Aspirin cardio®: detailed information

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT ASPIRIN CARDIO® (ASPIRIN CARDIO®)

Composition:

Active substance: acetylsalicylic acid;

1 tablet contains 100 mg of acetylsalicylic acid;

Excipients: microcrystalline cellulose, maize starch, methyl acrylate copolymer (type A), sodium lauryl sulfate, polysorbates, talc, triethyl citrate.

Pharmaceutical form. Enteric-coated tablets.

Main physical and chemical properties: white tablets coated with enteric coating.

Pharmacotherapeutic group. Antithrombotic agents.

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. Even small doses of acetylsalicylic acid (ASA) are absorbed, resulting in irreversible inhibition of all circulating platelets along the pathway from the gastrointestinal tract to the liver within the prehepatic mesenteric blood vessels. Meanwhile, posthepatic circulating concentrations of ASA only slightly inhibit endothelial cyclooxygenase (responsible for prostacyclin synthesis), since this enzyme 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 using 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 major gastrointestinal bleeding compared to control was 0.8% vs. 0.48%, and the risk of intracranial hemorrhage 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 interventions (diet, diabetes management, lipid correction, smoking cessation). Risk can be assessed using risk scores 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 versus 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 risk of extracranial bleeding in all high-risk patient categories.

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 protective effect on the gastric mucosa, this dosage form is preferable compared to conventional ASA formulations, especially during long-term therapy. Compared to Aspirin, peak plasma concentrations of salicylates are achieved 2–7 hours later.

Distribution. Salicylic acid is protein-bound in plasma to an extent of 60–90%.

The bioavailability of salicylates ranges from 80 to 100%.

Metabolism. The elimination half-life of systemically available ASA is approximately 15 minutes. Salicylic acid, formed during 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 via conjugation with glycine and further through conjugation with glucuronic acid or sulfuric acid. A small portion is oxidized to gentisic acid and converted into gentisic urinary acid.

Excretion. Excretion occurs almost entirely via the kidneys, primarily as 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 patient groups.

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

Excretion in patients with renal impairment. Renal impairment does not affect the rate of salicylic acid degradation; however, concentrations of inactive metabolites of salicylic acid, primarily conjugated salicyluric acid, are increased.

Salicylates cross the placenta, but are found in breast milk only in small amounts.

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 extensively 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 the child's learning ability after prenatal exposure to salicylates have been reported.

Clinical characteristics.

Indications.

Prevention of thrombosis (prevention of reocclusion) after aortocoronary bypass grafting, percutaneous transluminal coronary angioplasty, and 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 (based on benefit-risk assessment by the treating physician).
Unstable angina.
Prevention of arterial thrombosis following vascular surgery.
As part of standard therapy for acute myocardial infarction.
Prevention of vascular occlusion in arterial occlusive disease.

Contraindications.

Hypersensitivity to salicylates and/or other anti-inflammatory agents or to any component of the drug.
Bronchospasm, urticaria, or allergic symptoms in history after intake of acetylsalicylic acid or other nonsteroidal anti-inflammatory drugs (NSAIDs).
Hemorrhagic diathesis.
Active gastric and/or duodenal ulcer or gastrointestinal bleeding. Inflammatory gastrointestinal disorders (such as Crohn’s disease, ulcerative colitis).
Severe hepatic insufficiency (liver cirrhosis and ascites).
Severe renal insufficiency (creatinine clearance < 30 mL/min).
Severe heart failure (functional class III–IV according to the New York Heart Association classification of chronic heart failure).
Combination with methotrexate at doses of 15 mg/week or higher (see section «Interaction with other medicinal products and other types of interactions»).
Third trimester of pregnancy (see section «Use in pregnancy or lactation»).
Treatment of postoperative pain after coronary bypass surgery (using cardiopulmonary bypass machine).

Interaction with other medicinal products and other types of interactions.

Contraindicated combinations

When used concomitantly with methotrexate at doses of 15 mg/week or higher, hematological toxicity of methotrexate increases (due to decreased renal clearance of methotrexate caused 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: increased methotrexate toxicity (due to decreased renal clearance of methotrexate caused 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.
Elevated 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 levels of valproate increase, leading to a higher frequency of adverse reactions including signs of intoxication such as tremor, nystagmus, ataxia, and personality changes.
Enhanced effects and adverse reactions of all nonsteroidal anti-rheumatic agents.
Concomitant use with NSAIDs such as ibuprofen or naproxen on the same day may attenuate the irreversible inhibition of platelets 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 for use»).
Metamizole may reduce the effect of acetylsalicylic acid on platelet aggregation when taken simultaneously. Therefore, metamizole should be used with caution in patients taking low-dose acetylsalicylic acid for cardioprotection.
Antihypertensive agents (ACE inhibitors and β-blockers): patients receiving Aspirin Cardio® concomitantly with these medicinal products should be closely monitored for blood pressure, and dosage adjustments should be made as necessary.
Diuretics in combination with high doses of acetylsalicylic acid: reduced diuretic efficacy.
Reduced efficacy of uricosuric agents (e.g., probenecid, sulfinpyrazone).
Systemic glucocorticoids: increased risk of gastrointestinal ulcers and bleeding. Decreased blood levels of salicylates during corticosteroid therapy; risk of salicylate overdose after discontinuation of glucocorticoid therapy.
Alcohol: increased risk of gastrointestinal ulcers and bleeding, prolonged bleeding time.
Prolonged plasma elimination half-life of penicillin.

