Cardio-dar

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT Cardio-Dar® (Cardio-Dar)

Composition:

Active substance: acetylsalicylic acid;

One tablet contains 75 mg or 150 mg of acetylsalicylic acid;

Excipients: microcrystalline cellulose, magnesium hydroxide, pregelatinized starch, anhydrous citric acid, magnesium stearate, Opadry II 85F White.

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: 75 mg and 150 mg tablets – round, biconvex tablets, film-coated, white or almost white.

Pharmacotherapeutic group. Antithrombotic agents. Platelet aggregation inhibitors, excluding heparin. Acetylsalicylic acid. ATC code B01AC06.

Pharmacological Properties

Pharmacodynamics

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

The main pharmacological effect is inhibition of the formation of prostaglandins and thromboxanes. The analgesic effect is a secondary 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 the appearance of new platelets in blood plasma.

Salicylic acid (the active metabolite of acetylsalicylic acid) exerts anti-inflammatory effects and also influences respiratory processes, acid-base balance, and gastric mucosa. Salicylates stimulate respiration, primarily through a direct action on the bone marrow. Salicylates indirectly affect the 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. Following oral administration, absorption of the non-ionized form of acetylsalicylic acid occurs in the stomach and intestine. The rate of absorption is reduced after food intake and in patients experiencing migraine attacks, and increased in patients with achlorhydria or in those taking polysorbates or antacids. Maximum serum concentration is reached within 1–2 hours.

Distribution. Protein binding of acetylsalicylic acid to plasma proteins is 80–90%. The volume of distribution in adults is 170 mL/kg body weight. As plasma concentration increases, binding sites on plasma proteins 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 may cross the placental barrier.

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

Elimination. Salicylic acid is metabolized primarily in the liver. Thus, the steady-state concentration of salicylic acid in plasma increases disproportionately to the orally administered dose. When 325 mg of acetylsalicylic acid is administered, 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 urinary 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.

Prevention of recurrent thrombosis.

Primary prevention of thrombotic events and cardiovascular diseases, such as acute coronary syndrome, in patients aged 50 years and older who have risk factors for cardiovascular disease: arterial hypertension, hypercholesterolemia, diabetes mellitus, obesity (body mass index > 30), family history (myocardial infarction before age 55 in at least one parent or sibling).

Contraindications.

The medicinal product is contraindicated in the following conditions/diseases:

• Known or suspected hypersensitivity to acetylsalicylic acid, other salicylates, nonsteroidal anti-inflammatory drugs (NSAIDs), or to any component of the medicinal product;
• Tendency to bleeding (vitamin K deficiency, thrombocytopenia, hemophilia);
• Active peptic ulcers;
• Severe renal failure [glomerular filtration rate < 0.2 mL/sec (10 mL/min)];
• Severe hepatic insufficiency;
• Severe heart failure;
• Third trimester of pregnancy (see section "Use in pregnancy or lactation").

Interaction with other medicinal products and other forms of interaction.

Contraindications for concomitant use

Metotrexate. Concomitant use of acetylsalicylic acid and methotrexate at doses of 15 mg per 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).

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

Acetazolamide. Possible increased concentration of acetazolamide may lead to transfer of salicylates from plasma into tissues and result in acetazolamide toxicity (fatigue, lethargy, drowsiness, confusion, hyperchloremic metabolic acidosis) and salicylate toxicity (vomiting, tachycardia, hyperpnea, confusion).

Probenecid, sulfinpyrazone. When probenecid is used with high doses of salicylates (> 500 mg), metabolism of both medicinal products is inhibited and excretion of uric acid may be reduced.

Combinations requiring caution

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

Anticoagulants (warfarin, phenprocoumon). Possible reduction in thrombin production, resulting in indirect suppression of 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 indirect suppression of platelet activity, thereby increasing the risk of bleeding.

If two or more of the above-mentioned substances are used concomitantly with acetylsalicylic acid, this may result in a synergistic effect enhancing platelet inhibition and, consequently, increased 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 use 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, resulting in prolonged bleeding time.

