose. Adults: 300 mg/kg body weight. Children: single dose of 150 mg/kg or more than 100 mg/kg per day for over 2 days.

Chronic salicylate poisoning may be insidious in nature, as its signs and symptoms are nonspecific. Moderate chronic intoxication caused by salicylates, or salicylism, typically occurs only after repeated intake of high doses.

Symptoms of moderate chronic poisoning (resulting from prolonged use of high doses): dizziness, vertigo, deafness, increased sweating, fever, hyperventilation, tinnitus, respiratory alkalosis, metabolic acidosis, lethargy, moderate dehydration, headache, confusion, nausea, and vomiting.

Acute intoxication is indicated by a pronounced disturbance in acid-base balance, which may vary depending on age and severity of intoxication. The most common manifestation in children is metabolic acidosis. The severity of the condition cannot be assessed solely based on plasma salicylate concentration. Absorption of acetylsalicylic acid may be delayed due to delayed gastric emptying, formation of concretions in the stomach, or if the drug is taken in enteric-coated tablet form.

Symptoms of severe and acute poisoning (due to overdose): hypoglycemia (predominantly in children), encephalopathy, coma, hypotension, pulmonary edema, seizures, coagulopathy, cerebral edema, cardiac arrhythmias.

Acute salicylate poisoning (> 300 mg/kg) often causes acute renal failure, and a dose of 500 mg/kg may be lethal.

More pronounced toxic effects are observed in patients with chronic overdose or drug abuse, as well as in elderly patients or children.

Treatment. In case of acute overdose, gastric lavage and administration of activated charcoal are required. If a dose greater than 120 mg/kg body weight is suspected, activated charcoal should be administered repeatedly.

Serum salicylate levels should be measured at least every 2 hours after ingestion until salicylate levels are consistently decreasing and acid-base balance is restored.

Prothrombin time and/or INR (International Normalized Ratio) should be checked, especially if bleeding is suspected.

Fluid and electrolyte balance must be restored. Effective methods for removing salicylate from plasma include alkaline diuresis and hemodialysis. Hemodialysis should be used in cases of severe intoxication, as this method significantly accelerates salicylate elimination and restores acid-base and water-electrolyte balance.

Due to the complex pathophysiological effects of salicylate poisoning, clinical manifestations and symptoms/test results may include:

Manifestations and symptoms	Test results	Therapeutic measures
Mild or moderate intoxication		Gastric lavage, repeated administration of activated charcoal, forced alkaline diuresis
Tachypnea, hyperventilation, respiratory alkalosis	Alkalemia, alkaluria	Restoration of electrolyte and acid-base balance
Diaphoresis (excessive sweating)
Nausea, vomiting
Moderate or severe intoxication		Gastric lavage, repeated administration of activated charcoal, forced alkaline diuresis, hemodialysis in severe cases
Respiratory alkalosis with compensatory metabolic acidosis	Acidemia, aciduria	Restoration of electrolyte and acid-base balance
Hyperpyrexia		Restoration of electrolyte and acid-base balance
Respiratory: hyperventilation, noncardiogenic pulmonary edema, respiratory failure, asphyxia
Cardiovascular: arrhythmias, arterial hypotension, cardiovascular collapse	For example, changes in blood pressure, ECG
Fluid and electrolyte loss: dehydration, oliguria, renal failure	For example, hypokalemia, hypernatremia, hyponatremia, changes in renal function	Restoration of electrolyte and acid-base balance
Glucose metabolism disturbances, ketoacidosis	Hypoglycemia, hyperglycemia (especially in children), elevated ketone levels
Tinnitus, hearing loss
Gastrointestinal: gastrointestinal bleeding
Hematological: platelet inhibition, coagulopathy	For example, prolonged PT, hypoprothrombinemia
Neurological: toxic encephalopathy and CNS depression with manifestations such as lethargy, confusion, coma, and seizures

Adverse Reactions.

The most commonly observed adverse events are gastrointestinal disorders. Adverse events are usually dose- and duration-dependent.