Special precautions for use.

Aspirin Cardio® should be used with caution in the following situations:

Renal function impairment or cardiovascular circulatory disorders (e.g., renal vascular disease, congestive heart failure, hypovolemia, major surgery, sepsis, or severe bleeding), as acetylsalicylic acid may increase the risk of renal function impairment and acute renal failure;
Hepatic function impairment;
Concomitant use of NSAIDs such as ibuprofen or naproxen, since NSAIDs may reduce the inhibitory effect of acetylsalicylic acid on platelet aggregation. If Aspirin Cardio® is used before initiating NSAIDs as analgesics, the patient should consult a physician (see section "Interaction with other medicinal products and other forms of interaction");
Symptoms of chronic gastric or duodenal dyspepsia or its recurrence;
Bronchial asthma or general tendency to hypersensitivity, as acetylsalicylic acid may induce bronchospasm, asthma attacks, or other hypersensitivity reactions. Risk factors include 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;
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 infectious conditions;
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 existing bleeding during surgical procedures (including minor surgeries, such as tooth extraction);
Gastrointestinal ulcers, including chronic and recurrent ulcer disease or gastrointestinal bleeding in medical history;
Hypersensitivity to analgesics, anti-inflammatory, or antirheumatic agents, as well as allergy to other substances.

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 physician's prescription as second-line therapy (due to the risk of Reye's syndrome, a life-threatening encephalopathy characterized by severe vomiting, loss of consciousness, and hepatic dysfunction).

In certain viral infections, particularly influenza A, influenza B, and varicella, there is a risk of 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. If these conditions are accompanied by persistent vomiting, this may be a manifestation of Reye's syndrome.

Gastrointestinal ulcers, bleeding, or perforation may occur at any time during treatment with COX-2-selective or non-selective nonsteroidal anti-inflammatory drugs (NSAIDs), including without warning symptoms or history of prior events. To reduce this risk, the lowest effective dose should be used for the shortest possible duration.

Placebo-controlled studies in some selective COX-2 inhibitors have shown an increased risk of thrombotic cardiovascular and cerebrovascular complications. It is currently unknown whether this risk is directly correlated with the COX-1/COX-2 selectivity of the respective NSAID. Since comparable clinical trial data for acetylsalicylic acid at maximum doses and as long-term therapy are currently lacking, such an increased risk cannot be excluded. Until relevant data are available, acetylsalicylic acid should only be used after careful benefit-risk assessment in patients with clinically confirmed ischemic heart disease, cerebrovascular disease, peripheral arterial occlusive disease, or significant risk factors (such as arterial hypertension, hyperlipidemia, diabetes mellitus, smoking). In such cases, the lowest effective dose should also be used for the shortest possible duration.

The effect of NSAIDs on the kidneys may manifest as fluid retention with edema and/or hypertension. Acetylsalicylic acid should be used with caution in patients with cardiac dysfunction and other conditions predisposing to fluid retention.

Caution is also required in patients receiving diuretics or ACE inhibitors, and in those at increased risk of hypovolemia.

This medicinal product contains less than 1 mmol of sodium (23 mg) per tablet, i.e., essentially "sodium-free".

Use during pregnancy or breastfeeding.

Pregnancy. Inhibition of prostaglandin synthesis may adversely affect pregnancy and/or embryonic/fetal development. Epidemiological data indicate an increased risk of miscarriage and congenital heart defects and gastroschisis following the use of prostaglandin synthesis inhibitors in early pregnancy. The risk increases with increasing dose and duration of therapy.

Available epidemiological data do not confirm an association between the use of acetylsalicylic acid and an increased risk of miscarriage. Epidemiological data on miscarriage are inconsistent, but an increased risk of gastroschisis cannot be excluded with the use of acetylsalicylic acid. Results from a prospective study on the effect of the drug in early pregnancy (1st–4th 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

During the first and second trimesters of pregnancy, products containing acetylsalicylic acid should not be prescribed without clear clinical necessity. For women who may possibly be pregnant and for those in the first and second trimesters, the dose of acetylsalicylic acid-containing products 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 embryonic/fetal death. Furthermore, an increased frequency of severe developmental abnormalities, including cardiovascular malformations, 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. Prenatal monitoring for possible arterial duct constriction should be considered after acetylsalicylic acid use starting from week 20 of pregnancy. If arterial duct constriction occurs, acetylsalicylic acid therapy should be discontinued.

During the third trimester of pregnancy

All prostaglandin synthesis inhibitors may:

Affect the fetus by:
- Cardio-pulmonary toxicity (with premature closure of the arterial duct and pulmonary hypertension);
- Renal dysfunction with potential subsequent development of renal failure and oligohydramnios;
Affect both the mother and the fetus by:
- Prolonged bleeding time, anti-aggregatory effect, which may occur even with very low doses;
- Inhibition of uterine contractions and bleeding in the pregnant woman, leading to prolonged labor.