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

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 it from plasma protein binding, increasing its toxicity (central nervous system (CNS) depression, gastrointestinal (GI) disturbances).

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

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

Antacids. Possible increased renal clearance and reduced renal reabsorption (due to increased urine pH), leading to reduced effect 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. Alcohol consumption causes gastrointestinal mucosal damage 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 acetylsalicylic acid for cardioprotection.

Special precautions for use.

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

Prolonged use of the medicinal 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 cautiously for the treatment of acute or chronic ischemic heart disease, stroke, or for stroke or ischemic heart disease prophylaxis.

The medicinal product 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 types of interactions");
• Hypersensitivity to analgesics, anti-inflammatory, or antirheumatic agents, as well as allergy to other substances;
• Gastrointestinal ulcers, including chronic or recurrent peptic ulcer disease or history of gastrointestinal bleeding;
• Concomitant use of anticoagulants;
• Impaired renal function or cardiovascular circulation disorders (e.g., renal vascular disease, congestive heart failure, hypovolemia, major surgery, sepsis, or severe bleeding), since acetylsalicylic acid may increase the risk of renal function impairment and acute renal failure;
• Severe glucose-6-phosphate dehydrogenase deficiency, as acetylsalicylic acid may cause hemolysis or hemolytic anemia;
• Presence of factors that may increase the risk of hemolysis (high doses of the medicinal product, fever, or acute infectious conditions);
• Impaired liver function.

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

Acetylsalicylic acid may cause bronchospasm, asthma attacks, 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 medicinal products containing acetylsalicylic acid may increase the risk 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 gout attacks in predisposed patients.

Medicinal products containing acetylsalicylic acid should not be used in children and adolescents with acute viral respiratory infections, whether or not accompanied by elevated body temperature, without consulting a physician. In certain viral illnesses, 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 established. Persistent vomiting in such conditions may be a manifestation of Reye's syndrome.

If the risk of increased bleeding outweighs the risk of ischemia, temporary discontinuation of low-dose therapy should be considered a few days before a scheduled surgery.

Fertility. The use of acetylsalicylic acid may reduce fertility; therefore, the medicinal 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 indicate a risk of miscarriage and congenital malformations following the use of prostaglandin synthesis inhibitors early in pregnancy. The risk increases with higher doses and longer duration of therapy. According to available data, a link between acetylsalicylic acid use and an increased risk of miscarriage has not been confirmed.

Epidemiological data on congenital malformations are inconsistent; however, an increased risk of gastroschisis cannot be ruled out with acetylsalicylic acid use. Results from a prospective study on early pregnancy exposure (1–4 months) involving approximately 14,800 mother-child pairs did not indicate any association with an increased risk of malformations.

Animal studies indicate reproductive toxicity.

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

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

• Cardio-respiratory toxicity (premature closure of the ductus arteriosus and pulmonary hypertension);
• Impaired renal function, potentially leading to renal failure with oligohydramnios.

In late pregnancy, prostaglandin synthesis inhibitors may affect the mother and child as follows:

• Possible prolongation of bleeding time, anti-aggregatory effect, which may occur even after very low doses;
• Inhibition of uterine contractions, potentially leading to delayed or prolonged labor.

Due to these risks, 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 on the infant have been observed after the mother's use of the medicinal product during lactation, breastfeeding interruption is generally not required. However, if the medicinal product is used regularly or in high doses, breastfeeding should be discontinued early.

Fertility

Acetylsalicylic acid should not be used in women wishing to become pregnant, 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 as low as possible. The effect on fertility is reversible.

Ability to affect reaction speed when driving or operating machinery.

The medicinal product has no effect or a negligible effect on the ability to drive or operate machinery.

Administration and Dosage

The medicinal product is intended for oral administration.

Acute and chronic ischemic heart disease

Recommended initial dose: 150 mg per day. Maintenance dose: 75 mg per day.

Acute myocardial infarction. Unstable angina

Recommended dose is 150–450 mg, administered as soon as possible after symptom onset.