The information provided on adverse reactions is based on spontaneous post-marketing reports of adverse reactions observed during the use of all dosage forms and strengths of acetylsalicylic acid (including short- and long-term oral administration).

Adverse events are classified by frequency of occurrence as follows: very common (> 1/10), common (> 1/100 and < 1/10), uncommon (> 1/1,000 and < 1/100), rare (> 1/10,000 and < 1/1,000), very rare (< 1/10,000).

Investigations.

Very common: prolonged bleeding time.

Rare: increased levels of transaminases and alkaline phosphatase.

Blood and lymphatic system disorders.

Very common: inhibition of platelet aggregation.

Common: prolonged bleeding time.

Uncommon: occult bleeding.

Rare: anemia with long-term treatment, hemolysis in patients with congenital glucose-6-phosphate dehydrogenase deficiency.

Very rare: hypoprothrombinemia (with high doses), thrombocytopenia, neutropenia, eosinophilia, agranulocytosis, aplastic anemia.

Nervous system disorders.

Common: headache.

Uncommon: dizziness, drowsiness.

Rare: intracranial hemorrhage.

Ear and labyrinth disorders.

Uncommon: tinnitus.

Rare: dose-related reversible hearing loss and deafness (occurring at lower plasma salicylate concentrations).

Respiratory system disorders.

Common: bronchospasm in patients with asthma (see section "Special precautions for use").

Uncommon: dyspnea, allergic reactions (rhinitis, nasal congestion).

Gastrointestinal disorders.

Very common: heartburn, acid reflux, epigastric pain, abdominal pain.

Common: erosive-inflammatory lesions of the upper gastrointestinal tract, nausea, dyspepsia, vomiting, diarrhea.

Uncommon: peptic ulcer and upper gastrointestinal tract bleeding, hematemesis, melena.

Due to its antiplatelet effect, acetylsalicylic acid may be associated with an increased risk of bleeding and prolonged bleeding time. Such bleeding events include perioperative hemorrhages, hematomas, bleeding from the genitourinary organs, epistaxis, and gingival bleeding.

Rare: severe upper gastrointestinal tract bleeding such as gastrointestinal hemorrhage, cerebral hemorrhage (especially in patients with uncontrolled hypertension and/or concomitant use of antihemostatic agents), which in isolated cases may be potentially life-threatening, perforation.

Very rare: stomatitis, esophagitis, toxic lesions of the lower gastrointestinal tract with ulceration, strictures, colitis, or exacerbation of inflammatory bowel disease.

Renal and urinary disorders.

Rare: renal function impairment. Development of acute renal failure.

Skin and subcutaneous tissue disorders.

Uncommon: allergic reactions (urticaria, edema, pruritus, angioedema²).

Very rare: hemorrhagic rash, erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis (Lyell's syndrome).

Endocrine disorders.

Rare: hypoglycemia.

Vascular disorders.

Rare: hemorrhagic vasculitis.

Immune system disorders.

Uncommon: anaphylactic reactions.

Hepatobiliary disorders.

Very rare: dose-related mild reversible toxic hepatitis in certain viral infections (influenza A, B, and varicella). Salicylates may be a contributing factor in the development of Reye's syndrome in children (see section "Special precautions for use"). Cases of transient hepatic dysfunction with elevated serum transaminase and alkaline phosphatase levels have been reported.

Psychiatric disorders.

Common: insomnia.

1 Gastrointestinal hemorrhage 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, hypoperfusion.

2 Angioedema occurs more frequently in patients predisposed to allergies.

Shelf life. 2 years.

Do not use the medicinal product after the expiry date stated on the packaging.

Storage conditions.

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

Keep out of reach and sight of children.

Packaging.

10 tablets in a blister pack. 3 or 5 blister packs in a carton.

Prescription status. Over-the-counter – 30 tablets. Prescription only – 50 tablets.

Manufacturer.

JSC "Farmak".

Manufacturer's address and place of business.

74, Kyrylivska Street, Kyiv, 04080, Ukraine.