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

Fertility. The use of acetylsalicylic acid may impair female fertility; therefore, its use is not recommended in women attempting to conceive. For women trying to become pregnant or undergoing infertility evaluation, discontinuation of acetylsalicylic acid should be considered.

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

During forced use on medical grounds during lactation, breastfeeding should be discontinued in case of regular high-dose use (> 300 mg/day).

Ability to affect reaction speed when driving or operating machinery.

Aspirin Cardio® does not affect the ability to drive or operate machinery.

Method of Administration and Dosage

If the physician has not prescribed otherwise, the following dosages are recommended.

Cardiovascular indications without aortocoronary bypass grafting and percutaneous transluminal coronary angioplasty: 1 × 100 mg/day.

Prophylaxis of thrombosis after aortocoronary bypass grafting and percutaneous transluminal coronary angioplasty: 100–300 mg/day.

Prophylaxis of cerebrovascular stroke following 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 a meal. Drink ½–1 glass of water. To prevent premature release of the active ingredient before reaching the alkaline environment of the intestine, the tablets must not be crushed, broken, or chewed.

Acute myocardial infarction: In cases of acute myocardial infarction, administer 200–300 mg of acetylsalicylic acid either intravenously or orally in a rapidly dissolving form (not enteric-coated). Enteric-coated acetylsalicylic acid tablets should be crushed or chewed before administration to achieve faster absorption. Thereafter, 100 mg of Aspirin Cardio® should be administered daily.

Children.

Aspirin Cardio® must not be used in children and adolescents (under 18 years of age) due to lack of data on efficacy and safety in this patient group.

Administration of acetylsalicylic acid to children under 16 years of age may cause serious 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 Warnings and Precautions for Use”.

Overdose.

Severe intoxication may be life-threatening. Neonates are more sensitive than adults. Symptoms of severe poisoning may develop acutely or gradually, for example, within 12–24 hours after administration. After oral administration of doses up to 150 mg/kg body weight, moderate intoxication may occur; doses exceeding 300 mg/kg body weight may lead to 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 administered in enteric-coated tablet form.

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

Warning.

Local signs of irritation, which typically predominate in cases of ASA overdose—such as nausea, vomiting, and stomach pain—may be absent, as 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 remain unnoticed.

Therapy.

Due to potentially life-threatening conditions caused by severe intoxication, all necessary preventive measures must be taken immediately: immediate hospitalization, prevention or reduction of absorption by administering appropriate doses of activated charcoal within the first 4 hours (activated charcoal in a 10-fold amount relative to the ingested ASA); in cases of severe intoxication—gastric lavage or endoscopic removal of tablets.

Appropriate monitoring and correction of electrolytes. Administration of glucose and sodium bicarbonate in early stages to correct acidosis and enhance elimination (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 reported. Therefore, if possible, intubation should be performed after initiation of alkalization, apnea time should be minimized, and maintenance of hyperventilation must be closely observed.

Detailed information can be obtained from a toxicology center.

Side effects

Within each group, adverse reactions are listed in order of decreasing severity: very common: ≥ 1/10; common: ≥ 1/100 – < 1/10; uncommon: ≥ 1/1000 – < 1/100; rare: ≥ 1/10,000 – < 1/1000; very rare: < 1/10,000; frequency not known (cannot be estimated from the available data).

Information on other adverse reactions has been reported in spontaneous reports for all dosage forms of acetylsalicylic acid, including oral short-term and long-term therapy; therefore, classification by frequency cannot be established.

Blood and lymphatic system disorders:

Prolongation of bleeding time;

Rare: thrombocytopenia, agranulocytosis, pancytopenia, leukopenia, aplastic anemia, iron-deficiency anemia.

Frequency not known: hemolysis and hemolytic anemia have been observed in patients with severe forms of glucose-6-phosphate dehydrogenase deficiency.

Due to its 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 may potentially be life-threatening.

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 (Lyell’s syndrome).

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.

Formation of intestinal diaphragm-like structures, particularly with prolonged use.

Hepatobiliary disorders:

Rare: hepatic dysfunction;

Very rare: increased transaminase levels.

Renal and urinary disorders:

Rare: impaired renal function;

Frequency not known: acute renal failure.

Other:

Very rare: Reye’s syndrome (see section "Special precautions for use").

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after a medicinal product has been authorized is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals and patients, as well as their legal representatives, are encouraged to report any suspected adverse reactions and lack of efficacy via the automated pharmacovigilance information system at the following link: https://aisf.dec.gov.ua.

Shelf life. 5 years.

Storage conditions.

Store in a place inaccessible to children at a temperature not exceeding 25 °C.

Packaging.

14 tablets in a blister pack; 2, 4, or 7 blisters per cardboard box.

Prescription status.

Over-the-counter (without prescription).

Manufacturer.

Primary, secondary packaging and batch release:

Bayer Bitterfeld GmbH, Germany

Manufacturer's address.

Ortsteil Greppin, Salegaster Chaussee 1, 06803 Bitterfeld-Wolfen, Germany