Prevention of recurrent thrombosis

Recommended initial dose: 150 mg per day. Maintenance dose: 75 mg per day.

Primary prevention of thrombotic events and cardiovascular diseases, such as acute coronary syndrome in patients aged 50 years and older who have risk factors for cardiovascular disease

Recommended prophylactic dose: 75 mg 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. The medicinal product is contraindicated in patients with severe hepatic dysfunction. Dose adjustment may be required in patients with hepatic impairment.

Renal impairment. The medicinal product should not be used for the treatment of patients with severe renal impairment [glomerular filtration rate < 0.2 mL/s (10 mL/min)]. Dose adjustment may be necessary in patients with renal impairment.

Children.

The medicinal product is not recommended for use in children. Administration of acetylsalicylic acid to children under 15 years of age may cause serious adverse reactions (including Reye's syndrome, one of the signs of which is persistent vomiting). For further details, see section «Special precautions for use».

Overdose.

Toxicity

Potentially toxic dose. Adults: 300 mg/kg body weight. Children: single dose of 150 mg/kg or < 100 mg/kg per day for 2 days or more.

Chronic salicylate poisoning may have an insidious onset, as its signs and symptoms are nonspecific. Moderate chronic intoxication (salicylism) caused by salicylates usually occurs only after repeated administration of high doses.

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

Acute intoxication is indicated by marked disturbances in acid-base balance, which may vary depending on age and severity of intoxication. Metabolic acidosis is the most common manifestation in children. Severity of intoxication cannot be assessed solely based on plasma salicylate concentration. Absorption of acetylsalicylic acid may be delayed due to delayed gastric emptying, formation of gastric concretions, or administration of enteric-coated tablets.

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

Acute salicylate poisoning (> 300 mg/kg) often leads to acute renal failure; a dose of 500 mg/kg may be fatal.

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

Treatment

In case of acute overdose, gastric lavage and administration of activated charcoal are required. If ingestion of a dose > 120 mg/kg body weight is suspected, repeated doses of activated charcoal should be administered.

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 (PT) and/or international normalized ratio (INR) should be checked, especially if bleeding is suspected.

Fluid and electrolyte balance must be restored. Effective methods for removing salicylates 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 electrolyte balance.

The complex pathophysiological effects of salicylate poisoning may include the manifestations, symptoms, and laboratory findings listed in the table:

Adverse reactions.

The most common adverse reactions are gastrointestinal disorders.

Adverse reactions are usually dose- and duration-dependent.

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

Adverse reactions are classified by frequency of occurrence into the following categories: very common (> 1/10), common (> 1/100 and < 1/10), uncommon (> 1/1000 and < 1/100), rare (> 1/10000 and < 1/1000), very rare (< 1/10000).

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 (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 (with lower plasma salicylate concentrations).

Respiratory system disorders

Common: bronchospasm in patients with asthma (see section "Special instructions").

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 bleeding, hematemesis, melena.

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

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

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

Renal and urinary disorders

Rare: impaired renal function, development of acute renal failure.

Skin and subcutaneous tissue disorders

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

Very rare: hemorrhagic rashes, 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 factors in the development of Reye's syndrome in children (see section "Special instructions"). Cases of transient hepatic dysfunction with elevated serum transaminase and alkaline phosphatase levels have been reported.

Psychiatric disorders

Common: insomnia.

1 Hemorrhages 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.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after marketing authorization is an important procedure. It allows continuous monitoring of the benefit-risk ratio of the medicinal product. Healthcare professionals are required to report any suspected adverse reactions through the national reporting system.

Shelf life.

3 years – for containers №30, №100

1 year – for blister packs №30.

Storage conditions.

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

Packaging.

30 or 100 tablets in a container with a desiccant, 1 container per carton.

10 tablets in a blister pack, 3 blister packs in a carton.

Prescription status.

Prescription-only – for container №100.

Over-the-counter – for container №30 and blister pack №30.

Manufacturer.

JSC "Pharmaceutical company "Darnytsia".

Manufacturer's address and site of operations.

13, Boryspilska Street, Kyiv, 02093, Ukraine.